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Objectives: To assess health-related quality of life (HRQoL) with first-line pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) in the phase 3 KEYNOTE-048 trial (NCT02358031).Materials and Methods: HRQoL was measured using the European Organisation for Research and Treatment of Cancer 30-question quality-of-life (EORTC QLQ-C30), the EORTC 35-question quality-of-life head and neck cancer-specific module (EORTC QLQ-H&N35), and the EuroQol 5-dimension 3-level instruments (EQ-5D-3L). Secondary endpoints included mean change from baseline in EORTC QLQ-C30 global health status/quality of life (GHS/QoL) at week 15 and time to deterioration (TTD) in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing.Results: Of 882 enrolled participants, 844 received ≥ 1 dose of study treatment and completed ≥ 1 HRQoL assessment; adherence was ≥ 79% at week 15 across treatment groups. At week 15, EORTC QLQ-C30 GHS/QoL scores remained stable; no clinically meaningful between-group differences were observed (least squares mean difference, pembrolizumab vs cetuximab-chemotherapy, 0.24; 95% CI, -3.34 to 3.82; pembrolizumab-chemotherapy vs cetuximab-chemotherapy, 0.40; 95% CI, -3.46 to 4.26). Median TTD in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing scores was not reached over 51 weeks across groups, showing stable HRQoL. TTD was similar between groups for EORTC QLQ-C30 GHS/QoL (pembrolizumab vs cetuximab-chemotherapy: HR, 1.38; 95% CI, 0.95-2.00; pembrolizumab-chemotherapy vs cetuximab-chemotherapy: HR, 1.37; 95% CI, 0.94-2.00), as was TTD in EORTC QLQ-H&N35 pain and swallowing scores.Conclusions: Pembrolizumab monotherapy and pembrolizumab-chemotherapy extended OS while maintaining HRQoL, further supporting first-line use for R/M HNSCC. [ABSTRACT FROM AUTHOR]

Platinum-based chemotherapy in combination with anti-PD-L1 antibodies has shown promising results in mesothelioma. However, the immunological mechanisms underlying its efficacy are not well understood and there are no predictive biomarkers to guide treatment decisions. Here, we combine time course RNA sequencing (RNA-seq) of peripheral blood mononuclear cells with pre-treatment tumor transcriptome data from the single-arm, phase 2 DREAM trial (N = 54). Single-cell RNA-seq and T cell receptor sequencing (TCR-seq) reveal that CD8 + T effector memory (TEM) cells with stem-like properties are more abundant in peripheral blood of responders and that this population expands upon treatment. These peripheral blood changes are linked to the transcriptional state of the tumor microenvironment. Combining information from both compartments, rather than individually, is most predictive of response. Our study highlights complex interactions between the tumor and immune cells in peripheral blood during objective tumor responses to chemoimmunotherapy. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12616001170415., Competing Interests: Declaration of interests W.J.L. declares consultancy for Douglas Pharmaceuticals and research funding from Douglas Pharmaceuticals, AstraZeneca, and ENA therapeutics. W.J.L. is a director of the Cancer Research Trust, which has funded parts of this work, but is not involved in any funding decisions, which are based on independent external peer review. W.J.L. is a founder and director of Setonix Pharmaceuticals, which is not related to the presented work. W.J.L. is an inventor on patent applications unrelated to the presented work. A.K.N. declares consultancy for Douglas Pharmaceuticals and Bristol-Myers Squibb, institutional research funding from AstraZeneca, and consultancy (unrelated to this work) from AstraZeneca., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Locally advanced periorbital cutaneous squamous cell carcinoma (cSCC) may require orbital exenteration, which is highly morbid. As immunotherapy develops, orbit preservation may become widespread, and data benchmarking survival with current standard-of-care surgery and radiotherapy are essential to the integration of this emerging method into modern treatment paradigms. This study aimed to determine the survival of patients after orbital exenteration for cSCC and investigate contributing factors. It was hypothesized that postoperative radiotherapy would be associated with improved survival., Methods: This was a retrospective cohort study of patients with T3 and T4 cSCC undergoing orbital exenteration. Survival analysis was performed using Cox proportional hazards., Results: The study enrolled 40 patients with a median age of 61.5 years who met the criteria. None of the patients had received preoperative radiotherapy. Age (hazard ratio [HR], 1.09; p = 0.019) and residual disease (HR, 9.00; p = 0.003) were associated with worse survival. Postoperative radiotherapy (HR, 0.003; p < 0.001) was associated with improved survival. Perineural, lymphovascular, and bony invasion and T and N stage were not associated with survival. Survival with postoperative radiotherapy was 94 % at 1 year, 87 % at 2 years, and 84 % at 5 years., Conclusions: The oncologic outcomes of orbital exenteration with postoperative radiotherapy for locally advanced head and neck cSCC are good. However, amelioration of the morbidity caused by resection of the eye would be ideal. Data to support immunotherapy as a sole therapy are currently limited, but a combination of neoadjuvant immunotherapy and surgical treatment may facilitate orbit-preserving treatment in the future., Competing Interests: Disclosure: Brett Hughes served on the advisory boards of BMS, MSD, AstraZeneca, Pfizer, Roche, Sanofi, Eisai, and Amgen., (© 2025. Crown.)

Background: Head and neck squamous cell carcinoma (HNSCC) is linked to human papillomavirus (HPV) infection. HPV-positive and HPV-negative HNSCC exhibit distinct molecular and clinical characteristics. Although checkpoint inhibitors have shown efficiency in recurrent/metastatic HNSCC, response variability persists regardless of HPV status. This study aimed to explore the CD8 + T-cell landscape in HPV-negative HNSCC., Methods: We performed simultaneous single-cell RNA and TCR sequencing of CD8 + tumor-infiltrating lymphocytes (TILs) from treatment-naïve HPV-negative HNSCC patients. Additionally, cells were stimulated ex vivo, which allowed for the tracking of clonal transcriptomic responses., Results: Our analysis identified a subset of CD8 + TILs highly enriched for interferon-stimulated genes (ISG). TCR analysis revealed ISG cells are clonally related to a population of granzyme K (GZMK)-expressing cells. However, unlike GZMK cells, which exhibited rapid effector-like phenotypes following stimulation, ISG cells were transcriptionally inert. Additionally, ISG cells showed specific enrichment within tumor and were found across multiple tumor entities., Conclusions: ISG-enriched CD8 + TILs are a consistent feature of various tumor entities. These cells are poorly understood but possess characteristics that may impact antitumor immunity. Understanding the unique properties and functionality of ISG cells could offer innovative treatment approaches to improve patient outcomes in HPV-negative HNSCC and other cancer types., (© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)

Background: In the phase 2 EMPOWER-CSCC-1 study (NCT02760498), cemiplimab demonstrated antitumor activity against metastatic cutaneous squamous cell carcinoma (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 every 2 weeks [groups 1 and 2]) or cemiplimab (350 mg intravenously [groups 3 and 6]) every 3 weeks. The primary end point 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: Nonrandomized study, nonsurvival primary end point., 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., Competing Interests: Conflicts of interest Dr Hughes reports consulting/advisory roles at AstraZeneca, Bristol-Myers Squibb, Eisai, Merck, Merck Sharp & Dohme, Pfizer, and Roche; and institutional research funding from Amgen. Dr Guminski reports personal fees and advisory board and travel support from Bristol-Myers Squibb and Sun Pharma; advisory board fees from Eisai, Merck KGaA, and Pfizer; travel support from Astellas; and clinical trial unit support from PPD Australia. Dr Bowyer reports advisory board roles for Eli Lilly Australia, Ipsen, Merck Sharp & Dohme, and Sanofi; virtual meeting sponsorship from Bristol-Myers Squibb and Merck Sharp & Dohme Australia; and travel support from Merck Sharp & Dohme and AstraZeneca. Michael Migden reports honoraria and travel expenses from Regeneron Pharmaceuticals, Inc., and Sanofi; consulting fees from Feldan Therapeutics, Replimune, Stamford Pharma, and Sun Pharma; and institutional research funding from Regeneron Pharmaceuticals, Inc., and Replimune. Dr Schmults 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. Dr Khushalani reports grants and advisory board fees from Bristol-Myers Squibb, Merck, Novartis, and Regeneron Pharmaceuticals, Inc.; advisory board fees from AstraZeneca (data safety monitoring committee), Castle Biosciences, Incyte (data safety monitoring committee), Instil Bio, Iovance, Jounce Therapeutics, Nektar, and Replimune; grants from Celgene, GlaxoSmithKline, HUYA, Modulation Therapeutics, and Replimune; honoraria from Genzyme, National Comprehensive Cancer Network (grant funding from general research support through Pfizer), and Nektar (study steering committee); common stock ownership of Amarin, Bellicum Pharmaceuticals, and Transenetrix; study steering committee membership for Bristol-Myers Squibb, Regeneron Pharmaceuticals, Inc., and Replimune; and travel support from Regeneron Pharmaceuticals, Inc. Dr Chang reports consulting and advisory roles with Merck, and Regeneron Pharmaceuticals, Inc.; research funding from Galderma, Merck, Novartis, and Regeneron Pharmaceuticals, Inc., and consultancy for Castle Biosciences and Feldan. Dr Grob reports serving on an advisory board for Amgen, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Pfizer, Philogen, Roche, and Sanofi; and an advisory role for Bristol-Myers Squibb. Dr Lewis reports employment, stock, and other ownership interests at Regeneron Pharmaceuticals, Inc. At the time of this study, Dr Lewis was affiliated with the University of Colorado Denver Cancer Center and is now an employee of Regeneron Pharmaceuticals, Inc. Dr Day reports serving on an advisory board for Amgen, travel support from Merck; and clinical trial support (investigational medical product provision, no financial support) from AstraZeneca and Bristol-Myers Squibb. Dr Ladwa reports honoraria from AstraZeneca, Bristol-Myers Squibb, and Merck Sharp & Dohme; consulting or advisory roles for AstraZeneca, and Roche; and travel, accommodation, and expenses from Merck Sharp & Dohme. Dr Stein reports ownership of stocks/shares in Icon Group. Dr Muñoz Couselo reports serving on an advisory board for Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sanofi; honoraria from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, and Roche; and clinical trial participation (principal investigator) for Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sanofi. Dr Meier 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. Dr Hauschild reports institutional grants, speaker’s honoraria, and consultancy fees from Amgen, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Pierre Fabre, Provectus, Roche, and Novartis; institutional grants and consultancy fees from Merck Serono, Philogen, and Regeneron Pharmaceuticals, Inc.; and consultancy fees from OncoSec. Dr Schadendorf reports honoraria from 4SC AG, Array BioPharma, Bristol-Myers Squibb, Immunocore, InflarxGmbH, Merck, Merck Sharp & Dohme, NeraCare GmbH, Novartis, Pierre Fabre, Pfizer, Philogen, Regeneron Pharmaceuticals, Inc., Sandoz, Sanofi, Serono, Sun Pharma, Roche/Genentech, and Ultimovacs; advisory board and consulting fees from 4SC AG, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron Pharmaceuticals, Inc., Roche/Genentech, Sanofi, and Nektar; speaker fees from Bristol-Myers Squibb, Merck KGaA, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron Pharmaceuticals, Inc., and Sanofi; institutional research funding from Array BioPharma/Pfizer, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, and Roche; and travel/accommodation expenses from Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron Pharmaceuticals, Inc., Roche/Genentech, and Sanofi. Dr Basset-Seguin reports serving as an invited speaker, advisory board member, and consultant for Galderma, Regeneron Pharmaceuticals, Inc., Sanofi, and Sun Pharma. Dr Modi reports consulting/advisory board participation for Merck, Regeneron Pharmaceuticals, Inc., and Sanofi Genzyme; and speaker bureau participation for Regeneron Pharmaceuticals, Inc., and Sanofi Genzyme. Dr Dalac-Rat reports honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, and Sun Pharma. Dr Dunn reports advisory board participation for Merck and Regeneron Pharmaceuticals, Inc.; and research support from CUE-101, Regeneron Pharmaceuticals, Inc., Replimune Pharmaceuticals, and Seagen. Dr Flatz reports research funding from Hookipa Pharma; and advisory board fees from Bristol-Myers Squibb, Novartis, Philogen, and Sanofi. Dr Mortier reports personal fees and nonfinancial support from Bristol-Myers Squibb, and Merck Sharp & Dohme, Novartis, and Roche. Dr Guégan reports consulting fees from Bristol-Myers Squibb, Janssen, and Pierre Fabre; and technical support for congress attendance from Bristol-Myers Squibb, Janssen, Merck Sharp & Dohme, and Sanofi. Dr Heinzerling reports consulting fees from Bristol-Myers Squibb, Highlight Therapeutics, Novartis, Pierre Fabre, Roche, and Sanofi; lecture fees from Astellas, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Pfizer, Roche, and Sanofi; and travel grants from Bristol-Myers Squibb, Ipsen, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, and Roche. Dr Mehnert reports advisory board fees from Bristol-Myers Squibb, Eisai, Novartis, Pliant Therapeutics, Regeneron Pharmaceuticals, Inc., and Seagen; and consultancy fees from Merck. Dr Soria-Rivas reports speaker’s honoraria from Bristol-Myers Squibb, Immunocore, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche Pharma, and Sanofi Aventis; and advisory board fees from Bristol-Myers Squibb, Immunocore, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron Pharmaceuticals, Inc., and Sanofi Aventis. 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, Genesis Pharma, LEO Pharma, Novartis, and Pfizer. Dr Ulrich reports advisory board and speaker roles for Regeneron Pharmaceuticals, Inc., Roche, Sanofi, and Sun Pharma. Dr Wong reports grant funding to institution from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, F-Star Therapeutics, Genentech, Gilead, Kura Oncology, Merck Sharp & Dohme, Pfizer, Regeneron Pharmaceuticals, Inc., and TopAlliance Biosciences, and consulting fees from Blueprint Medicines Corporation, Genzyme/Sanofi, and Regeneron Pharmaceuticals, Inc. Dr Beylot-Barry reports institutional research funding from Roche and speaker honoraria from Sun Pharma. Dr Bossi reports advisory board or conference honoraria for Merck, Merck Sharp & Dohme, Sanofi-Regeneron, and Sun Pharma. Dr Bugés Sánchez reports personal fees from Amgen, Merck, Novartis, and Sanofi. Dr Chandra reports honoraria from Array BioPharma, Bristol-Myers Squibb, EMD Serono, Exicure, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., and Sanofi; consulting/advisory roles for Array BioPharma, Bristol-Myers Squibb, EMD Serono, Exicure, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., and Sanofi; and institutional research funding from Bristol-Myers Squibb, EMD Serono, Exicure, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., and Sanofi. Dr Robert reports grants, personal fees, and advisory board roles for Amgen, Biothera, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi, and Ultimovacs. Dr Silk reports institutional research grant and funding from Biohaven Pharmaceuticals, Merck, Morphogenesis, Regeneron Pharmaceuticals, Inc., Replimune, and Shattuck Laboratories; advisory board fees from Natera, Merck and Regeneron Pharmaceuticals, Inc.; consulting fees from Leerink, and royalties from UpToDate, Inc. Ms Booth and Drs, Yoo, Seebach, Lowy, and Fury report employment, stock, and other ownership interests at Regeneron Pharmaceuticals, Inc. Dr Rischin reports institutional research grant and funding from ALX Oncology, Bristol-Myers Squibb, GlaxoSmithKline, Kura Oncology, Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc., Roche, and Sanofi; and uncompensated scientific committee and advisory board roles for Eisai, Bicara, GlaxoSmithKline, Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc., and Sanofi. Drs Ansstas, Trabelsi, and Russell have no conflicts of interest to declare., (Copyright © 2024 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Aim: To evaluate the real-world treatment patterns and outcomes for patients with pleural mesothelioma (PM) in the era of immunotherapy., Methods: This retrospective audit included patients with PM diagnosed within three tertiary referral centers in Queensland, Australia from January 2017 to July 2023. Patient and treatment characteristics and outcomes were recorded. Data was analyzed using descriptive statistics and the Kaplan-Meier survival method., Results: A total of 90 patients were included: 84% were male, the median age was 75 years (range 70-79) and 85% had baseline Eastern Group Cooperative Group of 0-1. Subtypes included 54% epithelioid, 17% biphasic, 12% sarcomatoid, and 17% unspecified/unknown. First-line treatment was received by 57/90 patients (63%) and 33/90 patients (37%) received the best supportive care (BSC). Chemotherapy was most used (63%) overall, but first-line immunotherapy was more commonly used since ipilimumab/nivolumab was reimbursed by the Australian Pharmaceutical Benefits Scheme in July 2021. After first-line treatment, only 40% received second-line treatment and 60% received BSC. 12-month overall survival (OS) and progression-free survival for all patients were 53% (95% confidence interval [CI]: 43-65) and 25% (95% CI 15-40) respectively. 12-month OS was 72%, 64%, and 29% for immunotherapy, chemotherapy, and BSC, respectively. There was no significant difference in survival between chemotherapy and immunotherapy (hazard ratio 1.28, 95% CI: 0.65-2.5, p = 0.5)., Conclusion: In our unselected real-world cohort, both chemotherapy and immunotherapy are active against PM, but the prognosis remains guarded. There remains a need for better treatment options, especially in the first-line setting. Enrolment in clinical trials is crucial to improving outcomes in this debilitating disease., (© 2024 The Author(s). Asia‐Pacific Journal of Clinical Oncology published by John Wiley & Sons Australia, Ltd.)

Introduction: EGFR -mutant NSCLC is associated with low mutation burden and low levels of PD-L1 expression. We conducted a phase 2 trial to determine the efficacy of durvalumab, tremelimumab, and platinum-pemetrexed in EGFR- mutant NSCLC after progression with EGFR tyrosine kinase inhibitors (TKIs)., Methods: Participants were treated with induction durvalumab, tremelimumab, and platinum-pemetrexed, followed by durvalumab-pemetrexed maintenance. Participants were divided into two cohorts: (1) EGFR exon 20 T790M negative (T790M-, progressing on either first-line osimertinib, or on a single line of first/second generation TKI), and (2) T790M positive (T790M+, progressing on greater than or equal to 1 lines of TKI, including osimertinib). The primary endpoint was the confirmed objective response rate (ORR) assessed by the investigators. Progression-free survival and safety were secondary outcomes., Results: One hundred participants from Australia and Taiwan were enrolled. Median follow-up was 26 months with 88% and 96% experiencing progression events for T790M- and T790M+, respectively. The ORR for T790M- was 31% (95% confidence interval: 20-45), including two complete responses. The ORR for T790M+ was 21% (95% confidence interval: 12-34). Median durations of response were 9.5 months and 6.3 months for T790M- and T790M+, respectively; median progression-free survival rates were 6.5 months and 4.9 months, respectively. For T790M-, ORR was 27% for 50% or higher PD-L1 (n = 22) and 0% for less than 50% PD-L1 (n = 10), respectively. For T790M+, ORR was 17% for 50% or higher PD-L1 (n = 24). The safety profile was consistent with previous reports., Conclusions: Durvalumab, tremelimumab, and platinum-pemetrexed had modest anti-tumor activity in EGFR- mutant NSCLC after progression on TKI. The T790M- cohort had higher ORR and a longer duration of response. Immune adverse events were not increased with tremelimumab. The clinical registration number of this trial is NCT03994393., Competing Interests: Dr. Lee reports receiving grants or contracts from Rche, Amgen, AstraZeneca, and Merck kGA. He reports receiving honoraria from AstraZeneca, Amgen, Janssen, GSK, Merck kGA, Merck, Roche, Gilead, Novartis, and Takeda. Dr. Liao reports honoraria/speaker fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceuticals, Stone Pharmaceuticals, Eli Lilly, Merck, Merck Sharp & Dohme (MSD), Novartis, Ono Pharmaceuticals, Pfizer, Roche and Takeda. Dr. Chiu reports receiving honoraria/speaker fees from Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi-Sankyo, Eli Lilly, Janssen, Merck KGaA, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Roche, Shionogi, and Takeda. Dr. Mersiades reports receiving support to attend conferences from Pfizer. Dr. Hughes reports being an advisory board member for AstraZeneca. Dr. O’Byrne reports receiving honoraria from Merck Sharp & Dohme, BMS, Roche, Boehringer Ingelheim, AstraZeneca, Pfizer/EMD Serano, Merck Group, Ipsen, Seagen, Diacchi, Tristar Technology Group, Takeda, Amgen, BeiGene. He has consulting/advisory roles for Merck Sharp & Dohme, Boehringer Ingelheim, Roche/Genentech, Pfizer, AstraZeneca/MedImmune, BMS, Sanofi, Amgen, BeiGene, Ipsen, Seagen and Diacchi. He has stock and other ownership interests with Carpe Vitae Pharmaceuticals, Repluca Pharmaceuticals, and DGC Diagnostics and has four active patents (two published and two provisional). He has speaking roles for Merck Sharp & Dohme, Boehringer Ingelheim, BMS, Roche, Janssen, Pfizer, Merck Group, Seagen, and Beigene and has received travel/accommodation funding from Bayer Holding and Sanofi. Dr. Luo reports receiving honoraria from AstraZeneca, Boehringer Ingelheim, Pfizer, Chugai, and Takeda Oncology. Dr. Bray reports participation on a data safety monitoring or advisory board for the SHERLOCK study and the OCEANiC study. Dr. Moore reports receiving honoraria from Roche and Gilead, participation on a data safety monitoring or advisory board for Gilead, Merck, and Takeda and Leadership or Fiduciary role as Board Director, Thoracic Oncology Group of Australasia (TOGA). Dr. Stockler reports receiving support for the present manuscript from Cancer Australia and the Australian National Health and Medical Research Council. Grants or contracts to institution from Astellas, Celgene, Bionomics, Medivation, Sanofi, Pfizer, AstraZeneca, BMS, Roche, Amgen, Merck Sharp & Dohme, Tilray. Dr. Solomon reports receiving honoraria and is an advisory board member for AstraZeneca, Pfizer, Roche/Genetech, Lilly, Merck Sharpe Dohme, Bristol Myers Squibb, Amgen, Janssen and a Leadership or fiduciary role as board of directors for International Association for the study of Lung Cancer, Thoracic Oncology Group of Australasia, Cancer Council of Victoria. Dr. John reports receiving consulting fees to institution for BMS, AstraZeneca, Amgen, Roche, Pfizer, Takeda, Boehringer Ingelheim, MSD, Merck, Puma, Specialised Therapeutics, Gilead, Seagan, Johnson and Johnson. He reports receiving travel/speaker fees from AstraZeneca and MSD and support for attending meetings/conferences from AstraZeneca. Dr. Yang reports consulting/advisory role paid to institution from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck KGaA, Darmstadt Germany, Merck Sharp and Dohme, Novartis, Ono Pharmaceuticals, Pfizer, Roche.Genentech, Takeda Oncology, Yuhan Pharmaceuticals, Janssen Pharmaceuticals. He reports personal fees for consulting/advisory roles from Amgen, AstraZeneca, Boehringer Ingelheim, and Bristol Myers Squibb. He reports grants from AstraZeneca and Roche/Genentech. He reports institutional fees for advisory services from Gilead Sciences Inc., GSK, BeiGene, Regeneron Pharmaceutical, Taiho Pharmaceutical, ArriVent, AnHeart Therapeutics. Dr. Yang reports personal fees and others from Amgen, grants, personal fees and others from AstraZeneca, personal fees and others from Bayer, personal fees and others from Boehringer Ingelheim, personal fees and others from Bristol Myers Squibb, others from Daiichi Sankyo, other from Eli Lilly, other from Merck KGaA, Darmstadt, Germany, other from Merck Sharp & Dohme, other from Novartis, from Ono Pharmaceuticals, from Pfizer, grants and other from Roche/Genentech, other from Takeda Oncology, other from Yuhan Pharmaceuticals, other from Janssen Pharmaceuticals, other from Gilead Sciences Inc, other from GSK, other from BeiGene, other from Regeneron Pharmaceutical, other from Taiho Pharmaceutical, other from ArriVent, other from AnHeart Therapeutics, outside the submitted work. The remaining authors declare no conflict of interest., (© 2024 The Authors.)

Background: Programmed cell death ligand 1 (PD-L1) inhibitors have limited efficacy as monotherapy in patients with recurrent/metastatic (R/M) Human Papilloma Virus (HPV) oropharyngeal squamous cell carcinoma (OPSCC). A phase I study of the therapeutic HPV-16 DNA vaccine AMV002 in curatively treated patients with OPSCC demonstrated a measurable immune response against HPV while being associated with high safety and tolerability. This prospective phase Ib single centre pilot study aims to test the safety and tolerability of combined PD-L1 inhibitor, Durvalumab, with AMV002 in 12 patients with recurrent OPSCC., Methods: Participants had evidence of R/M HPV-associated OPSCC. They received three intradermal administrations of AMV002 with Durvalumab followed by Durvalumab maintenance. Safety and tolerability data was the primary endpoint. The study was conducted with ethical approval (HREC/2018/QMS/47293) in Brisbane, Australia., Findings: The most common adverse event (AE) related to vaccine administration was erythema at the injection site. There were no grade 3 or 4 vaccine related AEs. There was one presumed immune-related grade 3 elevation in lipase secondary to Durvalumab with no intervention required. No patient ceased study due to treatment-related AEs. At week 16, objective response rate was 8% (N=1) and disease control rate was 17% (N=2). At a median follow up of 25.6 (20.0-26.6) months there was one long term complete response while all other participants developed progressive disease. Of the 11 evaluated patients, 9, (82%) had E6 and/or E7-specific T cell responses to the vaccine., Conclusion: The combination of AMV002 therapeutic HPV-16 vaccine and Durvalumab was found to be safe and well tolerated with no increased safety signals generated. T cell responses to vaccine were observed but further work will be required to improve efficacy., Competing Interests: Author NF was employed by the company Jingang Medicine (Australia) Pty Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ladwa, Chandra, Woo, Finlayson, Liu, McGrath, See, Hughes, Cooper, Jackson, Dzienis, Xu, Panizza, Frazer and Porceddu.)

Introduction: The JAVELIN Lung 101 phase 1b/2 trial evaluated avelumab (immune checkpoint inhibitor) combined with lorlatinib or crizotinib (tyrosine kinase inhibitors) in ALK -positive or ALK -negative advanced NSCLC, respectively., Methods: Starting doses of lorlatinib 100 mg once daily or crizotinib 250 mg twice daily were administered with avelumab 10 mg/kg every 2 weeks. Primary objectives were assessment of maximum tolerated dose (MTD) and recommended phase 2 dose in phase 1 and objective response rate in phase 2. Primary end points were dose-limiting toxicity (DLT) and confirmed objective response per Response Evaluation Criteria in Solid Tumors, version 1.1., Results: In the avelumab plus lorlatinib group ( ALK -positive; n = 31; 28 in phase 1b; three in phase 2), two of 28 assessable patients (7%) had DLT, and the MTD and recommended phase 2 dose was avelumab 10 mg/kg every 2 weeks plus lorlatinib 100 mg once daily. In the avelumab plus crizotinib group ( ALK -negative; n = 12; all phase 1b), five of 12 assessable patients (42%) had DLT, and the MTD was exceeded with avelumab 10 mg/kg every 2 weeks plus crizotinib 250 mg twice daily; alternative crizotinib doses were not assessed. Objective response rate was 52% (95% confidence interval, 33%-70%) with avelumab plus lorlatinib (complete response, 3%; partial response, 48%) and 25% (95% confidence interval, 6%-57%) with avelumab plus crizotinib (all partial responses)., Conclusions: Avelumab plus lorlatinib treatment in ALK -positive NSCLC was feasible, but avelumab plus crizotinib treatment in ALK -negative NSCLC could not be administered at the doses tested. No evidence of increased antitumor activity was observed in either group., Clinicaltrialsgov Identifier: NCT02584634., Competing Interests: Dr. Solomon reports providing a consulting or advisory role for Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Cancer Council of Victoria, D3 Bio, Janssen, Lilly, the healthcare business of Merck KGaA, Darmstadt, Germany, Pfizer, Roche/Genentech, Takeda, and Thoracic Oncology Group of Australasia; has provided speaker services for Amgen, AstraZeneca, Pfizer, and Roche/Genentech; and has received institutional research funding from 10.13039/100017239BeiGene, 10.13039/100002491Bristol Myers Squibb, 10.13039/100020536Lilly, 10.13039/100004336Novartis, Nuvalent, 10.13039/100004319Pfizer, 10.13039/100004337Roche/10.13039/100004328Genentech, and 10.13039/100004339Sanofi. Prof. Dagogo-Jack reports providing a consulting or advisory role for AstraZeneca, Bayer, Boehringer Ingelheim, BostonGene, Catalyst Pharmaceuticals, Genentech, Janssen, Novocure, Pfizer, Sanofi, Syros Pharmaceuticals, and Xcovery; has received travel, accommodations, or expenses from Array BioPharma, Creative Educational Concepts, DAVA Oncology, Medscape, OncLive/MJH Life Sciences, Pfizer, The ASCO Post, and Total Health Conferencing; and has received institutional research funding from 10.13039/100007174Array BioPharma, 10.13039/100017658Calithera Biosciences, Genentech, Pfizer, 10.13039/100004336Novartis, and Vivace Therapeutics. Prof. Lee reports providing a consulting or advisory role for AstraZeneca/MedImmune, Bristol Myers Squibb, and Novartis; has received honoraria from AstraZeneca/MedImmune, the healthcare business of Merck KGaA, Darmstadt, Germany, and Roche; and has received travel, accommodations, or expenses from Novartis. Prof. Boyer reports providing a consulting or advisory role for AstraZeneca/MedImmune, Bristol Myers Squibb, and Merck & Co., Kenilworth, NJ; has received institutional research funding from 10.13039/100002429Amgen, 10.13039/100019621Ascentage Pharma, 10.13039/100004325AstraZeneca, 10.13039/100017239BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, 10.13039/100004334Merck & Co., Kenilworth, NJ, OncoMed, 10.13039/100012742Peregrine Pharmaceuticals, Pfizer, and Roche/Genentech; and has received travel, accommodations, or expenses from Boehringer Ingelheim, Bristol Myers Squibb, Merck & Co., Kenilworth, NJ, and Roche/Genentech. Prof. Ramalingam reports providing a consulting or advisory role for AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Lilly/ImClone, Roche/Genentech, Takeda, and the healthcare business of Merck KGaA, Darmstadt, Germany. Dr. Carcereny has no relationships to disclose. Prof. Felip reports providing a consulting or advisory role for AbbVie, Amgen, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, GlaxoSmithKline, Janssen, Merck & Co., Kenilworth, NJ, Novartis, Pfizer, Puma Biotechnology, Roche, Sanofi, Genzyme, Takeda, and the healthcare business of Merck KGaA, Darmstadt, Germany; has provided speaker services for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, Medscape, Merck & Co., Kenilworth, NJ, Novartis, PeerVoice, Pfizer, Prime Oncology, Roche, Springer, Takeda, touchIME, and CME Outfitters; has received research funding from grant for Oncology Innovation, Fundación Merck Salud, Madrid, Spain, an affiliate of Merck KGaA, Darmstadt, Germany; and is an independent member of the board of Grifol. Dr. Han reports providing a consulting or advisory role for Merck & Co., Kenilworth, NJ; has received honoraria from Novartis; and has received institutional research funding from Roche. Dr. Hida has received honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharma, Clovis Oncology, Kissei Pharmaceutical, Lilly, Merck & Co., Kenilworth, NJ, Novartis, Ono Pharmaceutical, Pfizer, and Taiho Pharmaceutical; and has received institutional research funding from 10.13039/100006483AbbVie, 10.13039/501100004948Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharma, Clovis Oncology Daiichi Sankyo, 10.13039/501100002975Dainippon Sumitomo Pharma, 10.13039/501100003769Eisai, 10.13039/100014584Ignyta, 10.13039/100016288Kissei Pharmaceutical, 10.13039/501100004095Kyowa Hakko Kirin, 10.13039/100004334Merck & Co., Kenilworth, NJ, Novartis, Ono Pharmaceutical, Pfizer, Servier, 10.13039/100009954Taiho Pharmaceutical, Takeda, and the healthcare business of Merck KGaA, Darmstadt, Germany. Dr. Hughes reports providing a consulting or advisory role for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eisai, Pfizer, Merck & Co., Kenilworth, NJ, and Roche. Dr. Kim has no relationships to disclose. Dr. Nishio has received lecture fees from Chugai Pharmaceutical, Pfizer, Novartis, and Takeda. Dr. Seto has received honoraria from Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharma, Kissei Pharmaceutical, Kyowa Hakko Kirin, Lilly Japan, Merck & Co., Kenilworth, NJ, Nippon Kayaku, Ono Pharmaceutical, Pfizer, Roche Singapore, Taiho Pharmaceutical, Takeda, and Yakult Honsha; and has received institutional research funding from Astellas Pharma, AstraZeneca, 10.13039/100015731Bayer Yakuhin, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo, Eisai, Kissei Pharmaceutical, Lilly, Merck & Co., Kenilworth, NJ, Novartis, Pfizer, and the healthcare business of Merck KGaA, Darmstadt, Germany. Dr. Okamoto has received honoraria from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Johnson & Johnson, Merck & Co., Kenilworth, NJ, Boehringer Ingelheim, Nippon Kayaku, Novartis, Ono Pharmaceutical, and Taiho Pharmaceutical; and has received institutional research funding from AnHeart Therapeutics, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Covidien Japan, Daiichi Sankyo, Lilly, KM Biologics, the healthcare business of Merck KGaA, Darmstadt, Germany, Merck & Co., Kenilworth, NJ, Boehringer Ingelheim, Nippon Kayaku, Novartis, Pfizer, and Taiho Pharmaceutical. Dr. Zhang is an employee of Pfizer and owns stock and has other ownership interests in Pfizer. Dr. Martini is an employee of Pfizer and owns stock and has other ownership interests in Pfizer. Dr. Wang was an employee of Pfizer at the time this study was conducted. Dr. De Beukelaer was an employee of Pfizer at the time this study was conducted and owns stock and has other ownership interests in Pfizer. Dr. Bauer reports providing a consulting or advisory role for AstraZeneca, Bayer, Lilly, and Pfizer; has provided speaker services for Bayer, Bristol Myers Squibb, Lilly, and Pfizer; and has received institutional research funding from AstraZeneca, Bayer, Bristol Myers Squibb, Lilly, and Pfizer., (© 2024 by the International Association for the Study of Lung Cancer.)

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.)

Objectives: To review the outcomes of immune checkpoint inhibitor (ICI) treatment of advanced cutaneous squamous cell carcinoma (CSCC) outside clinical trials., Study Design: Retrospective observational study; review of patient records in fifteen Australian institutions., Setting, Participants: All Australian adults with locally advanced or metastatic CSCC not amenable to curative surgery or radiotherapy treated with ICIs, 5 May 2017 - 23 May 2022, through a cemiplimab compassionate access scheme (Therapeutic Goods Administration Special Access Scheme) or who personally covered the cost of pembrolizumab prior to the start of the access scheme., Main Outcome Measures: Best overall response rate (ORR) according to standardised assessment criteria using the hierarchy: Response Evaluation Criteria in Solid Tumors (RECIST 1.1), the modified World Health Organization clinical response criteria, and the Positron Emission Tomography Response Criteria (PERCIST 1.0); overall and progression-free survival., Results: A total of 286 people with advanced CSCC received ICI therapy during May 2017 - May 2022 (cemiplimab, 270; pembrolizumab, 16). Their median age was 75.2 years (range, 39.3-97.5 years) and 232 were men (81%); median follow-up time was 12.2 months (interquartile range, 5.5-20.5 months). Eighty-eight people (31%) were immunocompromised, 27 had autoimmune disease, and 59 of 277 (21%) had ECOG performance scores of 2 or 3. The ORR was 60% (166 of 278 evaluable patients): complete responses were recorded for 74 (27%) and partial responses for 92 patients (33%). Twelve-month overall survival was 78% (95% confidence interval [CI], 72-83%); progression-free survival was 65% (95% CI, 58-70%). Poorer ECOG performance status was associated with poorer overall survival (per unit: adjusted hazard ratio [aHR], 3.0; 95% CI, 2.0-4.3) and progression-free survival (aHR, 2.4; 95% CI, 1.8-3.3), as was being immunocompromised (overall: aHR, 1.8; 95% CI, 1.1-3.0; progression-free: aHR, 1.8; 95% CI, 1.2-2.7). Fifty-five people (19%) reported immune-related adverse events of grade 2 or higher; there were no treatment-related deaths., Conclusion: In our retrospective study, the effectiveness and toxicity of ICI therapy were similar to those determined in clinical trials. Our findings suggest that ICIs could be effective and well tolerated by people with advanced CSCC who are ineligible for clinical trials., (© 2024 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

Background: Horizon scanning (HS) is the systematic identification of emerging therapies to inform policy and decision-makers. We developed an agile and tailored HS methodology that combined multi-criteria decision analysis weighting and Delphi rounds. As secondary objectives, we aimed to identify new medicines in melanoma, non-small cell lung cancer and colorectal cancer most likely to impact the Australian government's pharmaceutical budget by 2025 and to compare clinician and consumer priorities in cancer medicine reimbursement., Method: Three cancer-specific clinician panels (total n = 27) and a consumer panel (n = 7) were formed. Six prioritisation criteria were developed with consumer input. Criteria weightings were elicited using the Analytic Hierarchy Process (AHP). Candidate medicines were identified and filtered from a primary database and validated against secondary and tertiary sources. Clinician panels participated in a three-round Delphi survey to identify and score the top five medicines in each cancer type., Results: The AHP and Delphi process was completed in eight weeks. Prioritisation criteria focused on toxicity, quality of life (QoL), cost savings, strength of evidence, survival, and unmet need. In both curative and non-curative settings, consumers prioritised toxicity and QoL over survival gains, whereas clinicians prioritised survival. HS results project the ongoing prevalence of high-cost medicines. Since completion in October 2021, the HS has identified 70 % of relevant medicines submitted for Pharmaceutical Benefit Advisory Committee assessment and 60% of the medicines that received a positive recommendation., Conclusion: Tested in the Australian context, our method appears to be an efficient and flexible approach to HS that can be tailored to address specific disease types by using elicited weights to prioritise according to incremental value from both a consumer and clinical perspective., Policy Summary: Since HS is of global interest, our example provides a reproducible blueprint for adaptation to other healthcare settings that integrates consumer input and priorities., Competing Interests: Declaration of Competing Interest MA has received financial support to attend conferences and meetings by AstraZeneca and serves on the advisory board for Pfizer and Bristol Myers Squibb. PAA has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Canofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna, Bio-Al Health, ValoTX, Replimmune. He has received research funding grants from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi. He has received travel support from Pfizer. SA has served uncompensated on the boards of Health Issues Centre, Australia, Victorian Agency for Health Information, and Safer Care Victoria. MPB has received honoraria from BNS Australia, USD Oncology, and Novartis. He holds an advisory role for Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, and Cartherics for which his institution receives reimbursements. His institution has also received reimbursement for research support from Bristol Myers Squibb, Merck Sharp & Dohme, Pharmaust, Zucero Therapeutics, and CStone Pharmaceuticals. MB has received compensation and research support as an advisor and consultant to Pierre Fabre, MSD, GSK, Servier, and AstraZeneca. MI is on the advisory boards of Pfizer, Roche, Takeda, BeiGene, Amgen, Merck, and MSD and has received honoraria from Pfizer, Roche, Takeda, Novartis, as well as research funding from Pfizer. TJ reports consulting fees from AstraZeneca and MSD, and advisory boards and committees for AstraZeneca, Amgen, Bristol Myers Squibb, Merck & Co., MSD, Gilead, Puma, Pfizer Inc., Roche AG, Specialised Therapeutics, and Takeda Pharmaceutical, outside the submitted work. SK reports honoraria to institution from Astra Zeneca, Roche, Pfizer, Bristol Myers Squibb, MSD and Takeda; consulting fees from AstraZeneca, Pfizer, MSD, Novartis, Roche, Takeda, Amgen; and research funding to institution from Astra Zeneca. MK reports institutional grants from Nordic Farma, Merck-Serono, Pierre Fabre, Servier, Bayer, Bristol Myers Squibb, Merck, and Roche; and consulting fees and honoraria paid to institution from Pierre Fabre and Servier. BTL has served as an uncompensated advisor and consultant to Amgen, AstraZeneca, Boehringer Ingelheim, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, and Lilly. He has received research grants to his institution from Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Hengrui USA, and Lilly. He has received academic travel support from Amgen, Jiangsu Hengrui Medicine and MORE Health. He is an inventor on two institutional patents at MSK (US62/685,057, US62/514,661) and has intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press. BTL is supported by the Memorial Sloan Kettering Cancer Centre Support Grant P30 CA008748 and Research Project Grant R01CA249666 from the National Institutes of Health. GVL is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, OncoSec, PHMR Ltd, Pierre Fabre, Provectus, Qbiotics, Regeneron. JML receives research support from Ipsen Pharmaceuticals, Novartis and Amgen, and reports consulting fees and/or honoraria from Amgen, Ipsen, Taiho, Novartis, SAGA Diagnostics and Natera. BM is on the advisory boards of Amgen, MSD, Bristol Myers Squibb, Beigene and AstraZeneca. GAM has received research support from Bristol Myers Squibb and as Principal Investigator his institution has received reimbursement of trial costs from Roche-Genentech. TMM reports consulting fees and participation on advisory boards for Bristol Myers Squibb, MSD, Merck, AstraZeneca, Novartis, GSK, Eisai, and honoraria from AstraZeneca. TMM has received support to attend meetings from Bristol Myers Squibb and AstraZeneca. LN has received institutional consulting fees from Bristol Myers Squibb, Pfizer, and Merck Sharp & Dohme, and reports support to attend a research meeting from AstraZeneca. NP has served on advisory boards or received personal honoraria from Boehringer Ingelheim, MSD, Merck, Bristol-Myers Squib, Astra Zeneca, Takeda, Pfizer, Roche, Novartis, Ipsen and Bayer and has received research funding to his institution from Bayer, Pfizer and Roche. TMP has received research support from Roche and Pfizer, and holds a consulting or advisory role for Merck, Bristol Myers Squibb, Novartis, Sanofi/Regeneron, and Pfizer. SP is compensated consultant to Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer Ingelheim, Daiichi Sankyo, EQRx, GSK, Guardant Health, Incyte, Janssen, Lilly, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, declares expert testimony to Roche and Merck Serono, and travel support from Janssen and Roche.BJS is on the Advisory Boards/Honoraria for Pfizer, Novartis, Roche, AstraZeneca, Merck, Bristol Myers Squibb, Eli Lilly, Amgen, BeiGene, Janssen, Takeda. JAS has received support for conference attendance from MSD (virtual registration ASCO). JT has received consulting fees or honoraria from Haystack Oncology, Servier, Pierre Fabre, MSD, Merck Serono, Amgen, Novartis, Seres and AstraZeneca. JT is on the advisory boards of Beigene, Daiichi Sankyo, Gilead, Illumina, Novartis, BMS, and MSD. WX has received research support from Merck, honoraria from MSD, Merck and AstraZeneca, and support for attending meetings from MSD (virtual registration ASCO) and Eli Lilly (virtual registration SABCS). WX is on the advisory boards of MSD, Merck and Novartis, and holds unpaid positions as Chair of the Melanoma and Skin Cancer trials group and Australasian Merkel Cell Carcinoma interest group.DY has received institutional payments for his role on advisory boards for AstraZeneca, Servier, Specialised Therapeutics, MSD and BayerJZ serves in an advisory/consultancy role for Merck Sharp & Dohme, Specialised Therapeutics, CEND, Deciphera, Revolution Medicine, FivePHusion, Genorbio, 1Global, Novotech, Alloplex Biotherapeutics, NOUS Consulting, and Oncology Republic; owns stock in Biomarin, Ophthea, Amarin, Concert Pharmaceuticals, Frequency Therapeutics, Gilead, Madrigal Pharmaceuticals, UniQure, Zogenix, Orphazyme, Moderna Therapeutics, TWST, Novavax, and Teladoc; has received honoraria from Gilead Sciences, MSD Oncology, and Viatris; and his institution has received research funding from Bristol-Myers Squibb, AstraZeneca, Pfizer, IQvia, Mylan, Ipsen, Eisai, Medtronic, MSD Oncology and Servier; and has received travel, accommodations, expenses from ICON Group, MSD Oncology, and PRAXIS., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Mucosal head and neck squamous cell carcinoma (HNSCC) are the seventh most common cancer, with approximately 50% of patients living beyond 5 years. Immune checkpoint inhibitors (ICIs) have shown promising results in patients with recurrent or metastatic (R/M) disease, however, only a subset of patients benefit from immunotherapy. Studies have implicated the tumor microenvironment (TME) of HNSCC as a major factor in therapy response, highlighting the need to better understand the TME, particularly by spatially resolved means to determine cellular and molecular components. Here, we employed targeted spatial profiling of proteins on a cohort of pre-treatment tissues from patients with R/M disease to identify novel biomarkers of response within the tumor and stromal margins. By grouping patient outcome categories into response or non-response, based on Response Evaluation Criteria in Solid Tumors (RECIST) we show that immune checkpoint molecules, including PD-L1, B7-H3, and VISTA, were differentially expressed. Patient responders possessed significantly higher tumor expression of PD-L1 and B7-H3, but lower expression of VISTA. Analysis of response subgroups indicated that tumor necrosis factor receptor (TNFR) superfamily members including OX40L, CD27, 4-1BB, CD40, and CD95/Fas, were associated with immunotherapy outcome. CD40 expression was higher in patient-responders than non responders, while CD95/Fas expression was lower in patients with partial response (PR) relative to those with stable disease (SD) and progressive disease (PD). Furthermore, we found that high 4-1BB expression in the tumor compartment, but not in the stroma, was associated with better overall survival (OS) (HR= 0.28, p-adjusted= 0.040). Moreover, high CD40 expression in tumor regions (HR= 0.27, p-adjusted= 0.035), and high CD27 expression in the stroma (HR= 0.2, p-adjusted=0.032) were associated with better survival outcomes. Taken together, this study supports the role of immune checkpoint molecules and implicates the TNFR superfamily as key players in immunotherapy response in our cohort of HNSCC. Validation of these findings in a prospective study is required to determine the robustness of these tissue signatures., Competing Interests: NM, BC, NJ, and OB are employees of Akoya Biosciences. BH, advisory board member of Merck Sharpe and Dohme, Bristol Myers Squibb, Astra Zeneca, Pfizer, Takeda, Sanofi, Eisai. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sadeghirad, Liu, Monkman, Ma, Cheikh, Jhaveri, Tan, Warkiani, Adams, Nguyen, Ladwa, Braubach, O’Byrne, Davis, Hughes and Kulasinghe.)

Malnutrition and sarcopenia are prevalent in patients with head and neck squamous cell carcinoma (HNSCC). Pre-treatment sarcopenia and adverse oncological outcomes in this population are well described. The impact of myosteatosis and post-treatment sarcopenia is less well known. Patients with HNSCC ( n = 125) undergoing chemoradiotherapy, radiotherapy alone and/or surgery were assessed for sarcopenia and myosteatosis, using cross-sectional computed tomography (CT) imaging at the third lumbar (L3) vertebra, at baseline and 3 months post-treatment. Outcomes were overall survival (OS) at 12 months and 5 years post-treatment. One hundred and one participants had a CT scan evaluable at one or two time points, of which sixty-seven (66 %) participants were sarcopenic on at least one time point. Reduced muscle attenuation affected 93 % ( n = 92) pre-treatment compared with 97 % ( n = 90) post-treatment. Five-year OS favoured those without post-treatment sarcopenia (hazard ratio, HR 0·37, 95 % CI 0·16, 0·88, P = 0·06) and those without both post-treatment myosteatosis and sarcopenia (HR 0·33, 95 % CI 0·13, 0·83, P = 0·06). Overall, rates of myosteatosis were high at both pre- and post-treatment time points. Post-treatment sarcopenia was associated with worse 5-year OS, as was post-treatment sarcopenia in those who had myosteatosis. Post-treatment sarcopenia should be evaluated as an independent risk factor for decreased long-term survival post-treatment containing radiotherapy (RT) for HNSCC.

Background: Enteral nutrition (EN) is often required in patients with head and neck cancer (HNSCC); however, initiation criteria is limited or inconsistent. This study aimed to describe the relationship of treatment toxicities and requirement for EN and investigate toxicity and baseline characteristics association with EN duration., Methods: Acute toxicities and baseline characteristics were collected from patients with HNSCC (n = 110) undergoing H-IMRT. Percentage EN contributing to estimated requirements and EN duration were measured., Results: The threshold for patients needing ≥50% of estimated requirements via EN increased from week 3 to 4 for grade ≥2 oral/pharyngeal mucositis, dysgeusia, thick saliva and nausea, and for grade 3 dysphagia. Patients with grade 2-3 dysphagia had a reduced risk of ceasing EN compared to those with grade 0-1 dysphagia., Conclusions: Using acute toxicities in clinical practice may be a useful tool to inform prompt initiation of EN prior to decline in nutritional status and anticipate EN duration., (© 2022 Wiley Periodicals LLC.)

Purpose: Pembrolizumab and pembrolizumab-chemotherapy demonstrated efficacy in recurrent/metastatic head and neck squamous cell carcinoma in KEYNOTE-048. Post hoc analysis of long-term efficacy and progression-free survival on next-line therapy (PFS2) is presented., Methods: Patients were randomly assigned (1:1:1) to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Efficacy was evaluated in programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20, CPS ≥ 1, and total populations, with no multiplicity or alpha adjustment., Results: The median study follow-up was 45.0 months (interquartile range, 41.0-49.2; n = 882). At data cutoff (February 18, 2020), overall survival improved with pembrolizumab in the PD-L1 CPS ≥ 20 (hazard ratio [HR], 0.61; 95% CI, 0.46 to 0.81) and CPS ≥ 1 populations (HR, 0.74; 95% CI, 0.61 to 0.89) and was noninferior in the total population (HR, 0.81; 95% CI, 0.68 to 0.97). Overall survival improved with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.62; 95% CI, 0.46 to 0.84), CPS ≥ 1 (HR, 0.64; 95% CI, 0.53 to 0.78), and total (HR, 0.71; 95% CI, 0.59 to 0.85) populations. The objective response rate on second-course pembrolizumab was 27.3% (3 of 11). PFS2 improved with pembrolizumab in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.84) and CPS ≥ 1 (HR, 0.79; 95% CI, 0.66 to 0.95) populations and with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.86), CPS ≥ 1 (HR, 0.66; 95% CI, 0.55 to 0.81), and total (HR, 0.73; 95% CI, 0.61 to 0.88) populations. PFS2 was similar after pembrolizumab and longer after pembrolizumab-chemotherapy on next-line taxanes and shorter after pembrolizumab and similar after pembrolizumab-chemotherapy on next-line nontaxanes., Conclusion: With a 4-year follow-up, first-line pembrolizumab and pembrolizumab-chemotherapy continued to demonstrate survival benefit versus cetuximab-chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma. Patients responded well to subsequent treatment after pembrolizumab-based therapy.

Sarcopenia is a known independent prognostic factor for decreased survival in patients with head and neck cancer; yet, its importance for the growing number of younger patients diagnosed with human papillomavirus (HPV)-positive oropharyngeal carcinoma (OPC+) has not been established. This systematic literature review aimed to determine the prevalence and impact of computed tomography (CT)-defined sarcopenia on survival outcomes for adult OPC+ patients (>18 y) undergoing any treatment modality. Prospective studies were searched using PubMed, Embase, CENTRAL, CINAHL, and Web of Science up until and including February 2022. Bias was assessed using the Quality In Prognosis Studies (QUIPS) tool, and certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. In total, 9 studies (total pooled OPC+ patients, n  = 744) were identified and included in this review; 2 at low, 6 at moderate, and 1 at high risk of bias. All studies varied in sarcopenia assessment methods and skeletal muscle index threshold cutoff values. These studies demonstrated the cumulative prevalence of sarcopenia for OPC+ patients to be 42.9% (95% CI: 37.8%, 47.9%). While overall survival (3 studies, n = 253) and progression-free survival (1 study, n = 117) was lower in sarcopenic OPC+ patients, this was not statistically significant. GRADE certainty of evidence for impact of pretreatment sarcopenia on overall survival was low and progression-free survival was very low. Although these studies showed there to be a high prevalence of pretreatment sarcopenia in patients with OPC+, which may decrease survival, the impact on progression-free survival is very uncertain. Further, high-quality research utilizing consistent sarcopenia definitions and assessment methods that are conducted specifically in OPC+ is required to strengthen evidence certainty and determine if sarcopenia is an independent prognostic factor for this population., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Alectinib is a second generation of ALK -tyrosine kinase inhibitors ( ALK -TKIs), which has attracted much attention in the treatment of ALK -positive non-small cell lung cancer (NSCLC). At present, there are few reports on the efficacy and safety of alectinib in Chinese population. Moreover, biomarkers reflecting prognosis and efficacy are exceedingly needed. This study assessed the efficacy of alectinib in patients with ALK -positive NSCLC and analyzed the prognostic factors., Methods: Patients with ALK -positive NSCLC who were confirmed by histopathology or cytology at the Affiliated Cancer Hospital of Nanjing Medical University between October 2018 and October 2021 were enrolled. All patients were treated with alectinib. The clinical characteristics and circulating tumor biomarkers before and after treatment were collected. Kaplan-Meier test was used to calculate the progression-free survival (PFS). Univariate and multivariate Cox regression analyses were used to explore the influencing factors on PFS. Incidence of adverse events was observed., Results: Twenty patients progressed after first-line treatment (n=59) with alectinib, and 21 patients progressed following second-line treatment (n=36) with alectinib. The median PFS of first-line treatment patients was not achieved, and the median PFS of patients undergoing second-line treatment was 15.0 months [95% confidence interval (CI): 0.00-32.23]. The most common adverse reactions were liver dysfunction (37.50%), anemia (37.50%), and constipation (20.83%). The incidence of grade III and above adverse reactions was 6.25%. Univariate analysis showed that neutrophil-to-lymphocyte ratio [NLR; hazard ratio (HR) =0.424, P=0.005] carcinoembryonic antigen (CEA; HR =0.482, P=0.029), lactate dehydrogenase (LDH; HR =0.327, P<0.001), carbohydrate antigen (CA)199 (HR =0.313, P=0.002), and circulating cell free DNA (cfDNA; HR =0.229, P=0.008) concentration levels were associated with PFS, and multivariate analysis showed that NLR (HR =3.058, P=0.034) was independent prognostic factor. After three months of treatment, CEA, CA199, NLR, and LDH, could further predict the prognosis of alectinib treatment., Conclusions: The efficacy and safety of alectinib as a first-line or second-line treatment for ALK -positive NSCLC in keeping with published prospective studies. CEA, CA199, NLR, and LDH within the normal range after three months of treatment were associated with good prognosis. Detection of serum tumor markers can indicate therapeutic success in patients treated with alectinib., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-857/coif). AR declares consulting fees form AstraZeneca, participation on advisory board (Takeda), supporting for attending to meetings form Thermofisher and BMS. BGMH declares Advisory Board of Merck, Sharpe and Dohme, Eisai, Pfizer, Sanofi and Takeda. The other authors have no conflicts of interest to declare., (2022 Translational Lung Cancer Research. All rights reserved.)

Background: CD73 is widely expressed on immune cells playing a critical role in immunomodulatory functions including cell adhesion and migration, as a costimulatory molecule for T cells and in production of adenosine. The function of CD73 expressed on B cells has not been fully characterized. Mupadolimab is an anti-human CD73 antibody that activates B cells. We evaluated the characteristics of this antibody and its effects on immune cells in vitro and in vivo., Methods: Mupadolimab binding to CD73, inhibition of CD73 enzymatic activity, and effects on lymphocyte activation were evaluated in vitro by measuring changes in immunophenotype by flow cytometry. Cryogenic-transmission electron microscopy was used to determine epitope binding. Effects on human B cells in vivo were evaluated in immunodeficient NSG-SGM3 mice immunized with SARS-CoV-2 and influenza viral antigens. Safety and immune effects were evaluated in the completed dose escalation portion of a phase 1 trial conducted in patients with cancer., Results: Mupadolimab binds to a unique epitope on CD73 POS B cells resulting in their activation and differentiation through B cell receptor signaling pathways. Mupadolimab induces expression of CD69, CD83, CD86 and MHC class II on B cells along with morphological transformation into plasmablasts and expression of CD27, CD38 and CD138. These effects are independent of adenosine. Mupadolimab binds to the N-terminal of CD73 in the closed position and competitively inhibits substrate binding. Mupadolimab enhanced antigen specific antibody response to SARS-CoV-2 spike protein and influenza hemagglutinin in humanized mouse models. Mupadolimab was evaluated as a monotherapy in a phase 1 trial (NCT03454451) in 34 patients with advanced cancer and demonstrated binding to CD73 POS circulating cells and transient reduction in the number of B cells, with return of CD73 NEG B cells with memory phenotype. No dose-limiting toxicities or changes in serum immunoglobulins were seen., Conclusions: Mupadolimab activates B cells and stimulates the production of antigen specific antibodies. The effects in patients with cancer suggest that activated, CD69 POS B cells redistribute to lymphoid tissues. Minor tumor regression was observed in several patients. These results support further investigation of mupadolimab as an immunotherapy for cancer and its potential use as a vaccine adjuvant., Trial Registration Number: NCT03454451., Competing Interests: Competing interests: RAM, SH, SM and WBJ are employees and shareholders of Corvus Pharmaceuticals. SBW is a shareholder of Corvus Pharmaceuticals. RAM and SBW are also named inventors on patents related to mupadolimab. JJL reports DSMB: Abbvie, Immutep, Evaxion; Scientific Advisory Board: (no stock) 7 Hills, Bright Peak, Fstar, Inzen, RefleXion, Xilio (stock) Actym, Alphamab Oncology, Arch Oncology, Kanaph, Mavu, NeoTx, Onc.AI, Pyxis, STipe, Tempest; Consultancy with compensation: Abbvie, Alnylam, Bayer, Bristol-Myers Squibb, Castle, Checkmate, Codiak, Crown, Day One, Duke St, EMD Serono, Endeavor, Flame, Genentech, Gilead, HotSpot, Kadmon, Janssen, Ikena, Immunocore, Incyte, Macrogenics, Merck, Mersana, Nektar, Novartis, Partner, Pfizer, Regeneron, Servier, STINGthera, Synlogic, Synthekine; Research Support: (all to institution for clinical trials unless noted) AbbVie, Astellas, Astrazeneca, Bristol-Myers Squibb (IIT & industry), Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Merck, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer (IIT & industry) Replimune, Rubius, Servier (IIT), Scholar Rock, Synlogic, Takeda, Trishula, Tizona, Xencor; Patents: (both provisional) Serial #15/612,657 (Cancer Immunotherapy), hPCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof). TM reports having received research funding from Boehringer Ingelheim, Bristol-Myers Squibb, Merck, and Regeneron Pharmaceuticals, Inc. He has served on Advisory Boards and/or Data Safety Monitoring Boards for AstraZeneca, Atara, Boehringer Ingelheim, Celldex, Chimeric Therapeutics, Genentech, Regeneron, Surface, NGMbio, DBV Technologies, Glenmark Pharma and the Rockefeller University. JRM reports research support (institutional) for Corvus, Tizona Therapeutics, Trishula, Merck, Eisai, Genentech, Vyriad, Replimune, Silagen, Rubius Therapeutics, and BioNTech. BGMH reports advisory board member for Merck Sharpe and Dohme, Bristol Meyers Squibb, Roche, Pfizer, Astra Zeneca, Eisai, Takeda, Sanofi and institutional grant funding Amgen., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.)

Purpose: The phase III KEYNOTE-048 (ClinicalTrials.gov identifier: NCT02358031) trial of pembrolizumab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) included planned efficacy analyses in the total population and in participants with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 1 and CPS ≥ 20. To further characterize the predictive value of PD-L1 expression on outcome, we conducted efficacy analyses in the PD-L1 CPS < 1 and CPS 1-19 subgroups in KEYNOTE-048., Methods: Participants with R/M HNSCC and no prior systemic therapy for R/M disease were randomly assigned 1:1:1 to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Post hoc efficacy analyses of the PD-L1 CPS < 1 and CPS 1-19 subgroups were performed., Results: Of 882 participants enrolled, 128 had PD-L1 CPS < 1 and 373 had CPS 1-19. For pembrolizumab versus cetuximab-chemotherapy, the median overall survival was 7.9 versus 11.3 months in the PD-L1 CPS < 1 subgroup (hazard ratio [HR], 1.51 [95% CI, 0.96 to 2.37]) and 10.8 versus 10.1 months in the CPS 1-19 subgroup (HR, 0.86 [95% CI, 0.66 to 1.12]). For pembrolizumab-chemotherapy versus cetuximab-chemotherapy, the median overall survival was 11.3 versus 10.7 months in the PD-L1 CPS < 1 subgroup (HR, 1.21 [95% CI, 0.76 to 1.94]) and 12.7 versus 9.9 months in the CPS 1-19 subgroup (HR, 0.71 [95% CI, 0.54 to 0.94])., Conclusion: Increased efficacy of pembrolizumab or pembrolizumab-chemotherapy was observed with increasing PD-L1 expression. PD-L1 CPS < 1 subgroup analysis was limited by small participant numbers. Results from the PD-L1 CPS 1-19 subgroup support previous findings of treatment benefit with pembrolizumab monotherapy and pembrolizumab-chemotherapy in patients with PD-L1 CPS ≥ 1 tumors. Although PD-L1 expression is informative, exploration of additional predictive biomarkers is needed for low PD-L1-expressing HNSCC.

Background: Non-small cell lung cancer (NSCLC) often presents at an incurable stage, and majority of patients will be considered for palliative treatment at some point in their disease. Despite recent advances, the prognosis remains poor, with a median overall survival of 12-18 months. Liquid biopsy-based biomarkers have emerged as potential candidates for predicting prognosis and response to therapy in NSCLC patients. This pilot study evaluated whether combining circulating tumour cells and clusters (CTCs) and cell-free DNA (cfDNA) can predict progression-free survival (PFS) in NSCLC patients., Methods: CTC and cfDNA/ctDNA from advanced stage NSCLC patients were measured at study entry (T 0 ) and 3-months post-treatment (T 1 ). CTCs were enriched using a spiral microfluidic chip and characterised by immunofluorescence. ctDNA was assessed using an UltraSEEK® Lung Panel. Kaplan-Meier plots were generated to investigate the contribution of the presence of CTC/CTC clusters and cfDNA for PFS. Cox proportional hazards analysis compared time to progression versus CTC/CTC cluster counts and cfDNA levels., Results: Single CTCs were found in 14 out of 25 patients, while CTC clusters were found in 8 out of the 25 patients at T 0 . At T 1 , CTCs were found in 7 out of 18 patients, and CTC clusters in 1 out of the 18 patients. At T 0 , CTC presence and the combination of CTC cluster counts with cfDNA levels were associated with shorter PFS, p = 0.0261, p = 0.0022, respectively., Conclusions: Combining CTC cluster counts and cfDNA levels could improve PFS assessment in NSCLC patients. Our results encourage further investigation on the combined effect of CTC/cfDNA as a prognostic biomarker in a large cohort of advanced stage NSCLC patients., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors.)

Head and neck squamous cell carcinoma (HNSCC) often presents with locoregional or distant disease, despite multimodal therapeutic approaches, which include surgical resection, chemoradiotherapy, and more recently, immunotherapy for metastatic or recurrent HNSCC. Therapies often target the primary and nodal regional HNSCC sites, and their efficacy at controlling occult distant sites remains poor. While our understanding of the tumor microenvironment conducive to effective therapies is increasing, the biology underpinning locoregional sites remains unclear. Here, we applied targeted spatial proteomic approaches to primary and lymph node metastasis from an oropharyngeal SCC (OPSCC) cohort to understand the expression of proteins within tumors, and stromal compartments of the respective sites in samples of both matched and unmatched patients. In unmatched analyses of n = 43 primary and 11 nodal metastases, our data indicated that tumor cells in nodal metastases had higher levels of Ki-67, PARP, BAD, and cleaved caspase 9, suggesting a role for increased proliferation, DNA repair, and apoptosis within these metastatic cells. Conversely, in matched analyses (n = 7), pro-apoptotic markers BIM and BAD were enriched in the stroma of primary tumors. Univariate, overall survival (OS) analysis indicated CD25 in tumor regions of primary tumors to be associated with reduced survival (HR = 3.3, p = 0.003), while progesterone receptor (PR) was associated with an improved OS (HR = 0.33, p = 0.015). This study highlights the utility of spatial proteomics for delineating the tumor and stromal compartment composition, and utility toward understanding these properties in locoregional metastasis. These findings indicate unique biological properties of lymph node metastases that may elucidate further understanding of distant metastatic in OPSCC., Competing Interests: AM is employed by QCIF Bioinformatics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sadeghirad, Monkman, Mehdi, Ladwa, O’Byrne, Hughes and Kulasinghe.)

Background: Cabozantinib inhibits pathways involved in medullary thyroid cancer (MTC). Cabozantinib is approved as 140 mg/day in capsules for MTC and 60 mg/day in tablets for other solid tumors. This study compared the two doses in progressive metastatic MTC. Methods: In this Phase 4, randomized, double-blind noninferiority (NI) trial (NCT01896479), patients with progressive metastatic MTC were randomized 1:1 to cabozantinib 60 mg/day tablet or 140 mg/day capsules. The primary end point was progression-free survival (PFS) by blinded independent radiology committee (BIRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. NI would be concluded if the upper 95% confidence interval [CI] for the PFS hazard ratio (HR) was less than the NI margin, 1.58. The secondary end point was objective response rate (ORR) by BIRC per RECIST v1.1; additional end points included safety and pharmacokinetics. Results: At data cutoff (July 15, 2020), 247 patients were randomized to the 60 mg/day tablet arm ( n  = 123) and the 140 mg/day capsules arm ( n  = 124). NI was not met (median PFS 11.0 months vs. 13.9 months in the 60 and 140 mg/day arms [HR 1.24; CI 0.90-1.70; p  = 0.19]). The ORR was 33% in both arms. Generally, adverse event (AE) incidence was lower in the 60 mg/day arm (Grade 3/4, 63% vs. 72%), as were dose reductions (69% vs. 81%) and treatment discontinuations due to AEs (23% vs. 36%). Initially, cabozantinib plasma concentrations were higher in the 140 mg/day arm but became similar between arms at later time points. Conclusions: PFS NI of the cabozantinib 60 mg/day tablet vs. 140 mg/day capsules was not met. The 60 mg/day tablet had the same ORR and lower rates of AEs. Clinical Trial Registry: ClinicalTrials.gov NCT01896479.

Introduction: First-line therapy for patients with metastatic NSCLC includes checkpoint inhibitor monotherapy, dual checkpoint inhibition, or combination with chemotherapy. We compared outcomes with combination chemoimmunotherapy versus dual checkpoint inhibition as first-line treatment for patients with metastatic NSCLC., Methods: This open-label, randomized clinical trial was conducted at 44 sites in Canada and Australia. Patients with treatment-naive, metastatic NSCLC without sensitizing EGFR or ALK alterations were randomized (1:1) to receive treatment with durvalumab plus tremelimumab with or without platinum-doublet chemotherapy. The primary end point was overall survival (OS). Secondary end points were progression-free survival, overall response rate, and safety., Results: A total of 301 patients were randomized. Median OS was 16.6 months (95% confidence interval [CI]: 12.6-19.1) with chemotherapy plus immunotherapy and 14.1 months (95% CI: 10.6-18.3) with immunotherapy (hazard ratio = 0.88, 90% CI: 0.67-1.16, p = 0.46). Median progression-free survival with chemotherapy plus immunotherapy was 7.7 months (95% CI: 5.5-8.5) and 3.2 months (95% CI: 2.7-5.1) with immunotherapy (hazard ratio = 0.67, 95% CI: 0.52-0.88). The overall response rate with chemoimmunotherapy was 42.4% and 29.3% with immunotherapy (adjusted OR = 1.69, 95% CI: 1.04-2.76). The percentage of patients with grade 3 or higher adverse events was 82% in the chemotherapy plus immunotherapy group and 70% in the immunotherapy group. Exploratory analyses of programmed death-ligand 1 expression and blood-based tumor mutation burden revealed no differential treatment effect on OS., Conclusions: The addition of chemotherapy to durvalumab plus tremelimumab in the first-line treatment of stage IV NSCLC did not improve survival compared with durvalumab plus tremelimumab alone. Further study is warranted to identify patients that benefit from initial immunotherapy alone versus combination chemotherapy plus immunotherapy as first-line treatment., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: There is a strong theoretical rationale for combining checkpoint blockade with cytotoxic chemotherapy in pleural mesothelioma and other cancers. Two recent single-arm, phase 2 trials [DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and Phase II multicenter study of anti-PD-L1, durvalumab, in combination with cisplatin and pemetrexed for the first-line treatment of unresectable malignant pleural mesothelioma (PrE0505)] combining the programmed death ligand-1 (PD-L1) inhibitor durvalumab with standard first-line chemotherapy exceeded prespecified safety and activity criteria to proceed to a phase 3 confirmatory trial to assess this combination. We present the protocol of the DREAM3R trial., Methods and Analysis: This multicentre open-label randomised trial will recruit 480 treatment-naïve adults with advanced pleural mesothelioma, randomised (2:1) to either 3-weekly durvalumab 1500 mg plus 3-weekly doublet chemotherapy (cisplatin 75 mg/m 2 or carboplatin, Area Under the Curve,AUC 5 and pemetrexed 500 mg/m 2 ) 4-6 cycles, followed by 4-weekly durvalumab 1500 mg until disease progression, unacceptable toxicity or patient withdrawal; OR doublet chemotherapy alone for 4-6 cycles, followed by observation. The target accrual time is 27 months, with follow-up for an additional 24 months. This provides over 85% power if the true HR for overall survival (OS) is 0.70, with two-sided alpha of 0.05, assuming a median OS of 15 months in the control group. Randomisation is stratified by age (18-70 years vs >70), sex, histology (epithelioid vs non-epithelioid), platinum agent (cisplatin vs carboplatin) and region (USA vs Australia/New Zealand vs Other). The primary endpoint is OS. Secondary endpoints include progression-free survival, objective tumour response (by mRECIST V.1.1 and iRECIST), adverse events, health-related quality of life and healthcare resource use. Tertiary correlative objectives are to explore and validate potential prognostic and/or predictive biomarkers (including features identified in the DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and PrE0505 studies, PD-L1 expression, tumour mutational burden, genomic characteristics and human leukocyte antigen subtypes) in tissue and serial blood samples. An imaging databank will be assembled for validation of radiological measures of response, and studies of possible radiomic biomarkers in mesothelioma., Ethics and Dissemination: The protocol was approved by human research ethics review committees for all participating sites. Results will be disseminated in peer-reviewed journals and at scientific conferences., Drug Supply: AstraZeneca., Protocol Version: CTC 0231 / TOGA 18/001 / PrE0506 3.0, 29 July 2021., Trial Registration Number: ClinicalTrials.gov Identifier: NCT04334759 ACTRN 12620001199909., Competing Interests: Competing interests: ZS, CB, AC, SY, KaF, KarF, AB, MMC have nothing to disclose. PSK reports grants and fees from AstraZeneca and Pfizer, she is a consultant/ advisory board member of MSD, outside the submitted work; PMF reports grants and fees from AstraZeneca, BMS, Corvus, Novartis, Kyowa; he is a consultant/ advisory board member of Amgen, AstraZeneca, BMS, Novartis, Janssen, Iteos, Mirati, Sanofi; he is a Data Safety Monitoring Board member of Polaris, Flame, outside the submitted work; BH is a consultant/ advisory board member of MSD, BMS, Roche, Pfizer, AstraZeneca, Eisai, Takeda; his institution received grants from Amgen, outside the submitted work; SR reports grants and fees from Amgen, AstraZeneca, Genmab, Eisai, Lilly, Roche, Merck, Takeda and GSK; he is a Data Safety Monitoring Board member of Jansen; a member of Board for Gergia Society of Oncology and IASLC; his institution received grants from AstraZenca, Amgen, BMS, Merck, Genmab, Takeda, Advaxis and Pfizer, outside the submitted work; WJL reports grants and fees from Douglas Pharmaceuticals, and patents relating to immune checkpoint therapy, unrelated to this study, outside the submitted work; KO'B has received advisory board and/or speaker bureau and/or meeting travel/registration support from BMS, MSD, LillyOncology, Boehringer-Ingelheim, Pfizer, Novartis, Roche-Genentech,Teva, Mundipharma, Astrazeneca, Janssen, Natera and TriStar. He is a board member and stock holder for Carpe Vitae Pharmaceuticals and a stock holder for RepLuca Pharmaceuticals and DGC Diagnostics and holds patents for novel therapeutics and diagnostic tests, outside the submitted work; NP reports grants and fees from Boehringer Ingelheim, Bayer, Novartis, Pfizer, Roche, Takeda and Ipsen; he is an advisory board member of Boehringer Ingelheim, MSD, Merck, BMS, Astra Zeneca, Takeda, Pfizer and Roche; his institution received grants from Bayer, Pfizer and Roche, outside the submitted work; JB reports grants and fees from AstraZeneca, BMS, Genentech/Roche, Merck, RAPT Therapeutics, Revolution Medicines, Amgen, Eli Lilly, GlaxoSmithKline, Sanofi, Regeneron; she is a Data Safety Monitoring Board member of GlaxoSmithKline, Sanofi, Janssen; she is an advisory board member of IASLC; outside the submitted work; VA institution received grants from BMS and AstraZeneca; outside the submitted work; MS institution received grants from the following competitive funding bodies: Australian National Health and Medical Research Council, Canadian Cancer Trials Group, Cancer Australia, Medical Research Future Fund of Australia; and the following pharmaceutical companies: Astellas, Amgen, Astra Zeneca, Bayer, Beigene, Bionomics, Bristol-Myers Squibb, Celgene, Medivation, Merck, Merck Sharp & Dohme, Pfizer, Roche, Sanofi, Tilray, outside the submitted work; AKN reports grants and fees from Bayer Pharmaceuticals; Roche Pharmaceuticals; Boehringer Ingelheim; Merck Sharpe Dohme; Douglas Pharmaceuticals, Atara Biotherapeutics, Astra Zeneca (payment to institution); Pharmabcine; Trizell Ltd; Seagen; honoraria from Bristol Myers Squibb and her institution received grants from AstraZeneca and Douglas Pharmaceuticals, outside the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Epidermal growth factor receptor gene (EGFR) exon 20 insertion (ex20-ins) mutations are an uncommon and heterogeneous group of non-small cell lung cancers (NSCLCs), resistant to conventional EGFR tyrosine kinase inhibitors (TKIs). Characteristics and outcomes of patients with EGFR ex20-ins have not been fully established; we sought to clarify them using a multinational patient database., Patients and Methods: Patients with NSCLC from six Australian institutions with EGFR exon 20 mutations (ex20-mut), excluding T790M, were retrospectively reviewed. Clinical characteristics and outcomes with systemic treatments were collected and analyzed using comparative statistics., Results: Among 109 patients with ex20-mut, 61% were females and 75% were Caucasians. More males presented with de novo metastatic disease (84% vs. 51%; P = .002). Central nervous system (48%) and liver (24%) metastases were common within metastatic patients (n = 86). Thirty-nine patients received platinum-based chemotherapy (PBC) and achieved a 43% objective response rate (ORR), median progression-free survival (mPFS) of 6.9 months, and median overall survival (mOS) of 31.0 months. Twenty-three of the patients with ex20-ins received conventional TKIs, resulting in an ORR of 13%, mPFS of 3.4 months (95% confidence interval [CI], 1.91-6.25), and mOS of 31.0 months (95% CI, 15.09-not reached). Nine patients with S786I mutations received TKIs, resulting in an ORR of 50%, mPFS of 18.2 months (2.79-not reached), and mOS of 33.4 months (95% CI, 16.14-not reached). Twenty-three patients received immune checkpoint inhibitor monotherapy (ICIm), resulting in an ORR of 4%, mPFS of 2.6 months (95% CI, 1.91-4.83), and mOS of 30.8 months (95% CI, 17.62-41.62)., Conclusion: Although phenotypically similar to patients with common EGFR mutations, patients with EGFR ex20-mut had worse survival, perhaps due to the lack of targeted therapies. Chemotherapy was superior to conventional EGFR TKIs in patients with EGFR ex20-ins, although there was moderate activity of TKIs in S768I mutations. ICIm was ineffective., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Pembrolizumab provided durable responses and acceptable safety in recurrent or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC) in the KEYNOTE-629 study. In this elderly, fragile population with disfiguring tumours, preservation of health-related quality of life (HRQoL) is critical. Here, we present pre-specified exploratory HRQoL analyses from the first interim analysis of KEYNOTE-629., Methods: Patients with R/M cSCC not amenable to surgery or radiation therapy received pembrolizumab 200 mg every 3 weeks for ≤ 24 months. HRQoL end points included change from baseline to week 12 in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) global health status (GHS)/QoL, functioning, symptom and European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) scores and change from baseline through week 48 in EORTC QLQ-C30 GHS/QoL and physical functioning scores. Improvement (≥ 10-point increase post-baseline with confirmation) was assessed using the exact binomial method., Results: Analyses included 99 patients for EORTC QLQ-C30 and 100 for EQ-5D-5L. Compliance was > 80% at week 12. Mean scores were stable from baseline to week 12 for GHS/QoL (4.95 points; 95% confidence interval, -1.00 to 10.90) and physical functioning (-3.38 points; 95% confidence interval, -8.80 to 2.04). EORTC-QLQ-C30 functioning, symptom, and EQ-5D-5L scores remained stable at week 12. Post-baseline scores were improved in 29.3% of patients for GHS/QoL, 17.2% for physical functioning, and in a numerically higher proportion of responders versus non-responders (GHS/QoL, 55.6% versus 16.1%; physical functioning, 36.1% versus 7.1%)., Conclusions: In elderly patients with R/M cSCC, the clinical efficacy of pembrolizumab translates into a benefit validated by HRQoL preservation or improvement during treatment., Trial Registration: ClinicalTrials.gov identifier: NCT03284424., (© 2021. The Author(s).)

The activating receptor CD226 is expressed on lymphocytes, monocytes, and platelets and promotes anti-tumor immunity in pre-clinical models. Here, we examined the role of CD226 in the function of tumor-infiltrating lymphocytes (TILs) and resistance to immunotherapy. In murine tumors, a large proportion of CD8 + TILs had decreased surface expression of CD226 and exhibited features of dysfunction, whereas CD226 hi TILs were highly functional. This correlation was seen also in TILs isolated from HNSCC patients. Mutation of CD226 at tyrosine 319 (Y319) led to increased CD226 surface expression, enhanced anti-tumor immunity and improved efficacy of immune checkpoint blockade (ICB). Mechanistically, tumor-derived CD155, the ligand for CD226, initiated phosphorylation of Y319 by Src kinases, thereby enabling ubiquitination of CD226 by CBL-B, internalization, and proteasomal degradation. In pre-treatment samples from melanoma patients, CD226 + CD8 + T cells correlated with improved progression-free survival following ICB. Our findings argue for the development of therapies aimed at maintaining the expression of CD226., Competing Interests: Declaration of Interests M.J.S. has research agreements with Bristol Myers Squibb (BMS) and Tizona Therapeutics and is on the Scientific Advisory Board of Tizona Therapeutics and Compass Therapeutics. T.B. has research agreements with BMS. B.G.M.H. is a consultant advisor to BMS, Merck Sharp and Dohme, Roche, AstraZenca, Pfizer, Eisai, and Takeda and has research agreements with Amgen. G.V.L. is a consultant advisor to Aduro, Amgen, Mass-Array, BMS, Merck MSD, Novartis, Roche, OncoSec Medical, Sandoz, and Pierre Fabre. A.M. is a consultant advisor for BMS, Merck MSD, Novartis, Roche, and Pierre Fabre. W.C.D. declares a scientific research agreement with BMS, consulting agreements with Omeros Corp. and Cascadia Drug Development Group, and receipt of speaker’s honoraria from Amgen. A.V. has research agreements with BMS. R.A.S. has received fees for professional services from Novartis Pharma AG, MSD Sharp & Dohme (Australia), NeraCare, AMGEN Inc., BMS, Novartis Pharmaceuticals Australia Pty. Limited, Myriad Genetics GmbH, GlaxoSmithKline Australia. L.F. reported grants from the Swiss National Science Foundation, Swiss Cancer League, Hookipa Pharma, Krebsliga Schweiz, and Novartis Foundation as well as an advisory role for Novartis and BMS. S.E.N. has a research agreement with Servier. M.B., M.J.S., and T.B. have registered a patent for the use of CD226 in cancer immunotherapies (Australian Provisional Patent Application No. 2019900621)., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling in vivo . In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti-PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8 + T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. SIGNIFICANCE: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti-PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. See related commentary by Sitkovsky, p. 16 . This article is highlighted in the In This Issue feature, p. 1 ., (©2019 American Association for Cancer Research.)

Background  Perineural spread (PNS) is a marker of aggressiveness and has been shown to occur in cranial nerves due to advanced mucosal and cutaneous head and neck cancer. Receptors CXC chemokine receptor 4 (CXCR4) and programmed cell death-1 (PD-1) have been shown to be overexpressed in a variety of cancers with PNS, with the inhibition of these pathways offering a potential future treatment. Methods  Retrospective immunohistochemical staining for the CXCR4 and PD-1 receptors was performed on 28 head and neck specimens that demonstrated PNS from January 2017 to August 2017, at Royal Brisbane and Women's Hospital, Brisbane, Australia. Results  CXCR4 staining was positive in 52 and 60% of the squamous cell carcinoma (SCC) and adenoid cystic carcinoma PNS specimens, respectively. Cutaneous SCC tumors with no PNS stained positively in 33%. No significant staining for PD-1 in peritumoral lymphocytes or tumor specimens was seen. Conclusion  CXCR4 is overexpressed in advanced skin cancer and head and neck tumors that demonstrated PNS to large cranial nerves. Overall, these results provide strong support for using CXCR4 as a biomarker and further investigation of immunotherapeutic agents that could inhibit tumor progression via targeting CXCR4 expression.

Background: The optimal method of tube feeding for patients with head and neck cancer remains unclear. A validated protocol is available that identifies high-nutritional-risk patients who would benefit from prophylactic gastrostomy tube placement. Adherence to this protocol is ultimately determined by clinical team discretion or patient decision., Objective: The study aim was to compare outcomes after adherence and nonadherence to this validated protocol, thus comparing a prophylactic and reactive approach to nutrition support in this patient population., Design: We conducted a prospective comparative cohort study. Patients were observed during routine clinical practice over 2 years., Participants/setting: Patients with head and neck cancer having curative-intent treatment between August 2012 and July 2014 at a tertiary hospital in Queensland, Australia, were included if assessed as high nutrition risk according to the validated protocol (n=130). Patients were grouped according to protocol adherence as to whether they received prophylactic gastrostomy (PEG) per protocol recommendation (prophylactic PEG group, n=69) or not (no PEG group, n=61)., Main Outcome Measures: Primary outcome was percentage weight change during treatment. Secondary outcomes were feeding tube use and hospital admissions., Statistical Analysis Performed: Fisher's exact, χ 2 , and two sample t tests were performed to determine differences between the groups. Linear and logistic regression were used to examine weight loss and unplanned admissions, respectively., Results: Patients were 88% male, median age was 59 years, with predominantly stage IV oropharyngeal cancer receiving definitive chemoradiotherapy. Statistically significantly less weight loss in the prophylactic PEG group (7.0% vs 9.0%; P=0.048) and more unplanned admissions in the no PEG group (82% vs 75%; P=0.029). In the no PEG group, 26 patients (43%) required a feeding tube or had ≥10% weight loss., Conclusions: Prophylactic gastrostomy improved nutrition outcomes and reduced unplanned hospital admissions. Additional investigation of characteristics of patients with minimal weight loss or feeding tube use could help refine and improve the protocol., (Copyright © 2018 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

In recent years, there has been a major paradigm shift in the management of non-small cell lung cancer (NSCLC). NSCLC should now be further sub-classified by histology and driver mutation if one is known or present. Translational research advances now allow such mutations to be inhibited by either receptor monoclonal antibodies (mAb) or small molecule tyrosine kinase inhibitors (TKI). Whilst empirical chemotherapy with a platinum-doublet remains the gold standard for advanced NSCLC without a known driver mutation, targeted therapy is pushing the boundary to significantly improve patient outcomes and quality of life. In this review, we will examine the major subtypes of oncogenic drivers behind NSCLC as well as the development of targeted agents available to treat them both now and in the foreseeable future.

Advances in the treatment of non-small cell lung cancer (NSCLC) over the last decade have predominantly involved the development of therapies directed at molecular targets such as mutations in the epidermal growth factor receptor (EGFR) or rearrangements in the anaplastic lymphoma kinase (ALK) gene. Other targets have been discovered at low frequency, with multiple agents approved or in development for treatment of these rare molecular subtypes. The tumour microenvironment has also provided opportunities for therapies targeting angiogenesis and the host immune response. This review will provide an overview of current targeted therapies in NSCLC and promising treatment approaches on the horizon.