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Purpose: Preclinical data indicate that fianlimab (anti-lymphocyte activation gene-3) plus cemiplimab (anti-programmed cell death-1) enhances antitumor activity. Here, we report prespecified final analyses of the dose-escalation part of a first-in-human, phase 1 study (NCT03005782) of fianlimab as monotherapy and in combination with cemiplimab in patients with advanced malignancies., Experimental Design: Adult patients received fianlimab 1-40 mg/kg ± cemiplimab 350 mg every 3 weeks (Q3W) across various dose-escalation schedules. Primary objectives were rate of dose-limiting toxicities, adverse events (including immune-mediated), deaths, laboratory abnormalities, and pharmacokinetics. Secondary outcomes were objective response rate, best overall response, duration of response, and antidrug antibody variables., Results: Seventy-eight patients were enrolled (fianlimab + cemiplimab, n = 47; fianlimab monotherapy, n = 31). One patient treated with 3 mg/kg fianlimab + cemiplimab experienced dose-limiting toxicities, including increased blood creatine phosphokinase and myasthenic syndrome. No maximum tolerated dose was reached. Any-grade treatment-emergent adverse events occurred in 90% of patients with fianlimab monotherapy, 87% with fianlimab + cemiplimab, and 87% who transitioned from monotherapy to combination therapy. Fianlimab pharmacokinetics were dose-proportional, and similar in monotherapy and combination therapy. Across patients who received fianlimab + cemiplimab, five achieved a partial response; three of whom experienced a response after transitioning from monotherapy to combination therapy. Fianlimab 1600 mg Q3W (20 mg/kg in an 80 kg individual) is the selected dose for phase 2 and 3 studies., Conclusions: Fianlimab as monotherapy and in combination with cemiplimab demonstrated acceptable safety and preliminary antitumor activity, which is generally consistent with previous reports of cemiplimab.

Background: Lung cancer remains a critical public health issue, presenting multifaceted challenges in prevention, diagnosis, and treatment. This article aims to review the current landscape of lung cancer research and management, delineate the persistent challenges, and outline pragmatic solutions., Materials and Methods: Global experts from academia, regulatory agencies such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), the National Cancer Institute (NCI), professional societies, the pharmaceutical and biotech industries, and patient advocacy groups were gathered by the New York Lung Cancer Foundation to review the state of the art in lung cancer and to formulate calls to action., Results: Improving lung cancer management and research involves promoting tobacco cessation, identifying individuals at risk who could benefit from early detection programs, and addressing treatment-related toxicities. Efforts should focus on conducting well-designed trials to determine the optimal treatment sequence. Research into innovative biomarkers and therapies is crucial for more personalized treatment. Ensuring access to appropriate care for all patients, whether enrolled in clinical trials or not, must remain a priority., Conclusions: Lung cancer is a major health burden worldwide, and its treatment has become increasingly complex over the past two decades. Improvement in lung cancer management and research requires unified messaging and global collaboration, expanded education, and greater access to screening, biomarker testing, treatment, as well as increased representativeness, participation, and diversity in clinical trials., (Copyright © 2024 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: In the phase 2 EMPOWER-CSCC-1 study (NCT02760498), cemiplimab demonstrated antitumor activity against metastatic (mCSCC) and locally advanced cutaneous squamous cell carcinoma (laCSCC)., Objectives: To report final analysis of weight-based cemiplimab in mCSCC and laCSCC (Groups 1 and 2), fixed-dose cemiplimab in mCSCC (Group 3), and primary analysis of fixed-dose cemiplimab in mCSCC/laCSCC (Group 6)., Methods: Patients received cemiplimab (3 mg/kg intravenously [IV] every 2 weeks [Groups 1 and 2]) or cemiplimab (350 mg IV [Groups 3 and 6]) every 3 weeks. The primary endpoint was objective response rate (ORR). Duration of response (DOR) and progression-free survival (PFS) are presented per protocol, according to post-hoc sensitivity analyses that only include the period of protocol-mandated imaging assessments., Results: At 42.5 months, ORR for Groups 1-3 (n=193) was 47.2%, estimated 12-month DOR was 88.3%, and median PFS was 26.0 months. At 8.7 months, ORR for Group 6 (n=165 patients) was 44.8%; median DOR and median PFS were not reached. Serious treatment-emergent adverse event rates (grade ≥3) were Groups 1-3: 31.1% and Group 6: 34.5%., Limitations: Non-randomized study, non-survival primary endpoint., Conclusion: EMPOWER-CSCC-1 provides the largest prospective data on long-term efficacy and safety for anti-programmed cell death-1 therapy in advanced CSCC., (Copyright © 2024. Published by Elsevier Inc.)

Background: In the phase 3 EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 study, cemiplimab significantly improved overall survival (OS) versus chemotherapy for patients with recurrent or metastatic cervical cancer who progressed after first-line platinum-based chemotherapy. We present a post hoc subgroup analysis of patients enrolled in Japan., Methods: Patients were enrolled regardless of programmed cell death-ligand 1 status and randomized 1:1 to cemiplimab 350 mg intravenously every 3 weeks or investigator's choice  single-agent chemotherapy for up to 96 weeks. Primary endpoint was OS. Key secondary endpoints were progression-free survival (PFS) and objective response rate (ORR)., Results: Overall, 608 patients were randomized, of whom 56 (9.2%) were in Japan (cemiplimab, n = 29; chemotherapy, n = 27). The median (range) duration of follow-up was 13.6 (6.0-25.3) versus 18.2 (6.0-38.2) months for patients in Japan and for the overall population, respectively. Median OS (95% confidence interval [CI]) was 8.4 (7.0-not evaluable) and 9.4 (5.4-14.9) months for cemiplimab versus chemotherapy (hazard ratio [HR]: 0.86; 95% CI: 0.43-1.68). Median PFS (95% CI) was 4.0 (1.4-8.2) versus 3.7 (1.8-4.2) months with cemiplimab and chemotherapy (HR: 0.90; 95% CI: 0.50-1.61), respectively. ORR was 17.2% for cemiplimab and 7.4% for chemotherapy (odds ratio, 2.47; 95% CI, 0.44-13.99). Incidence of treatment-emergent adverse events at any grade was 79.3% for cemiplimab and 100% for chemotherapy. Grade ≥3 adverse events were 37.9% versus 66.7% with cemiplimab and chemotherapy, respectively., Discussion: While acknowledging limitations inherent to a small subgroup analysis, the HR of 0.86 observed in Japanese patients suggests an emerging survival benefit despite a 4.6-month shorter median duration of follow-up versus the overall study population., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Coblockade of lymphocyte activation gene-3 (LAG-3) and PD-1 receptors could provide significant clinical benefit for patients with advanced melanoma. Fianlimab and cemiplimab are high-affinity, human, hinge-stabilized IgG4 monoclonal antibodies, targeting LAG-3 and PD-1, respectively. We report results from a first-in-human phase-I study of fianlimab and cemiplimab safety and efficacy in various malignancies including advanced melanoma., Methods: Patients with advanced melanoma were eligible for enrollment into four cohorts: three for patients without and one for patients with previous anti-PD-1 therapy in the advanced disease setting. Patients were treated with fianlimab 1,600 mg and cemiplimab 350 mg intravenously once every 3 weeks for up to 51 weeks, with an optional additional 51 weeks if clinically indicated. The primary end point was objective response rate (ORR) per RECIST 1.1 criteria., Results: ORRs were 63% for patients with anti-PD-1-naïve melanoma (cohort-6; n = 40; median follow-up 20.8 months), 63% for patients with systemic treatment-naïve melanoma (cohort-15; n = 40; 11.5 months), and 56% for patients with previous neo/adjuvant treatment melanoma (cohort-16; n = 18, 9.7 months). At a median follow-up of 12.6 months for the combined cohorts (6 + 15 + 16), the ORR was 61.2% and the median progression-free survival (mPFS) 13.3 months (95% CI, 7.5 to not estimated [NE]). In patients (n = 13) with previous anti-PD-1 adjuvant therapy, ORR was 61.5% and mPFS 12 months (95% CI, 1.4 to NE). ORR in patients with previous anti-PD-1 therapy for advanced disease (n = 15) was 13.3% and mPFS 1.5 months (95% CI, 1.3 to 7.7). Treatment-emergent and treatment-related adverse events ≥grade 3 (G3) were observed in 44% and 22% of patients, respectively. Except for increased incidence of adrenal insufficiency (12%-G1-4, 4%-G3-4), no new safety signals were recorded., Conclusion: The current results show a promising benefit-risk profile of fianlimab/cemiplimab combination for patients with advanced melanoma, including those with previous anti-PD-1 therapy in the adjuvant, but not advanced, setting.

Background: Cemiplimab (Libtayo ® ), a human monoclonal immunoglobulin G4 antibody to the programmed cell death-1 receptor, is approved for the treatment of patients with advanced cutaneous squamous cell carcinoma (CSCC), who are not candidates for curative surgery or curative radiation, using an every-3-weeks (Q3W) dosing interval. Pharmacokinetic modeling indicated that C trough of extended intravenous dosing of 600 mg every 4 weeks (Q4W) would be comparable to the approved intravenous dosage of 350 mg Q3W. We examined the efficacy, pharmacokinetics, and safety of cemiplimab dosed Q4W., Methods: In this open-label, phase II trial (ClinicalTrials.gov identifier NCT02760498), the cohort of patients ≥18 years old with advanced CSCC received cemiplimab 600 mg intravenously Q4W for up to 48 weeks. Tumor measurements were recorded every 8 weeks. The primary endpoint was objective response rate by independent central review., Results: Sixty-three patients with advanced CSCC were treated with cemiplimab. The median duration of follow-up was 22.4 months (range: 1.0-39.8). An objective response was observed in 39 patients (62%; 95% CI: 48.8% to 73.9%), with 22% of patients (n = 14) achieving complete response and 40% (n = 25) achieving partial response. The most common treatment-emergent adverse events were diarrhea, pruritus, and fatigue., Conclusions: Extended dosing of cemiplimab 600 mg intravenously Q4W exhibited substantial antitumor activity, rapid and durable responses, and an acceptable safety profile in patients with advanced CSCC. These results confirm that cemiplimab is a highly active therapy for advanced CSCC. Additional data would help ascertain the benefit-risk profile for the 600 mg intravenous dosing regimen compared with the approved regimen., Competing Interests: Competing interests: DR reports institutional research grants and funding from Bristol-Myers Squibb, GlaxoSmithKline, Kura Oncology, Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc, ALX Oncology, Decibel Therapeutics and Roche; and uncompensated scientific committee and advisory board membership from GlaxoSmithKline, Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc and Sanofi. BGMH reports consulting or advisory roles at AstraZeneca, Bristol-Myers Squibb, Eisai, Merck Sharp & Dohme, Pfizer and Roche; and institutional research funding from Amgen. NB-S declares no conflict of interest. DS reports institutional patients’ fees from Regeneron Pharmaceuticals, Inc; advisory board, speaker honoraria and patients’ fees from Bristol-Myers Squibb, EMD Serono, Merck Sharp & Dohme, Novarti and Pierre Fabre; steering committee honoraria from 4SC, Bristol-Myers Squibb, InflaRx, Merck Sharp & Dohme, Nektar and Novartis; advisory board fees from Daiichi Sanyo, OncoSec Medical, Pfizer and Replimune; advisory board and patients’ fees from Philogen and Sun Pharma; and research funding to their institution from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme and Novartis. SB reports an advisory board role or speaker bureau for Sanofi, Ipsen, Lilly, Bristol-Myers Squibb and Merck Sharp & Dohme Australia; and virtual meeting sponsorship from Bristol-Myers Squibb and Merck Sharp & Dohme Australia. ST reports speaker honoraria and advisory board fees from AbbVie, Bristol-Myers Squibb, Novartis, Pierre Fabre and Sun Pharma. FM reports travel support, speaker’s fees or advisor’s honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche and Sanofi; and research funding from Novartis and Roche. TE reports consulting or advisory roles at Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche and Sanofi Genzyme; speaker’s bureau roles at Merck Sharp & Dohme and Roche; and research funding from Bristol-Myers Squibb and Novartis. VCE reports advisory board honoraria from AstraZeneca, GlaxoSmithKline, Merck Sharp & Dohme and Pharmamar; and speaker honoraria from AstraZeneca and Merck Sharp & Dohme. BS reports advisory board membership for Bristol-Myers Squibb Australia and Merck Sharp & Dohme. MBB reports serving as a speaker without honoraria for Sanofi. SD reports advisory board honoraria and travel expenses from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, PFO Global and Sun Pharma. BD reports consultancy for Sanofi. MRM reports honoraria and travel expenses from Genentech, Eli Lilly, Novartis, Regeneron Pharmaceuticals, Inc, Sanofi and Sun Pharma; and institutional research funding from Genentech, Eli Lilly, Novartis and Regeneron Pharmaceuticals, Inc. AH reports institutional grants, speaker’s honoraria and consultancy fees from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Provectus and Roche; institutional grants and consultancy fees from EMD Serono, Philogen and Regeneron Pharmaceuticals, Inc; and consultancy fees from OncoSec Medical. CDS reports steering committee membership for Castle Biosciences; steering committee membership and consultancy for Regeneron Pharmaceuticals, Inc; consultancy for Sanofi; research funding from Castle Biosciences, Genentech, Merck, Novartis and Regeneron Pharmaceuticals, Inc; and serving as a chair for the National Comprehensive Cancer Network. AML reports uncompensated advisory board participation from Merck Sharp & Dohme and Bristol-Myers Squibb with travel and accommodation expenses; and uncompensated consultancy for Eisai. S-YY, APaccaly, APapachristos, J-HN, EO, FS, JB and IL are employees of and shareholders in Regeneron Pharmaceuticals, Inc. MGF is an employee of, has patents pending with, and is a shareholder of Regeneron Pharmaceuticals, Inc. AG reports personal fees and nonfinancial support (advisory board and travel support) from Bristol-Myers Squibb and Sun Pharma; personal fees (advisory board) from Eisai, Merck KGaA and Pfizer; non-financial support (travel) from Astellas; and clinical trial unit support from PPD Australia., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Conflicts of interest Dr Stratigos reports advisory board or steering committee roles for Janssen, Regeneron Pharmaceuticals, Inc, Roche, and Sanofi; and research support from AbbVie, Bristol Myers Squibb, LEO Pharma, Pfizer, Genesis Pharma, and Novartis. Dr Sekulic reports advisory roles for Regeneron Pharmaceuticals, Inc and Roche. Dr Peris reports advisory board roles for AbbVie, LEO Pharma, Janssen, Almirall, Eli Lilly, Galderma, Novartis, Pierre Fabre, Sun Pharma, and Sanofi, outside the submitted work. Dr Bechter reports advisory board roles for Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, and Ultimovacs. Dr Prey reports no conflict of interest. Dr Lewis reports grants and personal fees from Regeneron Pharmaceuticals, Inc, and is now an employee of Regeneron Pharmaceuticals, Inc. Dr Basset-Seguin is a consultant and investigator for Regeneron Pharmaceuticals, Inc, Sanofi, and Sun Pharma. Dr Chang reports advisory roles for Castle, Feldan, Merck, and Regeneron Pharmaceuticals, Inc; and research funding from Regeneron Pharmaceuticals, Inc, Merck, Novartis, and Galderma. Dr Dalle reports research grants and travel fees from Bristol Myers Squibb and Merck Sharp & Dohme; and reports that their spouse is an employee of Sanofi with stock options. Dr Fernández Orland declares no conflict of interest. Dr Licitra reports institutional grants and personal fees from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Debiopharm International SA, Eisai, Novartis, and Roche; institutional grants from Celgene International, Exelixis, Hoffmann-La Roche, IRX Therapeutics, Medpace, Merck Serono, and Pfizer; and personal fees from Sobi, Ipsen, Incyte Biosciences Italy SRL, Doxa Pharma, Amgen, Nanobiotics SA, GSK, AccMed, Medical Science Foundation G. Lorenzini, Associazione Sinapsi, Think 2 IT, Aiom Servizi, Prime Oncology, WMA Congress Education, Fasi, DueCi Promotion SRL, MI&T, Net Congress & Education, PRMA Consulting, Kura Oncology, Health & Life SRL, and Immuno-Oncology Hub. Dr Robert reports grants, personal fees, and advisory board roles for Bristol Myers Squibb, Pierre Fabre, Novartis, Amgen, Merck, Roche, Merck Sharp & Dohme, Sanofi, Biothera, and Ultimovacs. Dr Ulrich reports advisory board and speaker roles for Roche, Sanofi, Regeneron Pharmaceuticals, and Sun Pharma. Dr Hauschild reports institutional funding and personal fees from Amgen, Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme, Merck & Co, Philogen, Pierre Fabre, Provectus, Regeneron Pharmaceuticals, Inc, Roche, Sanofi Genzyme, and Novartis; and consultancy fees from OncoSec, Almirall Hermal, and Sun Pharma. Dr Migden reports advisory roles for and travel fees from Regeneron Pharmaceuticals, Inc, and Sun Pharmaceuticals; an advisory role for Rakuten Medical; and research funding from Regeneron Pharmaceuticals, Inc, and PellePharm. Dr Dummer reports intermittent, project-focused consultant and advisory roles for Novartis, Merck Sharp & Dohme, Bristol Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron Pharmaceuticals, Inc, Alligator, MaxiVAX SA, and touchIME outside the submitted work. Drs Yoo, Inocencio, Chen, Seebach, Lowy, and Fury are employees and shareholders of Regeneron Pharmaceuticals, Inc. Mr Okoye is also an employee and shareholder of Regeneron Pharmaceuticals, Inc. Dr Bassukas reports non-financial support from Leo Pharma and Novartis, and institutional grants from Leo Pharma. Dr Loquai reports personal fees from Roche, Sun Pharma, Bristol Myers Squibb, Merck Sharp & Dohme, Merck, Novartis, Pierre Fabre, Kyowa Kirin, Almirall Hermal, and BioNTech. Dr De Giorgi reports no conflict of interest. Dr Eroglu reports advisory board fees from Regeneron Pharmaceuticals, Inc, Novartis, Pfizer, Genentech, Eisai, OncoSec, and Natera; and research grants from Novartis, Pfizer, and Boehringer Ingelheim. Dr Gutzmer reports documentation fees to their institution from Regeneron Pharmaceuticals, Inc; personal fees and non-financial support from Amgen, Bristol Myers Squibb, Roche Pharma, Merck Serono, Pierre Fabre, Sanofi, and Regeneron Pharmaceuticals, Inc; grants, personal fees, and non-financial support from Novartis; grants and personal fees from Pfizer; grants from Johnson & Johnson; and personal fees from Merck Sharp & Dohme, Almirall Hermal, Sun Pharma, 4SC, and Immunocore. Dr Ulrich reports grants and personal fees from Sanofi, Bristol Myers Squibb, Novartis, and Merck Sharp & Dohme; and personal fees from Roche, medac, and Sun Pharma. Dr Puig reports personal fees and non-financial support from Sanofi, Regeneron Pharmaceuticals, Inc, and Pfizer; grants from Avene; non-financial support from MAVIG, FotoFinder, 3Gen, AbbVie, Eli Lilly, and Merck Sharp & Dohme; grants, personal fees, and non-financial support from ISDIN, La Roche-Posay, and Roche; grants and personal fees from Sun Pharma, Leo Pharma, and Almirall; and personal fees from Ojer Pharma and Pierre Fabre. Dr LaFontaine reports employment at Sanofi and holds shares or stock in the company.

Background: Metastatic basal cell carcinoma (mBCC) is a rare condition with no effective second-line treatment options. Cemiplimab is an immune checkpoint inhibitor that blocks the binding of programmed cell death-1 (PD-1) to its ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). Here, we present the final analysis of cemiplimab in patients with mBCC after first-line hedgehog pathway inhibitor (HHI) treatment (NCT03132636)., Patients and Methods: In this open-label, single-arm, phase II study, adults with mBCC and Eastern Cooperative Oncology Group performance status ≤1, post-HHI treatment, received cemiplimab 350 mg intravenously every 3 weeks for ≤93 weeks or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by independent central review (ICR). Duration of response (DOR) was a key secondary endpoint. Other secondary endpoints were ORR per investigator assessment, progression-free survival (PFS), overall survival (OS), complete response rate, safety, and tolerability., Results: Fifty-four patients were enrolled: 70% were male and the median age of patients was 64 [interquartile range (IQR) 57.0-73.0] years. The median duration of follow-up was 8 months (IQR 4-21 months). The ORR per ICR was 22% [95% confidence interval (CI) 12% to 36%], with 2 complete responses and 10 partial responses. Among responders, the median time to response per ICR was 3 months (IQR 2-7 months). The estimated median DOR per ICR was not reached [95% CI 10 months-not evaluable (NE)]. The disease control rate was 63% (95% CI 49% to 76%) per ICR and 70% (95% CI 56% to 82%) per investigator assessment. The median PFS per ICR was 10 months (95% CI 4-16 months); the median OS was 50 months (95% CI 28 months-NE). The most common treatment-emergent adverse events were fatigue [23 (43%)] and diarrhoea [20 (37%)]. There were no treatment-related deaths., Conclusions: Cemiplimab demonstrated clinically meaningful antitumour activity, including durable responses, and an acceptable safety profile in patients with mBCC who had disease progression on or intolerance to HHI therapy., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

When compared to other malignancies, the tumor microenvironment (TME) of primary and castration-resistant prostate cancer (CRPC) is relatively devoid of immune infiltrates. While androgen deprivation therapy (ADT) induces a complex immune infiltrate in localized prostate cancer, the composition of the TME in metastatic castration-sensitive prostate cancer (mCSPC), and the effects of ADT and other treatments in this context are poorly understood. Here, we perform a comprehensive single-cell RNA sequencing (scRNA-seq) profiling of metastatic sites from patients participating in a phase 2 clinical trial (NCT03951831) that evaluated standard-of-care chemo-hormonal therapy combined with anti-PD-1 immunotherapy. We perform a longitudinal, protein activity-based analysis of TME subpopulations, revealing immune subpopulations conserved across multiple metastatic sites. We also observe dynamic changes in these immune subpopulations in response to treatment and a correlation with clinical outcomes. Our study uncovers a therapy-resistant, transcriptionally distinct tumor subpopulation that expands in cell number in treatment-refractory patients., Competing Interests: Declaration of interests Dr. Hawley has served as a paid consultant to Seagen, Daiichi Sankyo, and ImmunityBio and has received sponsored research funding to her institution from Astra Zeneca, Bristol Meyers Squibb, Crescendo Biologics, Macrogenics, and Vaccitech. Dr. Drake is a co-inventor on patents licensed from JHU to BMS and Janssen and is currently an employee of Janssen Research. Dr. Califano is founder, equity holder, and consultant of DarwinHealth Inc., a company that has licensed some of the algorithms used in this manuscript from Columbia University. Columbia University is also an equity holder in DarwinHealth Inc. Dr. Lowy is an employee and stockholder of Regeneron Pharmaceuticals., (Copyright © 2023. Published by Elsevier Inc.)

Background: We previously reported rates of pathological complete responses (51% [95% CI 39-62] per independent central review, the primary endpoint) and major pathological responses (13% per independent central review, a secondary endpoint) to neoadjuvant cemiplimab (an anti-PD-1 inhibitor) among 79 patients with locoregionally advanced, resectable cutaneous squamous cell carcinoma. Here, we present follow-up data, including event-free, disease-free, and overall survival., Methods: This single-arm, multicentre, phase 2 study included patients aged 18 years or older with resectable stage II-IV (M0) cutaneous squamous cell carcinoma and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received up to four planned doses of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by curative-intent surgery. After surgery, per investigator discretion, patients received either adjuvant cemiplimab for up to 48 weeks, radiotherapy, or observation alone. Secondary endpoints included in this follow-up analysis are event-free survival, disease-free survival, and overall survival, all summarised using the Kaplan-Meier method. Activity and safety endpoints were analysed for all enrolled patients who received at least one dose of neoadjuvant cemiplimab. In this report, safety data are reported for all patients who received at least one dose of adjuvant cemiplimab. This trial is registered with ClinicalTrials.gov, NCT04154943, has completed enrolment and follow-up is ongoing., Findings: Between March 20, 2020, and July 8, 2021, 79 patients were enrolled. Median age was 73 years (IQR 66-81), 67 (85%) patients were male, 12 (15%) were female, 69 (87%) were White, one was Asian (1%), one was other race (1%), and race was not reported for eight (10%). As of data cutoff (Dec 1, 2022), median follow-up was 18·7 months (IQR 15·6-22·1) for all 79 patients. Among 70 patients who had surgery, 65 (93%) had post-surgical management data: 32 (49%) of 65 were observed postoperatively, 16 (25%) received adjuvant cemiplimab, and 17 (26%) received adjuvant radiotherapy. 11 (14%) of 79 patients had event-free survival events, with an estimated 12-month event-free survival of 89% (95% CI 79-94) for all patients. None of 40 patients who had a pathological complete response and one (10%) of ten patients with major pathological response had recurrence. Six (9%) of 70 patients who completed surgery had a disease-free survival event, with an estimated 12-month disease-free survival of 92% (95% CI 82-97). Nine (11%) of 79 patients died, with an estimated 12-month overall survival for all patients of 92% (95% CI 83-96). Four (25%) of 16 patients who received adjuvant cemiplimab treatment had grade 3 adverse events, including one (6%) who had increased blood potassium, one (6%) who had traumatic limb amputation, and two who had serious adverse events (one [6%] cardiomyopathy and one [6%] hypophysitis). There were no grade 4 adverse events or treatment-related deaths., Interpretation: For patients with resectable stage II-IV cutaneous squamous cell carcinoma, neoadjuvant cemiplimab followed by surgery might be a potential treatment option, addressing a substantial unmet need., Funding: Regeneron Pharmaceuticals and Sanofi., Competing Interests: Declaration of interests NDG reports institutional research funding from Regeneron Pharmaceuticals; speaker honoraria from AiCME; and advisory board and consulting fees from PDS Biotechnology, Replimmune, Regeneron Pharmaceuticals, and Merck. DMM reports honoraria for advisory or consultant roles from Castle Biosciences, EMD Serono, Merck KGaA, Merck Sharpe & Dome, Pfizer, Regeneron Pharmaceuticals, Incyte, Sanofi Genzyme, and Bristol Myers Squibb; equity options from Checkpoint Therapeutics and Avstera Therapeutics Corp; and research funding from Kartos Therapeutics, NeoImmune Tech, and Regeneron Pharmaceuticals. NIK reports grants and advisory board fees from Regeneron Pharmaceuticals, Bristol Myers Squibb, Merck, Replimmune, and Novartis; advisory board fees from Iovance, Instil Bio, Castle Biosciences, Nektar, Incyte (data safety monitoring committee), AstraZeneca (data safety monitoring committee), and Jounce Therapeutics; grants from GlaxoSmithKline, HUYA, and Celgene; honoraria from Genzyme, National Comprehensive Cancer Network (paid by Pfizer), Nektar (study steering committee), Regeneron Pharmaceuticals (study steering committee), Bristol Myers Squibb (study steering committee). and Replimmune (study steering committee); grant from Modulation Therapeutics; travel support from Regeneron Pharmaceuticals; and common stock ownership of Bellicum Pharmaceuticals, Amarin, and Asensus Surgical (formerly Transenetrix). VD reports institutional research funding from Genentech, and advisory board fees from Regeneron Pharmaceuticals. ESR reports advisory board and consulting fees from Genentech, Feldan Therapeutics, Regeneron Pharmaceuticals, and Sanofi, and serves on the board of directors for Checkpoint Therapeutics. EJL reports institutional research funding from Regeneron Pharmaceuticals and Sanofi; institutional grants from Bristol Myers Squibb and Merck; advisory board fees from Bristol Myers Squibb, Eisai, Genentech, Instil Bio, Merck, Natera, Nektar Therapeutics, Odonate Therapeutics, Pfizer, Rain Therapeutics, Regeneron Pharmaceuticals, Replimmune, and Sanofi; payment for speaker's fee from Bristol Myers Squibb; and consulting fees from Bristol Myers Squibb, Macrogenics, OncoSec, Merck, Novartis, CareDX, and Pfizer. FM reports travel support, speaker's fees or advisor's honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sanofi; and research funding from Novartis and Roche. PLS reports institutional research grants from Ascentage Pharma and Pfizer, and advisory board roles for Elevar Therapeutics, Prelude Therapeutics, and Regeneron Pharmaceuticals. JA reports payment or honoraria for speakers bureaus and presentations from Bristol Myers Squibb and Regeneron Pharmaceuticals; advisory board and consulting fees from Bristol Myers Squibb, Castle Biosciences, Pfizer, Regeneron Pharmaceuticals, and Sanofi. JLG reports institutional research funding from Alkermes, EMD Serono, Merck, Regeneron Pharmaceuticals, and Roche/Genentech; and advisory board or consultant fees from Astellas, Exelixis, EMD Serono, Merck, and Regeneron Pharmaceuticals. AH reports grants and personal fees from Amgen, Bristol Myers Squibb, Merck-Pfizer, MSD/Merck, Philogen, Pierre Fabre, Regeneron Pharmaceuticals, Roche, Sanofi-Genzyme, Novartis Pharma, Eisai, Replimmune, NeraCare; consulting fees from Seagen, IO Biotech, Dermagnostix, Incyte, Highlight Therapeutics, and Iovance; speaker's honoraria from Kyowa Kirin; advisory board fees from Immunocore; and institutional grants from Huya Biosciences outside the submitted work. JHC reports consulting or advisory roles for Exelixis, Coherus Biosciences, Merck Sharp & Dohme, Eisai, and Regeneron Pharmaceuticals, and institutional research funding from Arcus Biosciences and Genmab. BGMH reports consulting or advisory roles at AstraZeneca, Bristol Myers Squibb, Eisai, Merck Sharp & Dohme, Pfizer, and Roche, and institutional research funding from Amgen. DS reports honoraria from Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Immunocore, Merck Serono, Array BioPharma, Pfizer, Pierre Fabre, Philogen, Regeneron Pharmaceuticals, 4SC, Sanofi, Regeneron Pharmaceuticals, NeraCare GmbH, Sun Pharma, InflarxGmbH, Ultimovacs, and Sandoz; consulting fees from Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, 4SC, Pierre Fabre, Sanofi, Regeneron Pharmaceuticals, and Nektar; speaker fees from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Regeneron Pharmaceuticals, and Merck; advisory board fees from AstraZeneca, Daiichi-Sankyo, Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, 4SC, Pierre Fabre, Sanofi, Regeneron Pharmaceuticals, and Nektar; institutional research funding from Bristol Myers Squibb, Novartis, Roche, MSD Oncology, and Array BioPharma/Pfizer; unpaid leadership or fiduciary roles with Dermatologic Cooperative Oncology Group, European Organisation for Research and Treatment of Cancer-Melanoma Group, Hiege-Stiftung, and Nationale Versorgungskonferenz Hautkrebs; and travel and accommodation expenses from Roche/Genentech, Bristol Myers Squibb, Merck Serono, Novartis, Merck Sharp & Dohme, Pierre Fabre, Sanofi, and Regeneron Pharmaceuticals. VAP reports honoraria for advisory or consulting roles from Sun Pharma, Almirall, Biofrontera, PhD Biosciences, Regeneron Pharmaceuticals, and Sanofi Genzyme; speakers bureau fees from Regeneron Pharmaceuticals, and Sanofi Genzyme, equity in Avstera Therapeutics and Science 37; and research funding from Regeneron Pharmaceuticals. JMT reports honoraria for advisory or consultant roles for Bristol Myers Squibb, Merck & Co, AstraZeneca, Genentech/Roche, Regeneron Pharmaceuticals, Compugen, Lunaphore, and Akoya Biosciences; stock options in Akoya Biosciences; equipment loan and reagent provision from Akoya Biosciences; and research funding from Bristol Myers Squibb and Akoya Biosciences. AML reports uncompensated consultancy for Eisai, research funding support from Sanofi/Regeneron Pharmaceuticals, and support from a Peter MacCallum Cancer Centre Discovery Partner Fellowship. RF reports grants or investigator-initiated trial support from Merck, Pfizer, Gilead, and Ayala; royalties from UpToDate for a chapter on olfactory neuroblastoma; payment for expert testimony from Guidepoint; and advisory board participation with Regeneron Pharmaceuticals, Prelude Therapeutics, Elevar Therapeutics, Eisai, Remix Therapeutics, and Coherus BioSciences. S-YY, HH, FS, and IL are employees and shareholders of Regeneron Pharmaceuticals. MM and MGF report receipt of support for attending meetings or travel, and are also employees, patent holders, and shareholders of Regeneron Pharmaceuticals. DR reports institutional research grant and funding from Regeneron Pharmaceuticals, Genentech, Sanofi, Kura Oncology, Roche, Merck Sharp & Dohme, Decibel Therapeutics, Bristol Myers Squibb, GlaxoSmithKline, and ALX Oncology; and uncompensated scientific committee and advisory board roles for Merck Sharp & Dohme, Regeneron Pharmaceuticals, Sanofi, and Eisai. YBS and JH declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Cemiplimab provided significant survival benefit to patients with advanced non-small-cell lung cancer with PD-L1 tumour expression of at least 50% and no actionable biomarkers at 1-year follow-up. In this exploratory analysis, we provide outcomes after 35 months' follow-up and the effect of adding chemotherapy to cemiplimab at the time of disease progression., Methods: EMPOWER-Lung 1 was a multicentre, open-label, randomised, phase 3 trial. We enrolled patients (aged ≥18 years) with histologically confirmed squamous or non-squamous advanced non-small-cell lung cancer with PD-L1 tumour expression of 50% or more. We randomly assigned (1:1) patients to intravenous cemiplimab 350 mg every 3 weeks for up to 108 weeks, or until disease progression, or investigator's choice of chemotherapy. Central randomisation scheme generated by an interactive web response system governed the randomisation process that was stratified by histology and geographical region. Primary endpoints were overall survival and progression free survival, as assessed by a blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumours version 1.1. Patients with disease progression on cemiplimab could continue cemiplimab with the addition of up to four cycles of chemotherapy. We assessed response in these patients by BICR against a new baseline, defined as the last scan before chemotherapy initiation. The primary endpoints were assessed in all randomly assigned participants (ie, intention-to-treat population) and in those with a PD-L1 expression of at least 50%. We assessed adverse events in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT03088540., Findings: Between May 29, 2017, and March 4, 2020, we recruited 712 patients (607 [85%] were male and 105 [15%] were female). We randomly assigned 357 (50%) to cemiplimab and 355 (50%) to chemotherapy. 284 (50%) patients assigned to cemiplimab and 281 (50%) assigned to chemotherapy had verified PD-L1 expression of at least 50%. At 35 months' follow-up, among those with a verified PD-L1 expression of at least 50% median overall survival in the cemiplimab group was 26·1 months (95% CI 22·1-31·8; 149 [52%] of 284 died) versus 13·3 months (10·5-16·2; 188 [67%] of 281 died) in the chemotherapy group (hazard ratio [HR] 0·57, 95% CI 0·46-0·71; p<0·0001), median progression-free survival was 8·1 months (95% CI 6·2-8·8; 214 events occurred) in the cemiplimab group versus 5·3 months (4·3-6·1; 236 events occurred) in the chemotherapy group (HR 0·51, 95% CI 0·42-0·62; p<0·0001). Continued cemiplimab plus chemotherapy as second-line therapy (n=64) resulted in a median progression-free survival of 6·6 months (6·1-9·3) and overall survival of 15·1 months (11·3-18·7). The most common grade 3-4 treatment-emergent adverse events were anaemia (15 [4%] of 356 patients in the cemiplimab group vs 60 [17%] of 343 in the control group), neutropenia (three [1%] vs 35 [10%]), and pneumonia (18 [5%] vs 13 [4%]). Treatment-related deaths occurred in ten (3%) of 356 patients treated with cemiplimab (due to autoimmune myocarditis, cardiac failure, cardio-respiratory arrest, cardiopulmonary failure, septic shock, tumour hyperprogression, nephritis, respiratory failure, [n=1 each] and general disorders or unknown [n=2]) and in seven (2%) of 343 patients treated with chemotherapy (due to pneumonia and pulmonary embolism [n=2 each], and cardiac arrest, lung abscess, and myocardial infarction [n=1 each]). The safety profile of cemiplimab at 35 months, and of continued cemiplimab plus chemotherapy, was generally consistent with that previously observed for these treatments, with no new safety signals INTERPRETATION: At 35 months' follow-up, the survival benefit of cemiplimab for patients with advanced non-small-cell lung cancer was at least as pronounced as at 1 year, affirming its use as first-line monotherapy for this population. Adding chemotherapy to cemiplimab at progression might provide a new second-line treatment for patients with advanced non-small-cell lung cancer., Funding: Regeneron Pharmaceuticals and Sanofi., Competing Interests: Declaration of interests MÖ reports consulting fees, support for attending meetings, and participation in an advisory board from Regeneron Pharmaceuticals. AS reports support for attending meeting from Regeneron Pharmaceuticals. MS reports research grants from Regeneron Pharmaceuticals, Bristol Myers Squibb, MSD, Roche, Merck Serono, AstraZeneca, Eli Lilly, Astellas, Amgen, BeiGene, Bayer, Eisai, Pfizer, GSK, AbbVie, Bioven, Novartis, Clovis, Daichii Sankyo, PharmaMar, Tesaro, and FivePrime. IC reports personal fees (paid to institution) from Pfizer, MSD Oncology, Roche, Novartis–Ipsen, Eli Lilly, Bristol Myers Squibb, SERVIER, Abdi Ibrahim, Nobelpharma, AbbVie, Teva, and Janssen Oncology; and speakers' bureau fees (paid to institution) from Novartis, Roche, Bristol Myers Squibb, Pfizer, and Abdi Ibrahim, all outside the submitted work. GFH reports research grants from EliLily, Regeneron Pharmaceuticals, MSD, AB Science, Astellas, Tessa Therapeutics, Roche, Arcus Bioscience, AstraZeneca, Pfizer, and Janssen Research & Development; payment or honoraria from MSD, Novartis, Roche, AstraZeneca, Boehringer Ingelheim, and Pfizer; support for attending meetings or travel from Ipsen, AstraZeneca, Bristol Myers Squibb, MSD, and Regeneron Pharmaceuticals; DSMB or advisory board fees from MSD, Novartis, Roche, AstraZeneca, Boehringer Ingelheim, and Pfizer; and receipt of equipment, materials, drugs, medical writing, gifts or other services from Pfizer, Novartis, Janssen Pharmaceuticals, Taiho, and EliLily. MCG reports personal financial interests in the form of consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, and participation on a DSMB or advisory board from AstraZeneca, MSD, BMS, Boehringer Ingelheim Italia, Celgene, Eli Lilly, Ignyta, Incyte, Inivata, MedImmune, Novartis, Pfizer, Roche, Takeda, Seattle Genetics, Mirati, Daiichi Sankyo, Regerenon, and Merck; institutional financial interests in the form of consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, participation on a DSMB or advisory board from Eli Lilly, MSD, Pfizer (MISP), AstraZeneca, MSD International, BMS, Boehringer Ingelheim Italia, Celgene, Eli Lilly, Ignyta, Incyte, MedImmune, Novartis, Pfizer, Roche, Takeda, Tiziana, Foundation Medicine, GSK, and Spectrum pharmaceuticals, Italian Association for Cancer Research, Italian Medicines Agency, Italian Moh, and TRANSCAN; research funding, support for attending meetings, and travel from Merck; and having a leadership or fiduciary role in European Society for Medical Oncology, American Society of Clinical Oncology, and International Association for the Study of Lung Cancer. XH, MK, EO, YL, SL, J-FP, and FS employees and shareholders of Regeneron Pharmaceuticals. GG is a former employee and shareholder of Regeneron Pharmaceuticals. IL and PR are employees of, have a patent pending (PCT/US2018/018747), and are shareholders of Regeneron Pharmaceuticals. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: EMPOWER-Lung 3 part 2 (NCT03409614), a double-blind, placebo-controlled phase 3 study, investigated cemiplimab (antiprogrammed cell death protein 1) plus chemotherapy versus placebo plus chemotherapy in patients with advanced NSCLC without EGFR, ALK, or ROS1 aberrations, with either squamous or nonsquamous histology, irrespective of programmed death-ligand 1 levels. At primary analysis, after 16.4 months of follow-up, cemiplimab plus chemotherapy improved median overall survival (OS) versus chemotherapy alone (21.9 versus 13.0 mo, hazard ratio [HR] = 0.71, 95% confidence interval [CI]: 0.53-0.93, p = 0.014). Here, we report protocol-specified final OS and 2-year follow-up results., Methods: Patients (N = 466) were randomized 2:1 to receive histology-specific platinum-doublet chemotherapy, with 350 mg cemiplimab (n = 312) or placebo (n = 154) every 3 weeks for up to 108 weeks. Primary end point was OS; secondary end points included progression-free survival and objective response rates., Results: After 28.4 months of median follow-up, median OS was 21.1 months (95% CI: 15.9-23.5) for cemiplimab plus chemotherapy versus 12.9 months (95% CI: 10.6-15.7) for chemotherapy alone (HR = 0.65, 95% CI: 0.51-0.82, p = 0.0003); median progression-free survival was 8.2 months (95% CI: 6.4-9.0) versus 5.5 months (95% CI: 4.3-6.2) (HR = 0.55, 95% CI: 0.44-0.68, p < 0.0001), and objective response rates were 43.6% versus 22.1%, respectively. Safety was generally consistent with previously reported data. Incidence of treatment-emergent adverse events of grade 3 or higher was 48.7% with cemiplimab plus chemotherapy and 32.7% with chemotherapy alone., Conclusions: At protocol-specified final OS analysis with 28.4 months of follow-up, the EMPOWER-Lung 3 study continued to reveal benefit of cemiplimab plus chemotherapy versus chemotherapy alone in patients with advanced squamous or nonsquamous NSCLC, across programmed death-ligand 1 levels., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: Programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, may suppress antitumor immunity. This phase I study sought to determine the safety and tolerability of anti-PD-1 blockade in patients with treatment-refractory solid tumors and to preliminarily assess antitumor activity, pharmacodynamics, and immunologic correlates., Patients and Methods: Thirty-nine patients with advanced metastatic melanoma, colorectal cancer (CRC), castrate-resistant prostate cancer, non-small-cell lung cancer (NSCLC), or renal cell carcinoma (RCC) received a single intravenous infusion of anti-PD-1 (MDX-1106) in dose-escalating six-patient cohorts at 0.3, 1, 3, or 10 mg/kg, followed by a 15-patient expansion cohort at 10 mg/kg. Patients with evidence of clinical benefit at 3 months were eligible for repeated therapy., Results: Anti-PD-1 was well tolerated: one serious adverse event, inflammatory colitis, was observed in a patient with melanoma who received five doses at 1 mg/kg. One durable complete response (CRC) and two partial responses (PRs; melanoma, RCC) were seen. Two additional patients (melanoma, NSCLC) had significant lesional tumor regressions not meeting PR criteria. The serum half-life of anti-PD-1 was 12 to 20 days. However, pharmacodynamics indicated a sustained mean occupancy of > 70% of PD-1 molecules on circulating T cells ≥ 2 months following infusion, regardless of dose. In nine patients examined, tumor cell surface B7-H1 expression appeared to correlate with the likelihood of response to treatment., Conclusion: Blocking the PD-1 immune checkpoint with intermittent antibody dosing is well tolerated and associated with evidence of antitumor activity. Exploration of alternative dosing regimens and combinatorial therapies with vaccines, targeted therapies, and/or other checkpoint inhibitors is warranted.

Monocytes are highly plastic immune cells that modulate antitumor immunity. Therefore, identifying factors that regulate tumor monocyte functions is critical for developing effective immunotherapies. Here, we determine that endogenous cancer cell-derived type I interferons (IFNs) control monocyte functional polarization. Guided by single-cell transcriptomic profiling of human and mouse tumors, we devise a strategy to distinguish and separate immunostimulatory from immunosuppressive tumor monocytes by surface CD88 and Sca-1 expression. Leveraging this approach, we show that cGAS-STING-regulated cancer cell-derived IFNs polarize immunostimulatory monocytes associated with anti-PD-1 immunotherapy response in mice. We also demonstrate that immunosuppressive monocytes convert into immunostimulatory monocytes upon cancer cell-intrinsic cGAS-STING activation. Consistently, we find that human cancer cells can produce type I IFNs that polarize monocytes, and our immunostimulatory monocyte gene signature is enriched in patient tumors that respond to anti-PD-1 immunotherapy. Our work exposes a role for cancer cell-derived IFNs in licensing monocyte functions that influence immunotherapy outcomes., Competing Interests: Declaration of interests All authors were employees of Regeneron Pharmaceuticals at the time of their contributions. E.O. is now an employee of Bristol Myers Squibb, X.Y. is now an employee of Novartis, and E.M. is now an employee of Calico., (Copyright © 2022. Published by Elsevier Inc.)

Although many patients with diffuse large B cell lymphoma (DLBCL) may achieve a complete response to frontline chemoimmunotherapy, patients with relapsed/refractory disease typically have poor outcomes. Odronextamab, a CD20xCD3 bispecific antibody that provides "signal 1" through the activation of the T cell receptor/CD3 complex, has exhibited early, promising activity for patients with highly refractory DLBCL in phase 1 trials. However, not all patients achieve complete responses, and many relapse, thus representing a high unmet medical need. Here, we investigated whether adding a costimulatory "signal 2" by engaging CD28 receptors on T cells could augment odronextamab activity. We demonstrate that REGN5837, a bispecific antibody that cross-links CD22-expressing tumor cells with CD28-expressing T cells, enhances odronextamab by potentiating T cell activation and cytolytic function. In preclinical DLBCL studies using human immune system-reconstituted animals, REGN5837 promotes the antitumor activity of odronextamab and induces intratumoral expansion of reprogrammable T cells while skewing away from a dysfunctional state. Although REGN5837 monotherapy shows limited activity and no toxicity in primate studies, it augments T cell activation when dosed in combination with odronextamab. In addition, analysis of non-Hodgkin lymphoma clinical samples reveals an increase in CD28 + CD8 + T cells after odronextamab treatment, demonstrating the presence of a population that could potentially be targeted by REGN5837. Collectively, our data demonstrate that REGN5837 can markedly enhance the antitumor activity of odronextamab in preclinical NHL models, and the combination of these two bispecific antibodies may provide a chemotherapy-free approach for the treatment of DLBCL.

First-line cemiplimab (anti-programmed cell death-1 (PD-1)) monotherapy has previously shown significant improvement in overall survival (OS) and progression-free survival (PFS) versus chemotherapy in patients with advanced non-small cell lung cancer (aNSCLC) and PD-ligand 1 (PD-L1) expression ≥50%. EMPOWER-Lung 3 ( NCT03409614 ), a double-blind, placebo-controlled, phase 3 study, examined cemiplimab plus platinum-doublet chemotherapy as first-line treatment for aNSCLC, irrespective of PD-L1 expression or histology. In this study, 466 patients with stage III/IV aNSCLC without EGFR, ALK or ROS1 genomic tumor aberrations were randomized (2:1) to receive cemiplimab 350 mg (n = 312) or placebo (n = 154) every 3 weeks for up to 108 weeks in combination with four cycles of platinum-doublet chemotherapy (followed by pemetrexed maintenance as indicated). In total, 57.1% (266/466 patients) had non-squamous NSCLC, and 85.2% (397/466 patients) had stage IV disease. The primary endpoint was OS. The trial was stopped early per recommendation of the independent data monitoring committee, based on meeting preset OS efficacy criteria: median OS was 21.9 months (95% confidence interval (CI), 15.5-not evaluable) with cemiplimab plus chemotherapy versus 13.0 months (95% CI, 11.9-16.1) with placebo plus chemotherapy (hazard ratio (HR) = 0.71; 95% CI, 0.53-0.93; P = 0.014). Grade ≥3 adverse events occurred with cemiplimab plus chemotherapy (43.6%, 136/312 patients) and placebo plus chemotherapy (31.4%, 48/153 patients). Cemiplimab is only the second anti-PD-1/PD-L1 agent to show efficacy in aNSCLC as both monotherapy and in combination with chemotherapy for both squamous and non-squamous histologies., (© 2022. The Author(s).)

Background: In a pilot study involving patients with cutaneous squamous-cell carcinoma, a high percentage of patients had a pathological complete response with the use of two doses of neoadjuvant cemiplimab before surgery. Data from a phase 2 study are needed to confirm these findings., Methods: We conducted a phase 2, confirmatory, multicenter, nonrandomized study to evaluate cemiplimab as neoadjuvant therapy in patients with resectable stage II, III, or IV (M0) cutaneous squamous-cell carcinoma. Patients received cemiplimab, administered at a dose of 350 mg every 3 weeks for up to four doses, before undergoing surgery with curative intent. The primary end point was a pathological complete response (the absence of viable tumor cells in the surgical specimen) on independent review at a central laboratory, with a null hypothesis that a pathological complete response would be observed in 25% of patients. Key secondary end points included a pathological major response (the presence of viable tumor cells that constitute ≤10% of the surgical specimen) on independent review, a pathological complete response and a pathological major response on investigator assessment at a local laboratory, an objective response on imaging, and adverse events., Results: A total of 79 patients were enrolled and received neoadjuvant cemiplimab. On independent review, a pathological complete response was observed in 40 patients (51%; 95% confidence interval [CI], 39 to 62) and a pathological major response in 10 patients (13%; 95% CI, 6 to 22). These results were consistent with the pathological responses determined on investigator assessment. An objective response on imaging was observed in 54 patients (68%; 95% CI, 57 to 78). Adverse events of any grade that occurred during the study period, regardless of whether they were attributed to the study treatment, were observed in 69 patients (87%). Grade 3 or higher adverse events that occurred during the study period were observed in 14 patients (18%)., Conclusions: Neoadjuvant therapy with cemiplimab was associated with a pathological complete response in a high percentage of patients with resectable cutaneous squamous-cell carcinoma. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov number, NCT04154943.)., (Copyright © 2022 Massachusetts Medical Society.)

Background: In a phase III, randomised, active-controlled study (EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9; R2810-ONC-1676; NCT03257267) and cemiplimab significantly improved survival versus investigator's choice of chemotherapy among patients with recurrent cervical cancer who had progressed on platinum-based therapy. Here we report patient-reported outcomes in this pivotal study., Methods: Patients were randomised 1:1 to open-label cemiplimab (350 mg intravenously every 3 weeks) or investigator's choice of chemotherapy in 6-week cycles. Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 during cycles 1-16. Least-squares mean changes from baseline in global health status (GHS)/quality of life (QoL) and physical functioning (PF) were secondary end-points in the statistical hierarchy., Results: Of 608 patients (304/arm), 77.8% patients had squamous cell carcinoma and 22.2% patients had adenocarcinoma. Questionnaire completion rates were ∼90% throughout. In the squamous cell carcinoma population, overall between-group differences statistically significantly favoured cemiplimab in GHS/QoL (8.49; 95% confidence interval [CI]: 3.77-13.21; P = 0.0003) and PF (8.35; 95% CI: 4.08-12.62; P &lt; 0.0001). Treatment differences favoured cemiplimab in both histologic populations by cycle 2. Overall changes from baseline in most functioning and symptom scales favoured cemiplimab, with clinically meaningful treatment differences in role functioning, appetite loss and pain in both populations. The sensitivity analyses, responder analyses and time to definitive deterioration favoured cemiplimab in both populations., Conclusions: Cemiplimab conferred favourable differences in GHS/QoL and PF compared with chemotherapy among patients with recurrent cervical cancer, with benefits in PF by cycle 2, and clinically meaningful differences favouring cemiplimab in role functioning, appetite loss, and pain., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.O. reports serving on advisory boards for Roche, AstraZeneca, MSD/Merck, PharmaMar, Clovis Oncology, Tesaro, Immunogen, Genmab, Mersana Therapeutic, GSK, SUTRO, AGENUS and Deciphera Pharmaceuticals; and support for travel or accommodation from Roche, AstraZeneca and PharmaMar. B.J.M. reports consulting honoraria from Aravive, Asymmetric Therapeutics, Boston Biomedical, ChemoCare, ChemoID, Circulogene, Conjupro Biotherapeutics, Eisai, Geistlich, Genmab/Seattle Genetics, Gynecologic Oncology Group Foundation, Immunogen, Immunomedics, Incyte, Laekna Health Care, Mateon/Oxigene, Merck, Mersana, Myriad, Nucana, Oncomed, Oncoquest, Oncosec, Perthera, Pfizer, Precision Oncology, Puma, Regeneron, Samumed, Takeda, VBL and Vigeo; and consulting or speaker honoraria from AstraZeneca, Clovis, Janssen/Johnson & Johnson, Roche/Genentech and Tesaro/GSK. I.V. reports consulting fees from AstraZeneca, Elevar Therapeutics, Genmab, GSK, Immunogen, Merck Sharp & Dohme and Oncoinvent; and contracted research from Genmab and Hoffmann-La Roche. A.C.M. has served on advisory boards for Merck Sharp & Dohme, Bristol-Myers Squibb and Libbs; has received support for travel or accommodation from AstraZeneca, Merck Sharp & Dohme, Bristol-Myers Squibb and Roche; and reports institutional research grant support from Clovis Oncology, Bristol-Myers Squibb, Roche, Novartis, Amgen, Merck Sharp & Dohme, Lilly, Pierre Fabre, Sanofi and Pfizer. Y.M.K. reports ownership of stock at Johnson & Johnson and Genolution for self and spouse; consulting or advisory role at Merck Sharp & Dohme; and research funding from Regeneron Pharmaceuticals, Inc., and Roche. A.S.L., V.S., H.S.K., E.A.G., F.D. and C.-L.C. declare no conflict of interest. S.T. reports honoraria from Daiichi Sankyo, Eisai, Bayer, Taiho Pharmaceutical, Merck Sharp & Dohme, Novartis, Chugai Pharma, AstraZeneca, Bristol-Myers Squibb Japan, Ono Pharmaceutical, Nihonkayaku, Pfizer and Lilly Japan; advisory role at Bayer; research funding from Daiichi Sankyo, Sanofi, Eisai, Bayer, Taiho Pharmaceutical, Merck Sharp & Dohme, Novartis, Chugai Pharma, AstraZeneca, Bristol-Myers Squibb, Lilly, Ono Pharmaceutical, PharmaMar and Pfizer/EMD Serono; and travel, accommodation and expenses from Daiichi Sankyo and Novartis. J.L., M.M., M.G.F., I.L., J.H. and C.C. are employees and shareholders of Regeneron Pharmaceuticals, Inc. C.I. and M.R. report employment at IQVIA and institutional research funding from Regeneron Pharmaceuticals, Inc. P.R.L. is an employee of, and may hold shares and stock options in Sanofi. K.T. reports honoraria from Tesaro and Clovis Oncology; consulting or advisory roles for Genentech, Tesaro, Clovis and AstraZeneca; serving on a speaker's bureau for Genentech, AstraZeneca, Merck, Tesaro and Clovis; institutional research funding from AbbVie, Genentech, Morphotek, Merck and Regeneron Pharmaceuticals, Inc.; and travel, accommodation and expenses from Genentech., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Odronextamab is a hinge-stabilised, fully human IgG4-based CD20 × CD3 bispecific antibody that binds CD3 on T cells and CD20 on B cells. We aimed to evaluate the safety and antitumour activity of odronextamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma., Methods: This single-arm, multicentre, phase 1, dose-escalation and dose-expansion (ELM-1) trial was conducted at ten academic sites across the USA and Germany. Patients aged 18 years or older with CD20-positive relapsed or refractory B-cell malignancies who previously received CD20-directed antibody therapy and who had at least one measurable lesion, and an ECOG performance status of 0 or 1 were included. Patients received intravenous odronextamab, according to a step-up dosing schedule in cycle 1, followed by treatment once per week at target doses ranging from 0·1 mg to 320 mg during cycles 2-4 (each cycle was 21 days). After cycle 4, maintenance treatment occurred every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint of safety was assessed by the incidence of adverse events and dose-limiting toxicities to determine the maximum tolerated dose or phase 2 dose of odronextamab, or both. Preliminary antitumour activity, as measured by objective response rate, was a secondary endpoint. This study is registered with ClinicalTrials.gov, NCT02290951., Findings: From Feb 4, 2015, to Sept 25, 2021, 145 heavily pretreated patients (median of 3 (IQR 2-5] previous therapies) were enrolled (94 to the dose-escalation and 51 to the dose-expansion part of the study). The median age of patients was 67·0 years (IQR 57·0-73·0); 101 (70%) were male and 44 (30%) were female; most participants were White (119 [82%]) and not Hispanic or Latino (132 [91%]). 42 (29%) patients received previous CAR T therapy and 119 (82%) were refractory to the last line of therapy. Median duration of follow-up was 4·2 months (IQR 1·5-11·5). During dose escalation, odronextamab was administered up to the maximum dose of 320 mg once per week and no dose-limiting toxicities were observed. The recommended dose for expansion in patients with follicular lymphoma grade 1-3a was 80 mg and was 160 mg for patients with diffuse large B-cell lymphoma. Cytokine release syndrome and neurological treatment-emergent adverse events were predominantly low grade and did not result in treatment discontinuation. The most common grade 3 or worse treatment-emergent adverse events were anaemia (36 [25%]), lymphopenia (28 [19%]), hypophosphataemia (27 [19%]), neutropenia (27 [19%]), and thrombocytopenia (20 [14%]). Serious treatment-emergent adverse events occurred in 89 (61%) of 145 patients; the most frequent were cytokine release syndrome (41 [28%]), pyrexia (11 [8%]), pneumonia (nine [6%]), and infusion-related reaction (six [4%]). Four deaths were considered related to treatment (gastric perforation in a patient with gastric involvement by lymphoma, lung infection, pneumonia, and tumour-lysis syndrome). Objective response rate was 51% (95% CI 42-59; 72 of 142). In patients with follicular lymphoma who received odronextamab doses of 5 mg or higher, the objective response rate was 91% (95% CI 75-98; 29 of 32) and the complete response rate was 72% (95% CI 53-86; 23 of 32). In patients with diffuse large B-cell lymphoma without previous CAR T-cell therapy who received doses of 80 mg or higher, the objective response rate was 53% (eight of 15) and all responses were complete responses. In patients with diffuse large B-cell lymphoma who had previous CAR T-cell therapy and received doses of 80 mg or higher, the objective response rate was 33% (ten of 30) and complete response rate was 27% (eight of 30)., Interpretation: Odronextamab monotherapy showed a manageable safety profile and encouraging preliminary activity, including durable responses in heavily pretreated patients with B-cell non-Hodgkin lymphoma, supporting further clinical investigation in phase 2 and 3 trials., Funding: Regeneron Pharmaceuticals., Competing Interests: Declaration of interests RB reports research funding from Regeneron Pharmaceuticals, paid to his institution; institutional payments for sponsored studies from AbbVie, Genentech, Pharmacyclics, and Roche; non-financial participation on advisory boards for Janssen Biotech; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from the 18th Annual International Ultmann Chicago Lymphoma Symposium and Curio Science–opinions in diffuse large B cell lymphoma; and his spouse holds stock options and is an employee of Sanofi-Pasteur. JEA reports participation on a data safety monitoring board or advisory board for Bristol Myers Squibb, Juno, and Regeneron Pharmaceuticals. RHA reports advisory board membership from ADC Therapeutics, Bristol Myers Squibb, Epizyme, Genentech, Gilead, Incyte, Karyopharm, Portola, and Seattle Genetics; and institutional research funding from Cyteir, Forty Seven, Genentech, Gilead, Janssen, Regeneron Pharmaceuticals, and Roche. JRB reports sponsored research funding paid to her institution from Gilead, Lilly (Loxo), SecuraBio (Verastem), Sun, and TG Therapeutics; consulting fees from AbbVie, Acerta, AstraZeneca, BeiGene, Bristol Myers Squibb, Catapult Therapeutics, Celgene, Dynamo Therapeutics, Eli Lilly and Company, Gilead, Genentech, Hutchmed, Janssen, Juno, Kite, Loxo, MEI Pharma, Morphosys, Nextcea, Novartis, Octapharma, Pfizer, Pharmacyclics, Rigel, Roche, Sunesis, TG Therapeutics, and Verastem; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen; and participation on a data safety monitoring board or advisory board for Invectys and Morphosys. JNA reports grants or contracts from Celgene, Genentech, Janssen, and TG Therapeutics, paid to his institution; consulting fees from AbbVie, ADC Therapeutics, Ascentage, AstraZeneca, BeiGene, Epizyme, Genentech, Janssen, Pharmacyclics, and TG Therapeutics; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, AstraZeneca, BeiGene, Janssen, and PCYC; payment for expert testimony from Calderhead and Lockemeyer Peschke; support for attending meetings and travel from AstraZeneca, BeiGene, and Janssen; and non-financial participation on a data safety monitoring board or advisory board for AstraZeneca. SMO reports consulting fees from AbbVie, Alexion, Amgen, Aptose Biosciences, Astellas, Autolus, Bristol Myers Squibb, Celgene, Eli Lilly and Company, GlaxoSmithKline, Janssen Oncology, Johnson and Johnson, Juno Therapeutics, Merck, NOVA Research, Vaniam, Verastem, and Vida Ventures; research support from Acerta, Caribou, Kite, and Regeneron Pharmaceuticals; and consultant and research support from Gilead, Pfizer, Pharmacyclics, Sunesis, and TG Therapeutics. JCC reports consulting fees from AbbVie, ADC Therapeutics, Janssen, Kymera, Novartis, and TenBio; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, BeiGene, Bristol Myers Squibb, Epizyme, and Morphosys. JLC reports research funding from AbbVie, Bayer, Merck, and Roche; and participation on a data safety monitoring board or advisory board for Incyte and Karyopharm. IL reports patents from Regeneron Pharmaceuticals for tumour treatment methods using CD20xCD3 bispecific antibody (US10662244) and a dosing strategy that mitigates cytokine release syndrome for therapeutic antibodies (US20200129617); and holds stock or stock options and is an employee of Regeneron Pharmaceuticals. MST reports research funding from Regeneron Pharmaceuticals; consulting fees from Gilead, Janssen, Kite, Novartis, Regeneron Pharmaceuticals, and Roche; and support for attending meetings or travel from Amgen and Janssen, or both. MU, JL, MZ, SRA, and AC hold stock or stock options for and are employees of Regeneron Pharmaceuticals. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. Published by Elsevier Ltd.. All rights reserved.)

Background: Surgical resection of early stage hepatocellular carcinoma is standard clinical practice; however, most tumours recur despite surgery, and no perioperative intervention has shown a survival benefit. Neoadjuvant immunotherapy has induced pathological responses in multiple tumour types and might decrease the risk of postoperative recurrence in hepatocellular carcinoma. We aimed to evaluate the clinical activity of neoadjuvant cemiplimab (an anti-PD-1) in patients with resectable hepatocellular carcinoma., Methods: For this single-arm, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma (stage Ib, II, and IIIb) were enrolled and received two cycles of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by surgical resection. Eligible patients were aged 18 years or older, had confirmed resectable hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate liver function. Patients were excluded if they had metastatic disease, if the surgery was not expected to be curative, if they had a known additional malignancy requiring active treatment, or if they required systemic steroid treatment or any other immunosuppressive therapy. After resection, patients received an additional eight cycles of cemiplimab 350 mg intravenously every 3 weeks in the adjuvant setting. The primary endpoint was significant tumour necrosis on pathological examination (defined as >70% necrosis of the resected tumour). Secondary endpoints included delay of surgery, the proportion of patients with an overall response, change in CD8 + T-cell density, and adverse events. Tumour necrosis and response were analysed in all patients who received at least one dose of cemiplimab and completed surgical resection; safety and other endpoints were analysed in the intention-to-treat population. Patients underwent pre-treatment biopsies and blood collection throughout treatment. This trial is registered with ClinicalTrials.gov (NCT03916627, Cohort B) and is ongoing., Findings: Between Aug 5, 2019, and Nov 25, 2020, 21 patients were enrolled. All patients received neoadjuvant cemiplimab, and 20 patients underwent successful resection. Of the 20 patients with resected tumours, four (20%) had significant tumour necrosis. Three (15%) of 20 patients had a partial response, and all other patients maintained stable disease. 20 (95%) patients had a treatment-emergent adverse event of any grade during the neoadjuvant treatment period. The most common adverse events of any grade were increased aspartate aminotransferase (in four patients), increased blood creatine phosphokinase (in three), constipation (in three), and fatigue (in three). Seven patients had grade 3 adverse events, including increased blood creatine phosphokinase (in two patients) and hypoalbuminaemia (in one). No grade 4 or 5 events were observed. One patient developed pneumonitis, which led to a delay in surgery by 2 weeks., Interpretation: This report is, to our knowledge, the largest clinical trial of a neoadjuvant anti-PD-1 monotherapy reported to date in hepatocellular carcinoma. The observed pathological responses to cemiplimab in this cohort support the design of larger trials to identify the optimal treatment duration and definitively establish the clinical benefit of preoperative PD-1 blockade in patients with hepatocellular carcinoma., Funding: Regeneron Pharmaceuticals., Competing Interests: Declaration of interests TUM has received research funding from Boehringer Ingelheim, Bristol Myers Squibb, Merck, and Regeneron Pharmaceuticals. TUM has served on advisory boards or data safety monitoring boards, or both, for AstraZeneca, Atara, Boehringer Ingelheim, Celldex, Chimeric Therapeutics, Genentech, Regeneron Pharmaceuticals, Riboscience, and the Rockefeller University. MIF reports involvements with the following organisations: President of the New York Pathological Society (2019–21); President of the Hans Popper Hepatopathology Society of the United States and Canadian Academy of Pathology (2016–18); Central Pathologist at Progenity; and Central Pathologist at Alexion Biopharma. SCW received salary support in 2021 from a Pilot Award (grant) from the Neuroendocrine Tumor Research Foundation; SCW will also be receiving salary support from a research grant from Boehringer Ingelheim International GmbH in 2021–23. DD reports consulting for Atheneum Partners, Boston Healthcare Associates, Boerhinger Ingelheim, Dedham Group, Global Data, Guidepoint Global Advisors, Ipsen, and MJH Life Sciences. AOK reports a consulting role with Engine Biosciences and Axon Advisors LLC. MWS reports consulting roles with Eisai and Genentech. NF, NTG, RD, WW, FW, JM, BK, SL, VJ, NJ, SCH, HKC, JSS, EM, GT, and IL are employees and shareholders eof Regeneron Pharmaceuticals. PTh reports stock ownership in Mannkind and is an employee and shareholder of Regeneron Pharmaceuticals. NB reports a consulting role with Regeneron Pharmaceuticals; stocks and other ownership interest in Avidea, Apricity, and PrimeVax; royalty payments from Neostem and Rome Therapeutics; scientific advisory board roles for Avidea, BioNTech, Boehringer Ingelheim Corporation, BreakBio, Carisma, CureVac, Duke University, Genentech, Genotwin, Gilead Sciences, Human Vaccines Project, MD Anderson Cancer Center, Novartis, Rome Therapeutics, Roswell Park, and Tempest Therapeutics; and both, for Merck, and research funding from Regeneron, Harbor Biomed, and the Parker Institute for Cancer Immunotherapy. SG reports consultancy or advisory roles, or both, for Bristol-Myers Squibb, Genentech, Janssen R&D, Merck, OncoMed, Pfizer, and Regeneron Pharmaceuticals; research funding from Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Genentech, Janssen R&D, Pfizer, Regeneron Pharmaceuticals, and Takeda; and is a named co-inventor on an issued patent for multiplex immunohistochemistry to characterise tumours and treatment responses. The technology is filed through the Icahn School of Medicine at Mount Sinai; the Icahn School of Medicine at Mount Sinai has received payments associated with licensing this technology and both the Icahn School of Medicine at Mount Sinai and SG is entitled to future payments. SG is also partially supported by the National Institutes of Health (grant numbers CA224319, DK124165, CA234212, and CA196521). BT reports grants from Bayer Healthcare, Regeneron Pharmaceuticals, Takeda, and Helio Health; and is a consultant for Bayer Healthcare and Helio Health. MM reports consulting roles with Asher Bio, Celsius Therapeutics, Compugen, Dren Bio, Genenta, Innate Pharma, Morphic Therapeutic, Myeloid Therapeutics, and Nirogy Therapeutics; receives research funding from Boehringer Ingelheim, Genentech, Regeneron Pharmaceuticals, and Takeda; honoraria from Amgen and GSK; and reports ownership interest less than 5% in Asher Bio, Celsius Therapeutics, Compugen, Dren Bio, Genenta, Morphic Therapeutic, Myeloid Therapeutics, and Nirogy Therapeutics. All other authors report no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Patients with recurrent cervical cancer have a poor prognosis. Cemiplimab, the fully human programmed cell death 1 (PD-1)-blocking antibody approved to treat lung and skin cancers, has been shown to have preliminary clinical activity in this population., Methods: In this phase 3 trial, we enrolled patients who had disease progression after first-line platinum-containing chemotherapy, regardless of their programmed cell death ligand 1 (PD-L1) status. Women were randomly assigned (1:1) to receive cemiplimab (350 mg every 3 weeks) or the investigator's choice of single-agent chemotherapy. The primary end point was overall survival. Progression-free survival and safety were also assessed., Results: A total of 608 women were enrolled (304 in each group). In the overall trial population, median overall survival was longer in the cemiplimab group than in the chemotherapy group (12.0 months vs. 8.5 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.84; two-sided P<0.001). The overall survival benefit was consistent in both histologic subgroups (squamous-cell carcinoma and adenocarcinoma [including adenosquamous carcinoma]). Progression-free survival was also longer in the cemiplimab group than in the chemotherapy group in the overall population (hazard ratio for disease progression or death, 0.75; 95% CI, 0.63 to 0.89; two-sided P<0.001). In the overall population, an objective response occurred in 16.4% (95% CI, 12.5 to 21.1) of the patients in the cemiplimab group, as compared with 6.3% (95% CI, 3.8 to 9.6) in the chemotherapy group. An objective response occurred in 18% (95% CI, 11 to 28) of the cemiplimab-treated patients with PD-L1 expression greater than or equal to 1% and in 11% (95% CI, 4 to 25) of those with PD-L1 expression of less than 1%. Overall, grade 3 or higher adverse events occurred in 45.0% of the patients who received cemiplimab and in 53.4% of those who received chemotherapy., Conclusions: Survival was significantly longer with cemiplimab than with single-agent chemotherapy among patients with recurrent cervical cancer after first-line platinum-containing chemotherapy. (Funded by Regeneron Pharmaceuticals and Sanofi; EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 ClinicalTrials.gov number, NCT03257267.)., (Copyright © 2022 Massachusetts Medical Society.)

Lessons Learned: Cemiplimab in combination with radiation therapy, cyclophosphamide, and granulocyte macrophage colony-stimulating factor did not demonstrate efficacy above what can be achieved with other PD-1 inhibitor monotherapies in patients with refractory and metastatic head and neck squamous cell carcinoma. The safety profile of cemiplimab combination therapy was consistent with previously reported safety profiles of cemiplimab monotherapy. No new safety signal was observed., Background: Refractory and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) generally does not respond to PD-1 inhibitor monotherapy. Cemiplimab is a human anti-PD-1 monoclonal antibody. An expansion cohort enrolled patients with R/M HNSCC in a phase I study combining cemiplimab plus radiation therapy (RT), cyclophosphamide, and granulocyte macrophage colony-stimulating factor (GM-CSF)., Methods: Patients with R/M HNSCC refractory to at least first-line therapy and for whom palliative RT is clinically indicated received cemiplimab plus RT, cyclophosphamide, and GM-CSF. The co-primary objectives were the safety, tolerability, and efficacy of cemiplimab plus RT, cyclophosphamide, and GM-CSF in 15 patients with R/M HNSCC., Results: Fifteen patients were enrolled. Patients discontinued treatment due to progression of disease. The most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (40.0%), constipation (26.7%), and asthenia, dyspnea, maculo-papular rash, and pneumonia (each 20%). The only grade ≥3 TEAE that occurred in two patients was pneumonia (13.3%). By investigator assessment, there was one partial response (6.7%); disease control rate was 40.0% (95% confidence interval [CI], 16.3-67.7; five patients with stable disease); seven patients had progressive disease, and two were not evaluable. Median progression-free survival by investigator assessment was 1.8 months (95% CI, 1.7-4.7)., Conclusion: The regimen demonstrated tolerability but not efficacy above that which can be achieved with anti-PD-1 inhibitor monotherapy for R/M HNSCC., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Background: To provide pooled longer term data from three groups of a phase 2 study of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (CSCC), and to determine duration of response (DOR) and impact on quality of life (QoL)., Methods: Patients received cemiplimab 3 mg/kg every 2 weeks (group 1, metastatic CSCC [mCSCC], n=59; group 2, locally advanced CSCC, n=78) or cemiplimab 350 mg every 3 weeks (group 3, mCSCC, n=56). Primary endpoint was objective response rate (ORR) per independent central review (ICR). QoL was repeatedly measured at day 1 of each treatment cycle (groups 1 and 2: 8 weeks; group 3: 9 weeks)., Results: Median duration of follow-up was 15.7 months. Overall, ORR per ICR was 46.1% (95% CI: 38.9% to 53.4%). Complete response (CR) rates were 20.3%, 12.8%, and 16.1% for groups 1, 2, and 3, respectively. Median time to CR was 11.2 months. Among patients with partial response or CR, the estimated proportion of patients with ongoing response at 12 months from the first objective response was 87.8% (95% CI: 78.5% to 93.3%), with median DOR not reached. Kaplan-Meier estimated probability of overall survival (OS) was 73.3% (95% CI: 66.1% to 79.2%) at 24 months, with median OS not reached. Global Health Status (GHS)/QoL improvements were observed as early as cycle 2 and were significantly improved and durable until last assessment. Kaplan-Meier estimate of median time to first clinically meaningful improvement for pain was 2.1 (95% CI: 2.0 to 3.7) months and was significantly improved in responders versus non-responders (p<0.0001)., Conclusions: This is the largest (n=193) clinical dataset for a programmed cell death-1 inhibitor against advanced CSCC, confirming the sustained substantial clinical activity of cemiplimab in these patients, including new findings of improved CR rates over time, increasing DOR, and durable pain control and GHS/QoL improvement., Trial Registration Number: ClinicalTrials.gov Registry (NCT02760498), https://clinicaltrialsgov/ct2/show/NCT02760498., Competing Interests: Competing interests: DR—institutional research grant and funding from Regeneron Pharmaceuticals, Roche, Merck Sharp & Dohme, Bristol-Myers Squibb, GlaxoSmithKline, and Sanofi; uncompensated scientific committee and advisory board from Merck Sharp & Dohme, Regeneron Pharmaceuticals, Sanofi, GlaxoSmithKline, and Bristol-Myers Squibb; and travel and accommodation from Merck Sharp & Dohme and GlaxoSmithKline. NIK—grants from Regeneron Pharmaceuticals; grants and advisory board fees from Bristol-Myers Squibb and HUYA Bioscience International; advisory board fees from EMD Serono, Regeneron Pharmaceuticals, Genentech, AstraZeneca (data safety monitoring committee), Incyte (data safety monitoring committee), Iovance, Merck, ARRAY Biopharma, Jounce Therapeutics, and Immunocore; grants from Merck, Novartis, GlaxoSmithKline, Celgene, and Amgen; honorarium from Sanofi; and common stock ownership of Bellicum Pharmaceuticals, Mazor Robotics, Amarin, and Transenetrix. CDS—steering committee member for Castle Biosciences; steering committee member and consultant for Regeneron Pharmaceuticals; consultant for Sanofi; received research funding from Castle Biosciences, Regeneron Pharmaceuticals, Novartis, Genentech, and Merck; and is a chair for the National Comprehensive Cancer Network. AG—personal fees and non-financial support (advisory board and travel support) from Bristol-Myers Squibb and Sun Pharma; personal fees (advisory board) from Merck KGaA, Eisai, and Pfizer; non-financial (travel) support from Astellas; and clinical trial unit support from PPD Australia. ALSC—consulting and advisory roles at Regeneron Pharmaceuticals and Merck; and research funding from Regeneron Pharmaceuticals, Novartis, Galderma, Jounce Therapeutics, and Merck. KDL—grants and personal fees from Regeneron Pharmaceuticals during the conduct of the study. AML—uncompensated advisory board from Merck Sharp & Dohme and Bristol-Myers Squibb with travel and accommodation expenses; and uncompensated consultancy for Eisai. LH-A—performed consulting and advisory roles at Massive Bio; speakers’ bureau roles at Sanofi and Regeneron Pharmaceuticals; received travel, accommodations, and expenses from Regeneron Pharmaceuticals, Sanofi, and Bristol-Myers Squibb; and research funding from Bristol-Myers Squibb, Regeneron Pharmaceuticals, Immunocore, Merck Sharp & Dohme, Polynoma, Corvus Pharmaceuticals, Roche, Merck Serono, Amgen, MedImmune, and Takeda. BGMH—consulting or advisory roles at Merck Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, Pfizer, Roche, Eisai, and Merck; and institutional research funding from Amgen. DS—institutional patients’ fees from Regeneron Pharmaceuticals; advisory board honorarium fees from Amgen and Leo Pharma; speaker fee from Boehringer Ingelheim; advisory board, speaker honorarium, and patients’ fees from Roche, Novartis, Bristol-Myers Squibb, and Merck-EMD; advisory board and speaker honorarium fees from Incyte and Pierre Fabre; advisory board honorarium and patients’ fees from MSD; steering committee honorarium fees from 4SC; advisory board fees from AstraZeneca, Pfizer, and Array; and advisory board and patients’ fees from Philogen. AH—institutional grants, speaker’s honoraria, and consultancy fees from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme/Merck, Pierre Fabre, Provectus, Roche, and Novartis; institutional grants and consultancy fees from Merck Serono, Philogen, and Regeneron Pharmaceuticals; and consultancy fees from OncoSec. ES, JB, S-YY, SL, ZC, EO, C-IC, VM, IL, MGF—employees of and shareholders in Regeneron Pharmaceuticals. MS—employee and shareholder in Sanofi. MRM—honoraria and travel expenses from Regeneron Pharmaceuticals, Sanofi, Novartis, Genentech, Eli Lilly, and Sun Pharma; and institutional research funding from Regeneron Pharmaceuticals, Novartis, Genentech, and Eli Lilly., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Before February, 2021, there was no standard treatment regimen for locally advanced basal cell carcinoma after first-line hedgehog inhibitor (HHI) therapy. Cemiplimab, a PD-1 antibody, is approved for treatment of advanced cutaneous squamous cell carcinoma and has shown clinical activity as monotherapy in first-line non-small-cell lung cancer. Here, we present the primary analysis data of cemiplimab in patients with locally advanced basal cell carcinoma after HHI therapy., Methods: We did an open-label, multicentre, single-arm, phase 2 trial across 38 outpatient clinics, primarily at academic medical centres, in Canada, Europe, and the USA. Eligible patients (aged ≥18 years and with an Eastern Cooperative Oncology Group performance status of 0 or 1) with a histologically confirmed diagnosis of metastatic basal cell carcinoma (group 1) or locally advanced basal cell carcinoma (group 2) who had progressed on or were intolerant to previous HHI therapy were enrolled. Patients were not candidates for further HHI therapy due to progression of disease on or intolerance to previous HHI therapy or having no better than stable disease after 9 months on HHI therapy. Patients received cemiplimab 350 mg intravenously every 3 weeks for up to 93 weeks or until progression or unacceptable toxicity. The primary endpoint was objective response by independent central review. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. The primary analysis is reported only for group 2; group 1 data have not reached maturity and will be reported when the timepoint, according to the statistical analysis plan, has been reached. This study is registered with ClinicalTrials.gov, NCT03132636, and is no longer recruiting new participants., Findings: Between Nov 16, 2017, and Jan 7, 2019, 84 patients were enrolled and treated with cemiplimab. At data cutoff on Feb 17, 2020, median duration of follow-up was 15 months (IQR 8-18). An objective response per independent central review was observed in 26 (31%; 95% CI 21-42) of 84 patients, including two partial responses that emerged at tumour assessments before the data cutoff and were confirmed by tumour assessments done subsequent to the data cutoff. The best overall response was five (6%) patients with a complete response and 21 (25%) with a partial response. Grade 3-4 treatment-emergent adverse events occurred in 40 (48%) of 84 patients; the most common were hypertension (four [5%] of 84 patients) and colitis (four [5%]). Serious treatment-emergent adverse events occurred in 29 (35%) of 84 patients. There were no treatment-related deaths., Interpretation: Cemiplimab exhibited clinically meaningful antitumour activity and an acceptable safety profile in patients with locally advanced basal cell carcinoma after HHI therapy., Funding: Regeneron Pharmaceuticals and Sanofi., Competing Interests: Declaration of interests AJS reports advisory board or steering committee roles with Janssen, Regeneron Pharmaceuticals, Roche, and Sanofi; and research support from Abbvie, Bristol Myers Squibb, Genesis Pharma, and Novartis. AS reports advisory roles with Regeneron Pharmaceuticals and Roche. KP reports advisory board roles with Abbvie, LEO Pharma, Janssen, Almirall, Eli Lilly, Galderma, Novartis, Pierre Fabre, Sun Pharma, and Sanofi, outside the submitted work. OB has advisory board roles with Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, and Ultimovacs. KDL reports grants from the University of Colorado; and grants and personal fees from Regeneron Pharmaceuticals. ALSC reports advisory roles with Regeneron Pharmaceuticals and Merck; and research funding from Regeneron Pharmaceuticals, Merck, Novartis, and Galderma. SD reports that their spouse is an employee of Sanofi. LL reports institutional grants and personal fees from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Debiopharm International SA, Eisai, Novartis, and Roche; institutional grants from Celgene International, Exelixis, Hoffmann-La Roche, IRX Therapeutics, Medpace, Merck-Serono, and Pfizer; and personal fees from Sobi, Ipsen, Incyte Biosciences Italy SRL, Doxa Pharma, Amgen, Nanobiotics SA, GlaxoSmithKline, AccMed, Medical Science Fundation G. Lorenzini, Associazione Sinapsi, Think 2 IT, Aiom Servizi, Prime Oncology, WMA Congress Education, Fasi, DueCi Promotion SRL, MI&T, Net Congress & Education, PRMA Consulting, Kura Oncology, Health & Life SRL, and Immuno-Oncology Hub. CR reports grants and personal fees advisory board roles with Bristol Myers Squibb, Pierre Fabre, Novartis, Amgen, Merck, Roche, Merck Sharp & Dohme, Sanofi, Biothera, and Ultimovacs. CU reports advisory board and speaker roles for Roche, Sanofi, Regeneron Pharmaceuticals, and Sun Pharma. AH reports institutional funding and personal fees from Amgen, Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme, Merck & Co, Philogen, Pierre Fabre, Provectus, Regeneron Pharmaceuticals, Roche, Sanofi Genzyme, and Novartis; and consultancy fees from OncoSec, Almirall Hermal, and Sun Pharma. MRM reports advisory roles with and travel fees from Regeneron Pharmaceuticals and Sun Pharmaceuticals; advisory role with Rakuten Medical; and research funding from Regeneron Pharmaceuticals and PellePharm. RD has intermittent, project focused consultant and advisory roles with Novartis, Merck Sharp & Dohme, Bristol Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron Pharmaceuticals, Alligator, MaxiVAX SA, and touchIME outside the submitted work. SL, S-YY, KM, EC, VJ, NF, EO, FS, DMW, and TB are employees and shareholders of Regeneron Pharmaceuticals. CL reports personal fees from Roche, Sun Pharma, Bristol Myers Squibb, Merck Sharp & Dohme, Merck, Novartis, Pierre Fabre, Kyowa Kirin, Almiral Hermal, and Biontech. ZE reports advisory board fees from Regeneron Pharmaceuticals, Novartis, Array, Genentech, and SunPharma; and grants from Novartis. RG reports documentation fees to institution from Regeneron Pharmaceuticals; personal fees and non-financial support from Amgen, Bristol Myers Squibb, Roche Pharma, Merck Serono, Pierre Fabre, Sanofi, and Regeneron Pharmaceuticals; grants, personal fees, and non-financial support from Novartis; grants and personal fees from Pfizer; grants from Johnson & Johnson; and personal fees from Merck Sharp & Dohme, Almirall Hermal, SUN Pharma, 4SC, and Bayer. JU reports grants and personal fees from Sanofi, Bristol Myers Squibb, Novartis, and Merck Sharp & Dohme; and personal fees from Roche, medac, and Sun Pharma. SPu reports personal fees and non-financial support from Sanofi; other (clinical trials) from Regeneron Pharmaceuticals; grants from Avene; non-financial support from Abbie; grants, personal fees, and non-financial support from ISDIN, La Roche-Posay, and Roche; grants and personal fees from Sun Pharma; non-financial support from Eli Lilly and Merck Sharp & Dohme; personal fees, non-financial support, and other (related to clinical trials) from Pfizer; grants, personal fees, and other from Leo Pharma and Almirall; personal fees and other (related to clinical trials) from Ojer Pharma; personal fees from Pierre Fabre; and non-financial support from MAVIG, FotoFinder, and 3Gen. GDY is an employee of, shareholder in, and a member of the Board of Directors at Regeneron Pharmaceuticals. GT is an employee of, patent holder, and shareholder of Regeneron Pharmaceuticals. IL and MGF are employees of, have patents pending, and are shareholders of Regeneron Pharmaceuticals. SPr, MK, NB-S, AFO, IB, and VDG declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: This study outlined cemiplimab intravenous (IV) dosing strategy to move from body weight (BW)-based 3 mg/kg every-2-week (Q2W) dosing in first-in-human study (study 1423; NCT02383212) to fixed 350 mg every-3-week (Q3W) dosing, utilizing population pharmacokinetics (PopPK) modeling and simulations, and supported by a limited dataset from a phase 2 study (study 1540; NCT02760498)., Methods: Cemiplimab concentration data from a total of 505 patients were pooled from study 1423 in advanced malignancies and study 1540 in advanced cutaneous squamous cell carcinoma (CSCC). All patients received weight-based cemiplimab dose (1, 3, 10 mg/kg Q2W or 3 mg/kg Q3W) except 4% who received 200 mg Q2W. A linear two-compartment PopPK model incorporating covariates that improved goodness-of-fit statistics was developed to compare cemiplimab exposure at 350 mg Q3W versus 3 mg/kg Q2W. Upon availability, observed cemiplimab concentration at 350 mg Q3W in study 1540 was then compared with the simulated values., Results: Post hoc estimates of cemiplimab exposure and variability (505 patients; weight range 30.9-156 kg; median 76.1 kg) at steady state were found to be similar at 350 mg Q3W and 3 mg/kg Q2W. Effect of BW on cemiplimab exposure was described by exposure versus BW plots and at extreme BW. Overlay of individual observed cemiplimab concentrations in 51 patients with metastatic CSCC on simulated concentration-time profiles in 2000 patients at 350 mg Q3W confirmed cemiplimab exposure similarity and demonstrated the robustness of dose optimization based on PopPK modeling and simulations., Conclusions: Cemiplimab 350 mg Q3W is being further investigated in multiple indications.

Objectives: Blockade of programmed cell death-1 (PD-1) and its ligand (PD-L1) has transformed the treatment of NSCLC. In a first-in-human, Phase 1, dose escalation and cohort expansion study, cemiplimab, a monoclonal antibody directed against PD-1, was evaluated for the treatment of patients with advanced solid tumors (NCT02383212). Here, we report results in patients with advanced NSCLC from the dose expansion cohort., Materials and Methods: Immune-checkpoint inhibitor naive patients with advanced NSCLC (stage III/IV), irrespective of PD-L1 status, who had progressed after, or were refractory to first- or later-line therapy were enrolled and received cemiplimab 200 mg every 2 weeks intravenously for up to 48 weeks. Primary study objectives were to assess safety and tolerability, and to evaluate clinical activity of cemiplimab., Results: Twenty patients with NSCLC were enrolled. Median age was 64.0 years (range: 50-82); 65.0 % were male; 80.0 % had an ECOG performance status of 1; 60.0 % had a histology of adenocarcinoma. Median number of prior lines of systemic therapy was 2 (range: 1-4). Median duration of follow-up was 7.0 months (range: 1.0-18.2). All patients experienced ≥1 treatment-emergent adverse event (TEAE) of any grade. Most common TEAEs were arthralgia, asthenia, cough, and dyspnea (each 4/20; 20.0 %). Grade ≥3 TEAEs occurred in 60.0 % (12/20) of patients. Of patients with measurable disease per independent central review (ICR), five had partial response (PR), four had stable disease (SD) and 10 had progressive disease. Objective response rate (ORR; complete response + PR) was 25.0 % (95 % CI: 8.7-49.1 %). Duration of response exceeded 8 months in four of the five responding patients at the time of data cut-off (April 30, 2019). The disease control rate per ICR (ORR + SD) was 50.0 % (95 % CI: 27.2-72.8 %)., Conclusion: Cemiplimab showed an acceptable safety profile and demonstrated antitumor activity in pretreated patients with NSCLC., (Copyright © 2021. Published by Elsevier B.V.)

Although radiotherapy has been used for over a century to locally control tumor growth, alone it rarely induces an abscopal response or systemic antitumor immunity capable of inhibiting distal tumors outside of the irradiation field. Results from recent studies suggest that combining immune checkpoint blockades to radiotherapy may enhance abscopal activity. However, the treatment conditions and underlying immune mechanisms that consistently drive an abscopal response during radiation therapy combinations remain unknown. Here, we analyzed the antitumor responses at primary and distal tumor sites, demonstrating that the timing of αPD-1 antibody administration relative to radiotherapy determined the potency of the induced abscopal response. Blockade of the PD-1 pathway after local tumor irradiation resulted in the expansion of polyfunctional intratumoral CD8 + T cells, a decrease in intratumoral dysfunctional CD8 + T cells, expansion of reprogrammable CD8 + T cells, and induction of potent abscopal responses. However, administration of αPD-1 before irradiation almost completely abrogated systemic immunity, which associated with increased radiosensitivity and death of CD8 + T cells. The subsequent reduction of polyfunctional effector CD8 + T cells at the irradiated tumor site generated a suboptimal systemic antitumor response and the loss of abscopal responses. Therefore, this report maximizes the potential synergy between radiotherapy and αPD-1 immunotherapy, information that will benefit clinical combinations of radiotherapy and immune checkpoint blockade., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: We aimed to examine cemiplimab, a programmed cell death 1 inhibitor, in the first-line treatment of advanced non-small-cell lung cancer with programmed cell death ligand 1 (PD-L1) of at least 50%., Methods: In EMPOWER-Lung 1, a multicentre, open-label, global, phase 3 study, eligible patients recruited in 138 clinics from 24 countries (aged ≥18 years with histologically or cytologically confirmed advanced non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0-1; never-smokers were ineligible) were randomly assigned (1:1) to cemiplimab 350 mg every 3 weeks or platinum-doublet chemotherapy. Crossover from chemotherapy to cemiplimab was allowed following disease progression. Primary endpoints were overall survival and progression-free survival per masked independent review committee. Primary endpoints were assessed in the intention-to-treat population and in a prespecified PD-L1 of at least 50% population (per US Food and Drug Administration request to the sponsor), which consisted of patients with PD-L1 of at least 50% per 22C3 assay done according to instructions for use. Adverse events were assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT03088540 and is ongoing., Findings: Between June 27, 2017 and Feb 27, 2020, 710 patients were randomly assigned (intention-to-treat population). In the PD-L1 of at least 50% population, which consisted of 563 patients, median overall survival was not reached (95% CI 17·9-not evaluable) with cemiplimab (n=283) versus 14·2 months (11·2-17·5) with chemotherapy (n=280; hazard ratio [HR] 0·57 [0·42-0·77]; p=0·0002). Median progression-free survival was 8·2 months (6·1-8·8) with cemiplimab versus 5·7 months (4·5-6·2) with chemotherapy (HR 0·54 [0·43-0·68]; p<0·0001). Significant improvements in overall survival and progression-free survival were also observed with cemiplimab in the intention-to-treat population despite a high crossover rate (74%). Grade 3-4 treatment-emergent adverse events occurred in 98 (28%) of 355 patients treated with cemiplimab and 135 (39%) of 342 patients treated with chemotherapy., Interpretation: Cemiplimab monotherapy significantly improved overall survival and progression-free survival compared with chemotherapy in patients with advanced non-small-cell lung cancer with PD-L1 of at least 50%, providing a potential new treatment option for this patient population., Funding: Regeneron Pharmaceuticals and Sanofi., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: To characterize the safety, tolerability, and anti-tumor activity of cemiplimab as monotherapy or in combination with hypofractionated radiation therapy (hfRT) in patients with recurrent or metastatic cervical cancer. To determine the association between histology and programmed death-ligand 1 (PD-L1) expression., Methods: In non-randomized phase I expansion cohorts, patients (squamous or non-squamous histology) received cemiplimab 3 mg/kg intravenously every 2 weeks for 48 weeks, either alone (monotherapy cohort) or with hfRT during week 2 (combination cohort). Due to insufficient tissue material, PD-L1 protein expression was evaluated in commercially purchased samples and mRNA expression levels were analyzed from The Cancer Genome Atlas (TCGA)., Results: Twenty patients enrolled in both cohorts in total; 10 had squamous histology. The most common adverse events of any grade were diarrhea, fatigue, and hypokalemia, occurring in 35%, 25%, and 25%, respectively. Objective response rate was 10% in each cohort; responders had squamous histology. Duration of response was 11.2 months and 6.4 months for the responder in the monotherapy and combination cohort, respectively. Irradiated lesions were not included in the response assessments. In separate archived specimens (N = 155), PD-L1 protein expression in tumor and immune cells was negative (<1%) more commonly in adenocarcinoma than in squamous tumors. PD-L1 mRNA levels were lower in adenocarcinoma than squamous cell tumors (1.2 vs 5.0 mean transcripts per million, respectively) in TCGA., Conclusions: Cemiplimab has activity in cervical squamous cell carcinoma. The phase I results, combined with results from other anti-PD-1 trials in cervical cancer and our biomarker analyses have informed the design of the ongoing phase III trial, with the primary overall survival hierarchical analyses being done first in patients with squamous histology., Competing Interests: Declaration of Competing Interest DR has received institutional clinical trial funding from Genentech and Kura Oncology; institutional clinical trial funding and uncompensated scientific committee and advisory board support from Regeneron Pharmaceuticals, Inc., Bristol Myers-Squibb, and GSK; and institutional clinical trial funding, uncompensated scientific committee, advisory board, and travel support from Merck. AGM has received consulting, advisory, speakers' bureau, and travel accommodation expenses from AstraZeneca, GSK-Tesaro, Clovis, Roche, Pharmamar, Genmab, MSD, Oncoinvent, Pfizer-Merck, Amgen, and Immunogen; and personal fees from Sotio. IB reports research funding and personal fees from AstraZeneca, Bristol-Myers Squibb, Merck Serono, MSD, Orion Pharma, Rakuten Aspyrian, Roche; research funding from Celgene, GlaxoSmithKline, Incyte, Janssen, Kura, Novartis, Pfizer, Shattuck Lab, VCN Biosciences. JYH is a consultant and receives fees from Foundation Medicine, Massive Bio, Inc., and Atheneum Consulting. DC has received consulting fees from Pfizer, Nectar, Torque, and Puretech. GF reports advisory roles to Fujifilm, EMD Serono and has received travel expenses from Bristol-Myers Squibb, EMD Serono, Fujifilm, Millennium, and Sarah Cannon Research Institute; speakers bureau expenses from Total Health Conferencing, royalties from Wolters Kluwer; and research funding to his institution from 3-V Biosciences, Abbisko, Abbvie, ADC Therapeutics, Aileron, American Society of Clinical Oncology, Amgen, ARMO, AstraZeneca, BeiGene, Bioatla, Biothera, Celldex, Celgene, Ciclomed, Curegenix, Curis, Cyteir, Daiichi, DelMar, eFFECTOR, Eli Lilly, EMD Serono, Epizyme, Exelixis, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, Ignyta, Incyte, Jacobio, Jounce, Kolltan, Loxo, MedImmune, Millennium, Merck, miRNA Therapeutics, National Institutes of Health, Novartis, OncoMed, Oncothyreon, Precision Oncology, Prelude, Regeneron, Rgenix, Ribon, Strategia, Syndax, Taiho, Takeda, Tarveda, Tesaro, Tocagen, Turning Point Therapeutics, U.T. MD Anderson Cancer Center, Vegenics, and Xencor. SJ reports grants, personal fees and non-financial support from Merck, grants from Nestle, outside the submitted work. KM reports institutional consultancy (honorarium and ad board) fees from Abbvie, Aravive, AstraZeneca, Eisai, Janssen, OncoMed, Pfizer, Samumed, Vavotar, VBL Therapeutics, Tarveda; institutional funding and personal fees from Clovis, Eli Lilly, Genentech Roche, Immunogen, and Tesaro. AN reports research funding from Eli Lily, Karyopharm Therapeutics, Incyte, Regeneron Pharmaceuticals, Inc., Merck, Bristol-Myers Squibb, Pfizer, Neon Therapeutics, Calithera Biosciences, TopAlliance BiosciencesPsiOxus, Arcus; research funding and advisory board roles with Novartis, CytomX Therapeutics, Kymab; advisory board role with Genome; research funding to spouse from Immune Deficiency Foundation. MGM and SF declare no conflict of interest. KPP has received institutional research funding (START) from Abbvie, MedImmune, Peleton Therapeutics, Regeneron Pharmaceuticals, Inc., Sanofi, ARMO BioSciences, ArQule, Amgen, Calithera Biosciences, Incyte, Merck, Jounce, ADC Therapeutics, 3D Medicines, EMD Serono, Syros Pharmaceuticals, Mersana, OncoMed, MabSpace Biosciences, Bayer, Basilia; advisory board roles with ArQule, Bayer, and Basilia. JB is a stockholder in Loxo Oncology, Forty-Seven, MorphoSys AG, and Zymeworks. MF, ES, JL, and S-YY are employees and shareholders of Regeneron Pharmaceuticals, Inc. MGF, IL, MM, NAY-D, and WF are employees of, patent holders (pending approval), and shareholders in Regeneron Pharmaceuticals, Inc., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Prior studies of conventional chemotherapy or epidermal growth factor receptor inhibitors for advanced (ie, locally advanced cutaneous squamous cell carcinoma [laCSCC] or metastatic [mCSCC]) cutaneous squamous cell cancer enrolled ≤ 40 patients. This retrospective, observational study assessed real-world treatment patterns and clinical outcomes in patients with unresectable laCSCC or mCSCC using electronic health records of patients who initiated first-line (1L) systemic treatment from 1 January 2008 to 31 December 2015, with follow-up to 30 September 2017. The median duration of follow-up from 1L treatment was 10.1 months (range 0.03-67.6 months). Duration of therapy (DOT) and overall survival (OS) were assessed using Kaplan-Meier analysis. Response rate was calculated as the proportion of patients who achieved physician-assessed-response. Eighty-two patients were identified (17 laCSCC and 65 mCSCC). Median age at 1L treatment initiation was 75 years; 85% were male, 88% had an Eastern Cooperative Oncology Group performance status of 1, and 84% had received radiotherapy. The most common 1L regimens were carboplatin + paclitaxel (27%) and cetuximab monotherapy (24%). The median 1L DOT was 4.1 months for laCSCC and 2.3 months for mCSCC. The physician-assessed response rate for 1L therapy was 17.6% for laCSCC, and 18.5% for mCSCC. The median OS from 1L treatment initiation was 16.2 months for laCSCC, and 15.3 months for mCSCC. Only 24 patients (29%) received second-line therapy. This is the largest retrospective data set regarding patients with advanced CSCC treated with anticancer systemic therapy prior to approval of the anti-programmed cell death-1 antibody, cemiplimab. Efficacy was low in both laCSCC and mCSCC. These data provide historic benchmarks for outcomes in patients with advanced CSCC prior to Food and Drug Administration approval of cemiplimab-rwlc., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Monoclonal antibodies that block the programmed cell death 1 (PD-1) checkpoint have revolutionized cancer immunotherapy. However, many major tumor types remain unresponsive to anti-PD-1 therapy, and even among responsive tumor types, most of the patients do not develop durable antitumor immunity. It has been shown that bispecific antibodies activate T cells by cross-linking the TCR/CD3 complex with a tumor-specific antigen (TSA). The class of TSAxCD3 bispecific antibodies have generated exciting results in early clinical trials. We have recently described another class of "costimulatory bispecifics" that cross-link a TSA to CD28 (TSAxCD28) and cooperate with TSAxCD3 bispecifics. Here, we demonstrate that these TSAxCD28 bispecifics (one specific for prostate cancer and the other for epithelial tumors) can also synergize with the broader anti-PD-1 approach and endow responsiveness-as well as long-term immune memory-against tumors that otherwise do not respond to anti-PD-1 alone. Unlike CD28 superagonists, which broadly activate T cells and induce cytokine storm, TSAxCD28 bispecifics display little or no toxicity when used alone or in combination with a PD-1 blocker in genetically humanized immunocompetent mouse models or in primates and thus may provide a well-tolerated and "off the shelf" combination approach with PD-1 immunotherapy that can markedly enhance antitumor efficacy., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Cemiplimab, a high-affinity, potent human immunoglobulin G4 monoclonal antibody to programmed cell death-1 demonstrated antitumor activity in a Phase 1 advanced cutaneous squamous cell carcinoma (CSCC) expansion cohort (NCT02383212) and the pivotal Phase 2 study (NCT02760498). Here we report the primary analysis of fixed dose cemiplimab 350 mg intravenously every 3 weeks (Q3W) (Group 3) and provide a longer-term update after the primary analysis of weight-based cemiplimab 3 mg/kg intravenously every 2 weeks (Q2W) (Group 1) among metastatic CSCC (mCSCC) patients in the pivotal study (NCT02760498)., Methods: The primary objective for each group was objective response rate (ORR) per independent central review (ICR). Secondary endpoints included ORR by investigator review (INV), duration of response (DOR) per ICR and INV, and safety and tolerability., Results: For Group 3 (n=56) and Group 1 (n=59), median follow-up was 8.1 (range, 0.6 to 14.1) and 16.5 (range, 1.1 to 26.6) months, respectively. ORR per ICR was 41.1% (95% CI, 28.1% to 55.0%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 45.2% (95% CI, 35.9% to 54.8%) in both groups combined. Per ICR, Kaplan-Meier estimate for DOR at 8 months was 95.0% (95% CI, 69.5% to 99. 3%) in responding patients in Group 3, and at 12 months was 88.9% (95% CI, 69.3% to 96.3%) in responding patients in Group 1. Per INV, ORR was 51.8% (95% CI, 38.0% to 65.3%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 50.4% (95% CI, 41.0% to 59.9%) in both groups combined. Overall, the most common adverse events regardless of attribution were fatigue (27.0%) and diarrhea (23.5%)., Conclusion: In patients with mCSCC, cemiplimab 350 mg intravenously Q3W produced substantial antitumor activity with durable response and an acceptable safety profile. Follow-up data of cemiplimab 3 mg/kg intravenously Q2W demonstrate ongoing durability of responses., Trial Registration Number: Clinicaltrials.gov, NCT02760498. Registered May 3, 2016, https://clinicaltrials.gov/ct2/show/NCT02760498., Competing Interests: Competing interests: DR: institutional research grant and funding from Regeneron Pharmaceuticals, Inc., Sanofi, Roche, Merck Sharp & Dohme, Bristol-Myers Squibb, and GlaxoSmithKline; uncompensated scientific committee and advisory board from Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc., Sanofi, GlaxoSmithKline, and Bristol-Myers Squibb; travel and accommodation from Merck Sharp & Dohme and GlaxoSmithKline. MRM: honoraria and travel expenses from Regeneron Pharmaceuticals, Inc., Sanofi, Novartis, Genentech, Eli Lilly, and Sun Pharma; and institutional research funding from Regeneron Pharmaceuticals, Inc., Novartis, Genentech, and Eli Lilly. AML: uncompensated advisory board from Merck Sharp & Dohme and Bristol-Myers Squibb with travel and accommodation expenses. CDS: steering committee member for Castle Biosciences; a steering committee member and consultant for Regeneron Pharmaceuticals, Inc.; a consultant for Sanofi; has received research funding from Castle Biosciences, Regeneron Pharmaceuticals, Inc., Novartis, Genentech, and Merck, and is a chair for the National Comprehensive Cancer Network. NIK: grants from Regeneron Pharmaceuticals, Inc.; grants and advisory board fees from Bristol-Myers Squibb and HUYA Bioscience International; advisory board fees from EMD Serono, Regeneron Pharmaceuticals, Inc., Genentech, AstraZeneca (data safety monitoring committee), Merck, Array BioPharma, and Immunocore; grants from Merck, Novartis, GlaxoSmithKline, Celgene, and Amgen; honorarium from Sanofi; and common stock ownership of Bellicum Pharmaceuticals, Mazor Robotics, Amarin, and TransEnterix. BGMH: consulting or advisory roles at Merck Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, Pfizer, Roche, Eisai, Merck, and institutional research funding from Amgen. DS: institutional patients’ fees from Regeneron Pharmaceuticals, Inc.; advisory board honorarium fees from Amgen and Leo Pharma; speaker fee from Boehringer Ingelheim; advisory board, speaker honorarium and patients’ fees from Roche, Novartis, Bristol-Myers Squibb, and Merck-EMD; advisory board and speaker honorarium fees from Incyte and Pierre Fabre; advisory board honorarium and patients’ fees from Merck Sharp & Dohme, steering committee honorarium fees from 4SC, advisory board fees from AstraZeneca, Pfizer, and Array; and advisory board and patients’ fees from Philiogen. LAD: advisory role at Regeneron Pharmaceuticals, Inc., and research funding from Eisai, Pfizer, Regeneron Pharmaceuticals, Inc. LH-A: performed consulting and advisory roles at Massive Bio; speakers’ bureau roles at Sanofi and Regeneron Pharmaceuticals, Inc., and received travel, accommodations, and expenses from Regeneron Pharmaceuticals, Inc., Sanofi, and Bristol-Myers Squibb, and research funding from Bristol-Myers Squibb, Regeneron Pharmaceuticals, Inc., Immunocore, Merck Sharp & Dohme, Polynoma, Corvus Pharmaceuticals, Roche, Merck Serono, Amgen, MedImmune, and Takeda. ALSC: consulting and advisory roles at Regeneron Pharmaceuticals, Inc., Merck; research funding from Regeneron Pharmaceuticals, Inc., Novartis, Galderma, and Merck. BM: speaker’s honoraria, travel, accommodations and expenses from Regeneron Pharmaceuticals, Inc. and Sanofi. AH: institutional grants, speaker’s honoraria, and consultancy fees from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme/Merck, Pierre Fabre, Provectus, Roche, and Novartis; institutional grants and consultancy fees from Merck Serono, Philogen, and Regeneron Pharmaceuticals, Inc.; and consultancy fees from OncoSec. CU: honoraria, consulting, or advisory roles, speaker’s bureau role, research funding and travel, accommodation, and expenses from Novartis, Sanofi, Galderma, and Almirall. TE: consulting or advisory roles at Sanofi Genzyme, Bristol-Myers Squibb, Roche, Novartis and Merck Sharp & Dohme; speakers’ bureau role at Roche and Merck Sharp & Dohme and research funding from Novartis and Bristol-Myers Squibb. BS: consulting or advisory roles at Merck Sharp & Dohme and Merck KGaA Australia. ACP: honoraria and consulting or advisory roles at Bristol-Myers Squibb, Merck, Regeneron Pharmaceuticals, Inc., Array, Novartis, Seattle Genetics, Amgen; research funding from Bristol-Myers Squibb, Merck, Regeneron Pharmaceuticals, Inc., Celldex, and Forance and travel, accommodation, expenses from Regeneron Pharmaceuticals, Inc., Array, and Seattle Genetics. JLG: research institution support for the study from and advisory board for Regeneron Pharmaceuticals, Inc. RG: honoraria from Almirall Hermal GmbH, Amgen, AstraZeneca, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron Pharmaceuticals, Inc., Roche/Genentech, Sanofi, and Sun Pharma; consulting or advisory role for 4SC, Almirall Hermal GmbH, Amgen, Bristol-Myers Squibb, Incyte, LEO Pharma, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche/Genentech, Sun Pharma, and Takeda; research funding from Amgen, Johnson & Johnson, Novartis, and Pfizer; travel, accommodations, expenses from Bristol-Myers Squibb, Merck Sorono, Pierre Fabre, and Roche. MA: consulting or advisory roles for Pulse Biosciences and Revance Therapeutics. EO, MM, VJ, ES, JB, SL, IL, MGF: employees and shareholders of Regeneron Pharmaceuticals, Inc. AG: personal fees and non-financial support (advisory board and travel support) from Bristol-Myers Squibb and Sun Pharma; personal fees (advisory board) from Merck KGaA, Eisai, and Pfizer; non-financial (travel) support from Astellas; and clinical trial unit support from PPD Australia., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: This first-in-human study assessed the safety, tolerability, dose-limiting toxicities (DLT), antitumor activity, and pharmacokinetics of cemiplimab, a monoclonal anti-programmed cell death-1 (PD-1), as monotherapy and in combination with hypofractionated radiotherapy (hfRT) and/or cyclophosphamide (CPA) in patients with advanced solid tumors., Patients and Methods: Patients were enrolled in 1 of 10 dose escalation cohorts and received cemiplimab 1, 3, or 10 mg/kg every 2 weeks intravenously for up to 48 weeks. Depending on the cohort, patients received hfRT and/or low-dose (200 mg/m 2 ) CPA. Safety was evaluated. Antitumor activity was assessed by Response Evaluation Criteria in Solid Tumors version 1.1., Results: Sixty patients were enrolled. The median duration of follow-up was 19.3 weeks (range, 2.3-84.3). There were no DLTs. The most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (45.0%), nausea (36.7%), and vomiting (25.0%). The most common immune-related adverse events (irAEs) of any grade were arthralgia (10.0%), hypothyroidism (8.3%), and maculopapular rash (8.3%). Cemiplimab pharmacokinetic parameters increased in a close to dose-proportional manner and were similar regardless of combination therapy regimen. Two patients (one with cutaneous squamous cell carcinoma and one with cervical cancer) experienced a complete response; 7 had a partial response. Observed duration of response was ≥12 months in 6 patients., Conclusions: The safety profile of cemiplimab was comparable with other anti-PD-1 agents. Addition of hfRT and/or CPA did not appear to increase grade ≥3 irAEs, suggesting that cemiplimab can be safely administered with hfRT and/or CPA. Cemiplimab exhibited encouraging antitumor activity with 2 complete responses and 7 partial responses observed; responses were also durable., (©2019 American Association for Cancer Research.)

The third multistakeholder Paediatric Strategy Forum organised by ACCELERATE and the European Medicines Agency focused on immune checkpoint inhibitors for use in combination therapy in children and adolescents. As immune checkpoint inhibitors, both as monotherapy and in combinations have shown impressive success in some adult malignancies and early phase trials in children of single agent checkpoint inhibitors have now been completed, it seemed an appropriate time to consider opportunities for paediatric studies of checkpoint inhibitors used in combination. Among paediatric patients, early clinical studies of checkpoint inhibitors used as monotherapy have demonstrated a high rate of activity, including complete responses, in Hodgkin lymphoma and hypermutant paediatric tumours. Activity has been very limited, however, in more common malignancies of childhood and adolescence. Furthermore, apart from tumour mutational burden, no other predictive biomarker for monotherapy activity in paediatric tumours has been identified. Based on these observations, there is collective agreement that there is no scientific rationale for children to be enrolled in new monotherapy trials of additional checkpoint inhibitors with the same mechanism of action of agents already studied (e.g. anti-PD1, anti-PDL1 anti-CTLA-4) unless additional scientific knowledge supporting a different approach becomes available. This shared perspective, based on scientific evidence and supported by paediatric oncology cooperative groups, should inform companies on whether a paediatric development plan is justified. This could then be proposed to regulators through the available regulatory tools. Generally, an academic-industry consensus on the scientific merits of a proposal before submission of a paediatric investigational plan would be of great benefit to determine which studies have the highest probability of generating new insights. There is already a rationale for the evaluation of combinations of checkpoint inhibitors with other agents in paediatric Hodgkin lymphoma and hypermutated tumours in view of the activity shown as single agents. In paediatric tumours where no single agent activity has been observed in multiple clinical trials of anti-PD1, anti-PDL1 and anti-CTLA-4 agents as monotherapy, combinations of checkpoint inhibitors with other treatment modalities should be explored when a scientific rationale indicates that they could be efficacious in paediatric cancers and not because these combinations are being evaluated in adults. Immunotherapy in the form of engineered proteins (e.g. monoclonal antibodies and T cell engaging agents) and cellular products (e.g. CAR T cells) has great therapeutic potential for benefit in paediatric cancer. The major challenge for developing checkpoint inhibitors for paediatric cancers is the lack of neoantigens (based on mutations) and corresponding antigen-specific T cells. Progress critically depends on understanding the immune macroenvironment and microenvironment and the ability of the adaptive immune system to recognise paediatric cancers in the absence of high neoantigen burden. Future clinical studies of checkpoint inhibitors in children need to build upon strong biological hypotheses that take into account the distinctive immunobiology of childhood cancers in comparison to that of checkpoint inhibitor responsive adult cancers., Competing Interests: Conflict of interest J.A. is medical and scientific director for TC Biopharm and holds stock and share options in TC Biopharm and Autolus Ltd; M.B. is an employee of Merck Group; CB. is an employee of Tesaro; EB. is an employee of Pfizer; R.C. is an employee of Novartis; H.C. is an employee of Roche; S.J.D. is an employee of Merck & Co; M.E. is an employee of Boehringer-Ingelheimm Pharma GmbH; B.G. attended at a Roche sponsored advisory board for atezolizumab; R.I. is an employee of Celgene; M.K. is an employee and owns stock in Bristol-Myers Squibb; I.L. is an employee of Regeneron; L.V.M. has participated in advisory boards for AstraZeneca, Merck, Tesaro, Bayer and Celgene; M.M. is an employee of Syndax Pharmaceuticals; C.O. is an employee of Sanofi; A.D.J.P. has participated in advisory boards for Novartis, Taked, Merck, Lilly and Celgene; V.G.R.P. is an employee and shareholder of Autolus Ltd; C.R. attended advisory boards for Amgen, Celgen, EUSA Pharma, Genentch, Novartis and Roche, speaker honaria for Bristol Myers Squibb, Pfizer and Roche; P.K.S. is an employee of AstraZeneka; P.S. is an employee of Immunicum AB; C.v.T. participated in advisory boards for Novartis and Bayer; T.Y. is an employee of Beigene., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Cemiplimab has shown substantial antitumour activity in patients with metastatic cutaneous squamous cell carcinoma. Patients with locally advanced cutaneous squamous cell carcinoma have poor prognosis with conventional systemic therapy. We present a primary analysis of the safety and antitumour activity of cemiplimab in patients with locally advanced cutaneous squamous cell carcinoma., Methods: This pivotal open-label, phase 2, single-arm trial was done across 25 outpatient clinics, primarily at academic medical centres, in Australia, Germany, and the USA. Eligible patients (aged ≥18 years with histologically confirmed locally advanced cutaneous squamous cell carcinoma and an Eastern Cooperative Oncology Group performance status of 0-1) received cemiplimab 3 mg/kg intravenously over 30 min every 2 weeks for up to 96 weeks. Tumour measurements were done every 8 weeks. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response, according to independent central review as per Response Evaluation Criteria in Solid Tumors version 1.1 for radiological scans and WHO criteria for medical photography. Data cutoff was Oct 10, 2018, when the fully enrolled cohort reached the prespecified timepoint for the primary analysis. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. This study is registered with ClinicalTrials.gov, number NCT02760498., Findings: Between June 14, 2016, and April 25, 2018, 78 patients were enrolled and treated with cemiplimab. The median duration of study follow-up was 9·3 months (IQR 5·1-15·7) at the time of data cutoff. An objective response was observed in 34 (44%; 95% CI 32-55) of 78 patients. The best overall response was ten (13%) patients with a complete response and 24 (31%) with a partial response. Grade 3-4 treatment-emergent adverse events occurred in 34 (44%) of 78 patients; the most common were hypertension in six (8%) patients and pneumonia in four (5%). Serious treatment-emergent adverse events occurred in 23 (29%) of 78 patients. One treatment-related death was reported that occurred after onset of aspiration pneumonia., Interpretation: Cemiplimab showed antitumour activity and an acceptable safety profile in patients with locally advanced cutaneous squamous cell carcinoma for whom there was no widely accepted standard of care., Funding: Regeneron Pharmaceuticals and Sanofi., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Successful combinations of radiotherapy and immunotherapy depend on the presence of live T cells within the tumor; however, radiotherapy is believed to damage T cells. Here, based on longitudinal in vivo imaging and functional analysis, we report that a large proportion of T cells survive clinically relevant doses of radiation and show increased motility, and higher production of interferon gamma, compared with T cells from unirradiated tumors. Irradiated intratumoral T cells can mediate tumor control without newly-infiltrating T cells. Transcriptomic analysis suggests T cell reprogramming in the tumor microenvironment and similarities with tissue-resident memory T cells, which are more radio-resistant than circulating/lymphoid tissue T cells. TGFβ is a key upstream regulator of T cell reprogramming and contributes to intratumoral Tcell radio-resistance. These findings have implications for the design of radio-immunotherapy trials in that local irradiation is not inherently immunosuppressive, and irradiation of multiple tumors might optimize systemic effects of radiotherapy.

Background: No systemic therapies have been approved for the treatment of advanced cutaneous squamous-cell carcinoma. This cancer may be responsive to immune therapy, because the mutation burden of the tumor is high and the disease risk is strongly associated with immunosuppression. In the dose-escalation portion of the phase 1 study of cemiplimab, a deep and durable response was observed in a patient with metastatic cutaneous squamous-cell carcinoma., Methods: We report the results of the phase 1 study of cemiplimab for expansion cohorts of patients with locally advanced or metastatic cutaneous squamous-cell carcinoma, as well as the results of the pivotal phase 2 study for a cohort of patients with metastatic disease (metastatic-disease cohort). In both studies, the patients received an intravenous dose of cemiplimab (3 mg per kilogram of body weight) every 2 weeks and were assessed for a response every 8 weeks. In the phase 2 study, the primary end point was the response rate, as assessed by independent central review., Results: In the expansion cohorts of the phase 1 study, a response to cemiplimab was observed in 13 of 26 patients (50%; 95% confidence interval [CI], 30 to 70). In the metastatic-disease cohort of the phase 2 study, a response was observed in 28 of 59 patients (47%; 95% CI, 34 to 61). The median follow-up was 7.9 months in the metastatic-disease cohort of the phase 2 study. Among the 28 patients who had a response, the duration of response exceeded 6 months in 57%, and 82% continued to have a response and to receive cemiplimab at the time of data cutoff. Adverse events that occurred in at least 15% of the patients in the metastatic-disease cohort of the phase 2 study were diarrhea, fatigue, nausea, constipation, and rash; 7% of the patients discontinued treatment because of an adverse event., Conclusions: Among patients with advanced cutaneous squamous-cell carcinoma, cemiplimab induced a response in approximately half the patients and was associated with adverse events that usually occur with immune checkpoint inhibitors. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT02383212 and NCT02760498 .).

Expression of cytotoxic T-lymphocyte antigen 4 (CTLA-4), a negative regulator of T-cell function, is increased in chronic HIV-1 infection. It was hypothesized that CTLA-4 blockade may enhance immune response to HIV-1 and result in better control of viremia. This open-label, multiple ascending dose study (NCT03407105)-the first to examine ipilimumab in participants with HIV-1 infection-assessed the safety, tolerability, and pharmacokinetics of ipilimumab, as well as whether ipilimumab enhanced immune response to HIV-1 and improved control of viremia. Twenty-four participants received 2 or 4 doses of ipilimumab (0.1, 1, 3, or 5 mg/kg) every 28 days. No serious adverse events (AEs) or dose-limiting toxicities were reported; one participant discontinued ipilimumab for an AE of grade 2 facial palsy. Twenty participants (83.3%) had ≥1 AE; all but 1 were grade 1 or 2. Eight participants (33.3%) had potentially immune-related AEs (7 had grade 1 diarrhea not requiring corticosteroids; 1 who had diarrhea also had transient antinuclear antibody positivity; 1 had grade 2 facial palsy requiring corticosteroids). Two participants (8.3%), one each in the 0.1- and 1-mg/kg dose groups, had a decrease from baseline HIV-1 RNA of 0.85 and 1.36 log10 copies/mL. Fourteen participants (58.3%) had an increase from baseline HIV-1 RNA (mean, 0.87 log10 copies/mL; range, 0.59-1.29). Of these 14 participants, all but 1 were in the higher ipilimumab dose groups (3 or 5 mg/kg). No pattern was noted regarding change from baseline in CD4 or CD8 T cells; ex vivo assessments of immune response were precluded because of inadequate cell viability. Serum concentration data for ipilimumab showed biphasic disposition, with steady state reached by dose 3. Ipilimumab treatment was well tolerated and was associated with variations in HIV-1 RNA in excess of expected repeat measures in most participants, but these were not related to combination antiretroviral therapy status or CD4 counts. The mechanism(s) underlying the increased variation in HIV-1 RNA is unclear and needs further study., Competing Interests: E.C. is a full-time employee and shareholder of Bristol-Myers Squibb. D. Grasela is a full-time employee and shareholder of Bristol-Myers Squibb. D. Gardiner is a full-time employee and shareholder of GlaxoSmithKline. R.P.B has no competing interests. B.V. is a full-time employee of Bristol-Myers Squibb. A.J.K. is a full-time employee of Bristol-Myers Squibb. I.L. is a stockholder of Bristol-Myers Squibb, which markets ipilimumab for cancer indications The authors confirm that the above disclosures do not alter our adherence to all PLOS ONE policies on sharing data and materials.

Autoimmune encephalitis is an uncommon complication of immune checkpoint inhibitor therapy. This article reports a case of fatal anti-Hu-associated autoimmune limbic encephalitis presenting within 8 weeks following anti-PD1 therapy in a patient with myxoid chondrosarcoma and pre-existing anti-Hu antibodies. Although tumor reduction occurred in response to PD-1 inhibitor therapy, the patient had a rapidly progressive decline in neurologic function despite initial stabilization with immunosuppression. Considering the increasing use of immune checkpoint inhibitors for the treatment of various malignancies, an increase in the occurrence of neurologic adverse events is likely, requiring prompt intervention and enhanced pharmacovigilance in malignancies associated with onconeuronal antibodies., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2017.)

The Programmed Death-1 (PD-1) receptor delivers inhibitory checkpoint signals to activated T cells upon binding to its ligands PD-L1 and PD-L2 expressed on antigen-presenting cells and cancer cells, resulting in suppression of T-cell effector function and tumor immune evasion. Clinical antibodies blocking the interaction between PD-1 and PD-L1 restore the cytotoxic function of tumor antigen-specific T cells, yielding durable objective responses in multiple cancers. This report describes the preclinical characterization of REGN2810, a fully human hinge-stabilized IgG4(S228P) high-affinity anti-PD-1 antibody that potently blocks PD-1 interactions with PD-L1 and PD-L2. REGN2810 was characterized in a series of binding, blocking, and functional cell-based assays, and preclinical in vivo studies in mice and monkeys. In cell-based assays, REGN2810 reverses PD-1-dependent attenuation of T-cell receptor signaling in engineered T cells and enhances responses of human primary T cells. To test the in vivo activity of REGN2810, which does not cross-react with murine PD-1, knock-in mice were generated to express a hybrid protein containing the extracellular domain of human PD-1, and transmembrane and intracellular domains of mouse PD-1. In these mice, REGN2810 binds the humanized PD-1 receptor and inhibits growth of MC38 murine tumors. As REGN2810 binds to cynomolgus monkey PD-1 with high affinity, pharmacokinetic and toxicologic assessment of REGN2810 was performed in cynomolgus monkeys. High doses of REGN2810 were well tolerated, without adverse immune-related effects. These preclinical studies validate REGN2810 as a potent and promising candidate for cancer immunotherapy. Mol Cancer Ther; 16(5); 861-70. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (CSCC) share exposure to UV light as the dominant risk factor, and these tumors therefore harbor high mutation burdens. In other malignancies, high mutation burden has been associated with clinical benefit from therapy with antibodies directed against the Programmed Death 1 (PD-1) immune checkpoint receptor. Highly mutated tumors are more likely to express immunogenic tumor neoantigens that attract effector T cells, which can be unleashed by blockade of the PD-1 immune checkpoint., Case Presentations: This report describes a patient with metastatic BCC and a patient with metastatic CSCC who were treated with REGN2810, a fully human anti-PD-1 monoclonal antibody, in an ongoing phase 1 trial (NCT02383212). The CSCC patient has experienced an ongoing complete response (16+ months), and the BCC patient has experienced an ongoing partial response (12+ months)., Conclusions: These case reports suggest that UV-associated skin cancers, beyond melanoma, are sensitive to PD-1 blockade., Trial Registration: Clinicaltrials.gov NCT02383212. Registered 2 February 2015.

Anti-VEGF therapies benefit several cancer types, but drug resistance that limits therapeutic response can emerge. We generated cell lines from anti-VEGF-resistant tumor xenografts to investigate the mechanisms by which resistance develops. Of all tumor cells tested, only A431 (A431-V) epidermoid carcinoma cells developed partial resistance to the VEGF inhibitor aflibercept. Compared with the parental tumors, A431-V tumors secreted greater amounts of IL6 and exhibited higher levels of phospho-STAT3. Notably, combined blockade of IL6 receptor (IL6R) and VEGF resulted in enhanced activity against A431-V tumors. Similarly, inhibition of IL6R enhanced the antitumor effects of aflibercept in DU145 prostate tumor cells that displays high endogenous IL6R activity. In addition, post hoc stratification of data obtained from a clinical trial investigating aflibercept efficacy in ovarian cancer showed poorer survival in patients with high levels of circulating IL6. These results suggest that the activation of the IL6/STAT3 pathway in tumor cells may provide a survival advantage during anti-VEGF treatment, suggesting its utility as a source of response biomarkers and as a therapeutic target to heighten efficacious results. Cancer Res; 76(8); 2327-39. ©2016 AACR., (©2016 American Association for Cancer Research.)

With the recent FDA approvals of pembrolizumab and nivolumab, and a host of additional immunomodulatory agents entering clinical development each year, the field of cancer immunotherapy is changing rapidly. Strategies that can assist researchers in choosing the most promising drugs and drug combinations to move forward through clinical development are badly needed in order to reduce the likelihood of late-stage clinical trial failures. On October 5, 2014, the Cancer Immunotherapy Consortium of the Cancer Research Institute, a collaborative think tank composed of stakeholders from academia, industry, regulatory agencies, and patient interest groups, met to discuss strategies for de-risking immunotherapy development, with a focus on integrating preclinical and clinical studies, and conducting smarter early-phase trials, particularly for combination therapies. Several recommendations were made, including making better use of clinical data to inform preclinical research, obtaining adequate tissues for biomarker studies, and choosing appropriate clinical trial endpoints to identify promising drug candidates and combinations in nonrandomized early-phase trials., (©2016 American Association for Cancer Research.)

Purpose: Nesvacumab (REGN910) is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that specifically binds and inactivates the Tie2 receptor ligand Ang2 with high affinity, but shows no binding to Ang1. The main objectives of this trial were to determine the safety, tolerability, dose-limiting toxicities (DLT), and recommended phase II dose (RP2D) of nesvacumab., Experimental Design: Nesvacumab was administered intravenously every two weeks with dose escalations from 1 to 20 mg/kg in patients with advanced solid tumors., Results: A total of 47 patients were treated with nesvacumab. No patients in the dose escalation phase experienced DLTs, therefore a maximum tolerated dose (MTD) was not reached. The most common nesvacumab-related adverse events were fatigue (23.4%), peripheral edema (21.3%), decreased appetite, and diarrhea (each 10.6%; all grade ≤ 2). Nesvacumab was characterized by linear kinetics and had a terminal half-life of 6.35 to 9.66 days in a dose-independent manner. Best response by RECIST 1.1 in 43 evaluable patients included 1 partial response (adrenocortical carcinoma) of 24 weeks duration. Two patients with hepatocellular carcinoma had stable disease (SD) > 16 weeks, with tumor regression and >50% decrease in α-fetoprotein. Analyses of putative angiogenesis biomarkers in serum and tumor biopsies were uninformative for treatment duration., Conclusions: Nesvacumab safety profile was acceptable at all dose levels tested. Preliminary antitumor activity was observed in patients with treatment-refractory advanced solid tumors. On the basis of cumulative safety, antitumor activity, pharmacokinetic and pharmacodynamic data, the 20 mg/kg dose was determined to be the RP2D., (©2015 American Association for Cancer Research.)

Background: Cancer-related disturbances in myeloid lineage development, marked by high levels of myeloid-derived suppressor cells (MDSC) and impaired dendritic cell (DC) development, are associated with poor clinical outcome due to immune escape and therapy resistance. Redressing this balance may therefore be of clinical benefit. Here we investigated the effects of combined Prostate GVAX/ipilimumab immunotherapy on myeloid subsets in peripheral blood of castration-resistant prostate cancer (CRPC) patients as well as the putative predictive value of baseline and on-treatment myeloid parameters on clinical outcome., Methods: Patients with CRPC (n = 28) received thirteen intradermal administrations of Prostate GVAX, consisting of two allogeneic GM-CSF-transduced and irradiated prostate cancer cell lines (LN-CaP and PC3) and six infusions of escalating doses of anti-CTLA4/ipilimumab. Frequencies and activation status of peripheral blood DC (PBDC) and MDSC were determined before, during and after treatment by flowcytometric analysis and related to clinical benefit., Results: Significant treatment-induced activation of conventional and plasmacytoid DC subsets (cDC and pDC) was observed, which in the case of BDCA1/CD1c(+) cDC1 and MDC8(+)/6-sulfoLacNAc(+) inflammatory cDC3 was associated with significantly prolonged overall survival (OS), but also with the development of autoimmune-related adverse events. High pre-treatment levels of CD14(+)HLA-DR(-)monocytic MDSC (mMDSC) were associated with reduced OS. Unsupervised clustering of these myeloid biomarkers revealed particular survival advantage in a group of patients with high treatment-induced PBDC activation and low pretreatment frequencies of suppressive mMDSC in conjunction with our previously identified lymphoid biomarker of high pretreatment CD4(+)CTLA4(+) T cell frequencies., Conclusions: Our data demonstrate that DC and MDSC subsets are affected by prostate GVAX/ipilimumab therapy and that myeloid profiling may contribute to the identification of patients with possible clinical benefit of Prostate GVAX/ipilimumab treatment.

Background: In patients with melanoma, ipilimumab (an antibody against cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) prolongs overall survival, and nivolumab (an antibody against the programmed death 1 [PD-1] receptor) produced durable tumor regression in a phase 1 trial. On the basis of their distinct immunologic mechanisms of action and supportive preclinical data, we conducted a phase 1 trial of nivolumab combined with ipilimumab in patients with advanced melanoma., Methods: We administered intravenous doses of nivolumab and ipilimumab in patients every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses (concurrent regimen). The combined treatment was subsequently administered every 12 weeks for up to 8 doses. In a sequenced regimen, patients previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses., Results: A total of 53 patients received concurrent therapy with nivolumab and ipilimumab, and 33 received sequenced treatment. The objective-response rate (according to modified World Health Organization criteria) for all patients in the concurrent-regimen group was 40%. Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease for ≥24 weeks) was observed in 65% of patients. At the maximum doses that were associated with an acceptable level of adverse events (nivolumab at a dose of 1 mg per kilogram of body weight and ipilimumab at a dose of 3 mg per kilogram), 53% of patients had an objective response, all with tumor reduction of 80% or more. Grade 3 or 4 adverse events related to therapy occurred in 53% of patients in the concurrent-regimen group but were qualitatively similar to previous experience with monotherapy and were generally reversible. Among patients in the sequenced-regimen group, 18% had grade 3 or 4 adverse events related to therapy and the objective-response rate was 20%., Conclusions: Concurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy, with rapid and deep tumor regression in a substantial proportion of patients. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; ClinicalTrials.gov number, NCT01024231.).

Unlabelled: Expression of the programmed death 1 (PD-1) receptor and its ligands are implicated in the T cell exhaustion phenotype which contributes to the persistence of several chronic viral infections, including human hepatitis C virus (HCV). The antiviral potential of BMS-936558 (MDX-1106) - a fully human anti-PD-1 monoclonal immunoglobulin-G4 that blocks ligand binding - was explored in a proof-of-concept, placebo-controlled single-ascending-dose study in patients (N = 54) with chronic HCV infection. Interferon-alfa treatment-experienced patients (n = 42) were randomized 5∶1 to receive a single infusion of BMS-936558 (0.03, 0.1, 0.3, 1.0, 3.0 mg/kg [n = 5 each] or 10 mg/kg [n = 10]) or of placebo (n = 7). An additional 12 HCV treatment-naïve patients were randomized to receive 10 mg/kg BMS-936558 (n = 10) or placebo (n = 2). Patients were followed for 85 days post-dose. Five patients who received BMS-936558 (0.1 [n = 1] or 10 mg/kg) and one placebo patient achieved the primary study endpoint of a reduction in HCV RNA ≥0.5 log10 IU/mL on at least 2 consecutive visits; 3 (10 mg/kg) achieved a >4 log10 reduction. Two patients (10 mg/kg) achieved HCV RNA below the lower limit of quantitation (25 IU/mL), one of whom (a prior null-responder) remained RNA-undetectable 1 year post-study. Transient reductions in CD4(+), CD8(+) and CD19(+) cells, including both naïve and memory CD4(+) and CD8(+) subsets, were observed at Day 2 without evidence of immune deficit. No clinically relevant changes in immunoglobulin subsets or treatment-related trends in circulating cytokines were noted. BMS-936558 exhibited dose-related exposure increases, with a half-life of 20-24 days. BMS-936558 was mostly well tolerated. One patient (10 mg/kg) experienced an asymptomatic grade 4 ALT elevation coincident with the onset of a 4-log viral load reduction. Six patients exhibited immune-related adverse events of mild-to-moderate intensity, including two cases of hyperthyroidism consistent with autoimmune thyroiditis. Further investigation of PD-1 pathway blockade in chronic viral disease is warranted., Trial Registration: ClinicalTrials.gov NCT00703469.

Immune checkpoint blockade enhances antitumor responses, but can also lead to severe immune-related adverse events (IRAE). To avoid unnecessary exposure to these potentially hazardous agents, it is important to identify biomarkers that correlate with clinical activity and can be used to select patients that will benefit from immune checkpoint blockade. To understand the consequences of CTLA-4 blockade and identify biomarkers for clinical efficacy and/or survival, an exploratory T cell monitoring study was performed in a phase I/II dose escalation/expansion trial (n = 28) of combined Prostate GVAX/ipilimumab immunotherapy. Phenotypic T cell monitoring in peripheral blood before and after Prostate GVAX/ipilimumab treatment revealed striking differences between patients who benefited from therapy and patients that did not. Treatment-induced rises in absolute lymphocyte counts, CD4(+) T cell differentiation, and CD4(+) and CD8(+) T cell activation were all associated with clinical benefit. Moreover, significantly prolonged overall survival (OS) was observed for patients with high pre-treatment frequencies of CD4(+)CTLA-4(+), CD4(+)PD-1(+), or differentiated (i.e., non-naive) CD8(+) T cells or low pre-treatment frequencies of differentiated CD4(+) or regulatory T cells. Unsupervised clustering of these immune biomarkers revealed cancer-related expression of CTLA-4(+) in CD4(+) T cells to be a dominant predictor for survival after Prostate GVAX/ipilimumab therapy and to thus provide a putative and much-needed biomarker for patient selection prior to therapeutic CTLA4 blockade.