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Purpose: Nivolumab plus relatlimab and nivolumab plus ipilimumab have been approved for advanced melanoma on the basis of the phase II/III RELATIVITY-047 and phase III CheckMate 067 trials, respectively. As no head-to-head trial comparing these regimens exists, an indirect treatment comparison was conducted using patient-level data from each trial., Methods: Inverse probability of treatment weighting (IPTW) adjusted for baseline characteristic differences. Minimum follow-ups (RELATIVITY-047, 33 months; CheckMate 067, 36 months) were selected to best align assessments. Outcomes included progression-free survival (PFS), confirmed objective response rate (cORR), and melanoma-specific survival (MSS) per investigator; overall survival (OS); and treatment-related adverse events (TRAEs). A Cox regression model compared PFS, OS, and MSS. A logistic regression model compared cORRs. Subgroup analyses were exploratory., Results: After IPTW, key baseline characteristics were balanced for nivolumab plus relatlimab (n = 339) and nivolumab plus ipilimumab (n = 297). Nivolumab plus relatlimab demonstrated similar PFS (hazard ratio [HR], 1.08 [95% CI, 0.88 to 1.33]), cORR (odds ratio, 0.91 [95% CI, 0.73 to 1.14]), OS (HR, 0.94 [95% CI, 0.75 to 1.19]), and MSS (HR, 0.86 [95% CI, 0.67 to 1.12]) to nivolumab plus ipilimumab. Subgroup comparisons showed larger numerical differences favoring nivolumab plus ipilimumab with acral melanoma, BRAF -mutant melanoma, and lactate dehydrogenase >2 × upper limit of normal, but were limited by small samples. Nivolumab plus relatlimab was associated with fewer grade 3-4 TRAEs (23% v 61%) and any-grade TRAEs leading to discontinuation (17% v 41%)., Conclusion: Nivolumab plus relatlimab demonstrated similar efficacy to nivolumab plus ipilimumab in the overall population, including most-but not all-subgroups, and improved safety in patients with untreated advanced melanoma. Results should be interpreted with caution.

Background: Immune checkpoint inhibitors (ICIs) have been employed in the adjuvant and metastatic setting of renal cell carcinoma (RCC) treatment. Among ICIs, combined immunotherapy has the highest risk for immune-related adverse events (irAEs). We aimed to document the incidence of irAEs in RCC patients treated with nivolumab and ipilimumab as data from the European population remain limited., Materials and Methods: We analysed data from 88 RCC patients treated with nivolumab + ipilimumab between May 2022 and June 2024 across six high-volume oncology units in Poland. We reviewed irAEs and estimated their impact on survival parameters via univariate and multivariate Cox proportional hazards regression models, along with log-rank tests., Results: With a median follow-up of 11.3 months, the median overall survival (OS) was not reached, whereas the median progression-free survival (PFS) was 12.8 months (6.3-19.3). A total of 74 irAEs were recorded in 50 patients. The most frequent events were endocrine (n = 20, 27%), hepatic (n = 15, 17%), general (n = 12, 13.6%), and cutaneous (n = 11, 12.5%). The occurrence of irAEs was associated with a 60% lower risk of disease progression (hazard ratio 0.44, 95% confidence interval 0.2-0.87, p = 0.018) without impacting OS and higher disease control rate (n = 45, 90% vs. n = 24, 63.2%, p = 0.004). In contrast, patients with hepatotoxicity had poorer outcomes, with a 2.6-fold greater risk of death (p = 0.05)., Conclusions: IrAEs may serve as a predictive factor for the efficacy of the nivolumab + ipilimumab regimen in RCC patients. Special attention is needed for hepatotoxicity, as it can significantly impact survival outcomes., Competing Interests: Declarations Competing interests RPM travel grants from Accord, BMS, MSD, lecture fees from BMS, GSK, Novartis, Roche; AD travel grants and lecture fees from Roche, BMS, Janssen, Molteni, MSD, Accord; ŁS travel grants from BMS, Accord; AD travel grants and lecture fees from BMS, MSD, Astellas, Merck, Servier, Astra Zeneca, Pfizer; JD travel grants and lecture fees from Amgen, AstraZeneca, BMS, MSD, Novartis, Nutricia; AGW travel grants and lecture fees from Roche, Novaris, Lili, Astellas, Pfizer, Amgen, Swixx, Pierre Fabre, Egis, BMS, MSD; AR travel grants and lecture fees from Roche, BMS, Ipsen, Pfizer, Novartis, Gilead, MSD; DTM travel grants and lecture fees from MSD, Pierre Fabre, BMS, Novartis, Pfizer; JW no declared; PB travel grants, lecture fees, and advisory boards from AstraZeneca, MSD, GSK, Pharma; MP travel grants and lecture fees from AstraZeneca, Roche, Novartis, Elli Lilly, Janssen, Gilead and Amgen; Ethical approval The study protocol was approved by the Bioethics Committee of Jagiellonian University Medical College (decision number 118.0043.1.115.2024 dated April 19, 2024). Informed consent Standard institutional informed consent was obtained from each patient before initiating the nivolumab + ipilimumab treatment. Consent for publication Not applicable., (© 2024. The Author(s).)

Background: Clear cell sarcoma (CCS) and alveolar soft part sarcoma (ASPS) are rare, and standard systemic therapy is not established except for sunitinib in ASPS. It is known that CCS and ASPS have a common biological feature of melanoma and Xp11.2/TFE3 translocation renal cell carcinoma, and immune-checkpoint inhibitors (ICIs) are effective in these tumors. The authors conducted a phase 2 trial to evaluate the efficacy and safety of nivolumab for CCS and ASPS., Methods: The number of patients expected to be enrolled was 15-25 and was determined based on the Bayesian design. The primary end point was the confirmed objective response rate (ORR) according to the central review and the secondary end points included ORR, progression-free survival (PFS), overall survival (OS), and safety., Results: A total of 26 patients (CCS, 12; ASPS, 14) were enrolled. Efficacy and safety were analyzed on 25 and 26 patients, respectively. The minimum number of responses required for a positive conclusion regarding the efficacy was four. However, only one patient (4.0%) with ASPS had a partial response. Complete response, stable disease, progression disease, and not evaluable were 0%, 60%, 32%, and 4.0%, respectively. Adverse events of grade 3 or 4 occurred in 57.7% (15 of 26). The median PFS was 4.9 months (95% confidence interval [CI], 3.7-8.6 months) and the median OS was 15.8 months (95% CI, 8.2-not reached)., Conclusions: The primary end point of the ORR was not met for CCS and ASPS on the central review. Further studies are needed to evaluate ICIs in patients with ASPS., (© 2024 American Cancer Society.)

Pancreatic ductal adenocarcinoma (PDA) is characterized by low cytotoxic lymphocytes, abundant immune-suppressive cells, and resistance to immune checkpoint inhibitors (ICI). Preclinical PDA models showed the HDAC inhibitor entinostat reduced myeloid cell immunosuppression, sensitizing tumors to ICI therapy. This phase II study combined entinostat with nivolumab (PD1 inhibitor) in patients with advanced PDA (NCT03250273). Patients received entinostat 5 mg orally once weekly for 14-day lead-in, followed by entinostat and nivolumab. The primary endpoint was the objective response rate (ORR) by RECIST v1.1. Secondary endpoints included safety, duration of response, progression free-survival and overall survival. Between November 2017 and November 2020, 27 evaluable patients were enrolled. Three showed partial responses (11% ORR, 95% CI, 2.4%-29.2%) with a median response duration of 10.2 months. Median progression-free survival (PFS) and overall survival (OS) were, respectively, 1.89 (95% CI, 1.381-2.301) and 2.729 (95% CI, 1.841-5.622) months. Grade ≥3 treatment-related adverse events occurred in 19 patients (63%), including decreased lymphocyte count, anemia, hypoalbuminemia, and hyponatremia. As exploratory analysis, peripheral and tumor immune profiles changes were assessed using CyTOF, mIHC, and RNA-seq. Entinostat increased dendritic cell activation and maturation. Gene expression analysis revealed an enrichment in inflammatory response pathways with combination treatment. Although the primary endpoint was not met, entinostat and nivolumab showed durable responses in a small subset of PDA patients. Myeloid cell immunomodulation supported the preclinical hypothesis, providing a basis for future combinatorial therapies to enhance clinical benefits in PDA., Competing Interests: Competing interests M.B. served on advisory boards for AstraZeneca, Incyte. C.B.B is an employee of, and holds equity in, Akoya Biosciences, Inc. W.J.H. reports patent royalties from Rodeo/Amgen; grants from Sanofi, NeoTX, and Riboscience; speaking/travel honoraria from Exelixis and Standard BioTools. MY receives grant/research support (to Johns Hopkins) from Bristol-Myers Squibb, Exelixis, Incyte, and Genentech; receives honoraria from Genentech, Exelixis, AstraZeneca, Replimune, Hepion, Lantheus; MY is the co-inventor of patents pertaining to cancer vaccines and is a cofounder with equity of Adventris Pharmaceuticals, all outside of the submitted work. E.J.F is on the scientific advisory board for Resistance Bio, has consulted for Merck and Mestag Therapeutics, and receives research grants from Roche/Genetech and Abbvie Inc. L.M.C. has received reagent support from Cell Signaling Technologies, Syndax Pharmaceuticals, Inc., ZielBio, Inc., and Hibercell, Inc.; holds sponsored research agreements with Syndax Pharmaceuticals, Hibercell, Inc., Prospect Creek Foundation, Lustgarten Foundation for Pancreatic Cancer Research, Susan G. Komen Foundation, and the National Foundation for Cancer Research; is on the Advisory Board for Dispatch Biotherapeutics, Carisma Therapeutics, Inc., CytomX Therapeutics, Inc., Shasqi, Kineta, Inc., Hibercell, Inc., Cell Signaling Technologies, Inc., Alkermes, Inc., Raska Pharma, Inc., NextCure, Guardian Bio, AstraZeneca Partner of Choice Network (OHSU Site Leader), Genenta Sciences, Pio Therapeutics Pty Ltd., and Lustgarten Foundation for Pancreatic Cancer Research Therapeutics Working Group, Inc. E.J. reports other support from Abmeta, other support from Adventris, personal fees from Achilles, personal fees from DragonFly, non-financial support from Parker Institute, personal fees from Surge, grants from Lustgarten, grants from Genentech, personal fees from Mestag, personal fees from Medical Home Group, non-financial support from BMS, grants from Break Through Cancer, personal fees from CPRIT, personal fees from Neuvogen, non-financial support from HDT Bio, and personal fees from NeoTx outside the submitted work. N.S.A. receives grant/research support (to Johns Hopkins) from Bristol-Myers Squibb. L.D., J.N.D., L.C., D.N.S., J.A.T., S.C., N.G., A.H., C.T., R.W., J.L., S.M., B.C., A.S., D.A.G., S.Y. declare no competing interest related to this study., (© 2024. The Author(s).)

Background: In phase 1-2 trials in patients with resectable, macroscopic stage III melanoma, neoadjuvant immunotherapy was more efficacious than adjuvant immunotherapy., Methods: In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma to two cycles of neoadjuvant ipilimumab plus nivolumab followed by surgery or surgery followed by 12 cycles of adjuvant nivolumab. Only patients in the neoadjuvant group with a partial response or nonresponse received adjuvant treatment. The primary end point was event-free survival., Results: A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% in patients in the neoadjuvant group who had a major pathological response, 76.1% among those with a partial response, and 57.0% among those with a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of patients in the neoadjuvant group and in 14.7% in the adjuvant group., Conclusions: Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.)., (Copyright © 2024 Massachusetts Medical Society.)

Background/aim: Nivolumab and ipilimumab (NIVO+IPI) is standard therapy for patients with intermediate and poor risk advanced renal cell carcinoma (RCC). However, the efficacy and safety of NIVO+IPI in elderly patients aged >75 years remains unclear. This study aimed to determine the efficacy and safety of first-line NIVO+IPI treatment in patients aged >75 years with advanced RCC., Patients and Methods: This study included 59 patients with advanced RCC who received NIVO+IPI as first-line therapy between September 2018 and December 2023. Objective response rates (ORRs), along with progression-free survival (PFS) and overall survival (OS) were compared between patients aged <75 years and ≥75 years, to assess survival outcomes., Results: A total of 46 (78.0%) and 13 (22.0%) patients were classified into <75 years and ≥75 years groups, respectively, at NIVO+IPI initiation. The ORRs were 45.7% for <75 years and 53.8% for ≥75 years (p=0.2422). No significant differences in PFS (p=0.0729) were observed between groups. In contrast, patients aged ≥75 years had better OS than those aged <75 years (p=0.0212). However, no significant difference was observed in the OS between the two groups of patients with clear cell histology (p=0.0532). The incidence of immune-related adverse events higher than Grade 3 was not significantly different between the two groups (p=0.5016)., Conclusion: NIVO and IPI combination therapy is both safe and efficacious in patients aged ≥75 years with advanced RCC., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Perioperative immunotherapy improves short-term outcomes in resectable non-small-cell lung cancer (NSCLC). We now report 5-year survival from the NADIM trial to assess its long-term benefit., Methods: NADIM was a multicentre, single-arm, phase 2 trial conducted across 18 hospitals in Spain. Patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had histologically or cytologically confirmed, treatment-naive, resectable stage IIIA NSCLC (American Joint Committee on Cancer, 7th edition criteria). The neoadjuvant treatment consisted of three cycles of intravenous paclitaxel (200 mg/m 2 ) and carboplatin (area under the curve 6 mg/mL per min) with nivolumab (360 mg). After surgery, 1 year of adjuvant treatment with intravenous nivolumab monotherapy was administered (240 mg every 2 weeks for 4 months, followed by 480 mg every 4 weeks for 8 months). The primary endpoint was 24-month progression-free survival, with 5-year progression-free survival and overall survival as secondary endpoints, assessed in the intention-to-treat population (ie, all patients who received neoadjuvant treatment). Toxicity profile was also assessed as a secondary endpoint. This trial is registered at ClinicalTrials.gov (NCT03081689) and is complete; this is the final report of the trial., Findings: Between April 26, 2017, and Aug 25, 2018, 51 patients were assessed for eligibility, of whom 46 comprised the intention-to-treat population (34 [74%] male and 12 [26%] female, median age 63 years [IQR 58-70]). Follow-up was concluded at 60 months (data cutoff July 11, 2023; median follow-up 60·0 months [IQR 60·0-60·0]). 5-year progression-free survival in the intention-to-treat population was 65·0% (95% CI 49·4-76·9), and overall survival was 69·3% (53·7-80·6). Disease progression occurred in 11 (24%) patients; 14 (30%) patients died, including nine (20%) from disease relapse and five (11%) from non-tumour-related causes. Treatment-related adverse events (TRAEs) of grade 3 or worse occurred in 14 (30%) of 46 patients during neoadjuvant treatment and in seven (19%) of 37 during adjuvant treatment. The most common grade 3 or worse TRAEs were increased lipase and febrile neutropenia (three [7%] each) during neoadjuvant treatment, and elevated serum lipase (four [7%]) and elevated serum amylase (three [8%]) during adjuvant treatment. Serious TRAEs included elevated serum lipase and neutropenia (one [2%] each) during neoadjuvant treatment, and elevated serum lipase (one [3%]) during adjuvant treatment. No treatment-related surgery delays, deaths, or unexpected long-term toxicities were reported., Interpretation: Perioperative chemoimmunotherapy showed a promising long-term benefit with no concerning safety data, reinforcing its use in resectable stage IIIA NSCLC., Funding: Bristol-Myers Squibb, Spanish Ministry of Science, Instituto de Salud Carlos III, European Union., Competing Interests: Declaration of interests MP reports non-financial support (reagents for T-cell receptor sequencing) from ThermoFisher Scientific; grants, consulting fees, and non-financial support from Bristol Myers Squibb, Roche, and AstraZeneca; and consulting fees from MSD and Takeda; outside the submitted work. EN reports grants from Roche, Pfizer, Bristol Myers Squibb, Merck, and Nanostring; consulting fees from Roche, Bristol Myers Squibb, Merck Sharpe & Dohme, Merck-Serono, Sanofi, Pfizer, Lilly, Amgen, Janssen, Daiichi-Sankyo, Boehringer-Ingelheim, AstraZeneca, Takeda, Sanofi, Pierre Fabre, Qiagen, and Bayer; payment of honoraria from Roche, Bristol Myers Squibb, Merck Sharpe & Dohme, Sanofi, Pfizer, Lilly, Amgen, Janssen, Daiichi-Sankyo, Boehringer-Ingelheim, AstraZeneca, Takeda, Sanofi, and Qiagen; support for attending meetings or travel from Takeda, MSD, Janssen, and Roche; and participation on advisory boards for Apollomics, Roche, and Pfizer. AI reports consulting fees from Pfizer, Amgen, and Astra Zeneca; payment for expert testimony from Bristol Myers Squibb, Roche, Pfizer, Astra Zeneca, and Takeda; support for attending meetings or travel from Roche, Takeda, and Pfizer; and participation on advisory boards for Roche and Bristol Myers Squibb. RG-C reports consulting fees from Bristol Myers Squibb, MSD, Roche, Pfizer, and AstraZeneca. MD reports consulting fees from AstraZeneca, Bristol Myers Squibb, MSD Oncology, Pfizer, Roche, and Takeda; and support for attending meetings or travel from AstraZeneca, MSD Oncology, Pfizer, and Takeda. BM reports consulting fees from Astra Zeneca and Amgen; payment or honoraria from Roche, Bristol Myers Squibb, and MSD; and support for attending meetings or travel from MSD and AstraZeneca. MM reports grants from Roche and Astra Zeneca; payment of honoraria from Roche, AstraZeneca, MSD, Pfizer, Helsinn, Cassen, Amgen, Janssen, Sanofi, Pierre Fabre, Bristol Myers Squibb, and Takeda; and support for attending meetings or travel from MSD, Roche, and AstraZeneca. DR-A reports honoraria for lectures from MSD, Roche, Bristol Myers Squibb, Novartis, Takeda, Lilly, and AstaZeneca; support for attending meetings or travel from Roche, MSD, Novartis, and Sanofi; and participation on advisory boards for Merck Sharpe & Dohme, Regeneron, Bristol Myers Squibb, GSK, and Lilly. AM-M reports consulting fees from AstraZeneca/MedImmune, Bristol Myers Squibb, F. Hoffmann La Roche, Merck Sharpe & Dohme, MSD Oncology, Pfizer, and Janssen; payment for expert testimony from AstraZeneca, MedImmune, Bristol Myers Squibb, and F. Hoffmann La Roche; support for attending meetings or travel from AstraZeneca, MedImmune, Bristol-Myers Squibb, F. Hoffmann La Roche, Merck Sharpe & Dohme, MSD Oncology, Pfizer, Janssen, and Lilly; and participation on advisory boards for AstraZeneca, MedImmune, Merck Sharpe & Dohme, F. Hoffmann La Roche, and Bristol-Myers Squibb. JdC reports consulting fees from AstraZeneca, Bristol Myers Squibb, Roche, MSD, Boehringer, Janssen, Lilly, Sanofi, Takeda, Pfizer, and GSK; support for attending meeting or travel from AstraZeneca, MSD, and Roche; participation on advisory boards for AstraZeneca, Bristol Myers Squibb, Roche, MSD, Glaxo, Janssen, and Gilea; and speaker's bureau fees from AstraZeneca/MedImmune, Bristol-Myers Squibb, F. Hoffmann La Roche, Merck Sharpe & Dohme, MSD Oncology, Pfizer, and Janssen. DG reports payment or honoraria from Astra Zeneca and Bristol Myers Squibb. VC reports consulting fees from Roche, AstraZeneca, MSD, Bristol Myers Squibb, Takeda, Sanofi, and Amgen; payment or honoraria from Roche, AstraZeneca, MSD, Bristol Myers Squibb, Takeda, SanofiI, and Amgen; and support for attending meetings or travel from AstraZeneca, Roche, MSD, and Takeda. RP reports payment or honoraria from Guardant Health and Pfizer; and support for attending meetings or travel from Merck Sharpe & Dohme; participation on an advisory board for AstraZeneca. AR reports payment or honoraria from Illumina, Health in Code, and ThermoFisher Scientific; support for attending meetings or travel from ThermoFisher Scientific, Bristol Myers Squibb Foundation, and Takeda; and advisory board participation for Takeda. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Immune checkpoint inhibitors (ICIs) carry the risk of immune-related adverse events (irAEs), a significant concern as therapy has transitioned to the adjuvant setting. Balancing therapeutic benefits against potential risks is crucial, necessitating real-world data from an unselected patient population in addition to clinical trial data to ensure optimal clinical decision-making., Methods: This nationwide real-world study assessed irAEs in patients receiving adjuvant anti-PD1 therapy, primarily nivolumab, for resected stage III-IV melanoma between 2018-2022. Data were retrieved from two national databases: the IMMUNOTOX database and the Danish Metastatic Melanoma Database (DAMMED). IrAEs were sub-grouped according to organ systems graded using CTCAE ver. 5.0 ranging from mild toxicities (grade 1-2) to severe (grade 3-4) and fatal (grade 5)., Results: Among 792 included patients, (55 % male, median age 62 years (range 16-88)), 697 patients (88 %) experienced an irAE. Severe irAEs occurred in 116 patients (15 %) and five (0.6 %) died due to toxicity. A landmark analysis showed that patients who experienced at least one irAE before the 1st evaluation at 90 days had an increased progression free survival (PFS) (p = 0.032) and overall survival (OS) (p = 0.0071). Additionally, a seasonal pattern was noted with higher incidence of irAEs during summer., Conclusion: The prevalence of irAEs in real-world patients is comparable to the observed risk in clinical trials. Patients experiencing irAEs demonstrate a lower risk of melanoma relapse. Further, gender, age and seasonal variation may impact the incidence of irAEs., Competing Interests: Declaration of Competing Interest Within the last two years: RSJ received travel/conference expenses from Pierre Fabre. LMG has received honoraria for lectures from BMS and from MSD for travel and conference support. MD has received proprietary data access from Bristol Myers Squibb and Genentech and is an advisor of Achilles Therapeutics. CAH has received honoraria for lectures from BMS, AstraZeneca and GSK and consultancies for AstraZeneca. HSC has received research grant from MSD. CHR reports grants from Novo Nordisk Foundation and Helsinn Healthcare SA, and personal fees from Bristol-Myers Squibb, Helsinn Healthcare SA, Pharmanovia, and Astellas Pharma outside the submitted work. IMS has received honoraria for consultancies and lectures from IO Biotech, Novartis, MSD, Pierre Fabre, BMS, Novo Nordisk, TILT Bio; research grants from IO Biotech, BMS, Lytix, Adaptimmune, TILT Bio. EE received honoraria from BMS, Pierre Fabre, Novartis, and MSD for consultancies and lectures, and from MSD and Pierre Fabre for travel and conference support. MD has received honoraria for lectures from Roche (past 2 years) and received access to research data from Bristol Myers Squibb and from Genentech. All other authors declare that they have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Nivolumab (Opdivo ® ) is the first anti-PD-1 antibody approved in the world. LY01015 is a potential biosimilar of nivolumab., Objectives: This phase I study aimed to establish the pharmacokinetic equivalence between LY01015 and the original investigational nivolumab (Opdivo ® ) in healthy Chinese male subjects. Additionally, safety and immunogenicity were assessed., Patients and Methods: A randomized, double-blind, parallel-controlled, phase I trial was conducted with 176 healthy male adults receiving a single intravenous infusion of LY01015 or nivolumab at 0.3 mg/kg. Pharmacokinetics, safety, and immunogenicity were evaluated over a 99-day period. The primary pharmacokinetics endpoint was AUC 0-∞ , and the secondary pharmacokinetic endpoints included AUC 0-t and C max . Pharmacokinetic bioequivalence was confirmed using standard equivalence margins of 80.00-125.00%., Results: This study is the first to report on the pharmacokinetics, safety, and immunogenicity of Opdivo ® in healthy individuals. The pharmacokinetics profiles of LY01015 and Opdivo ® were found to be comparable. The geometric mean ratios (90% confidence intervals) for the AUC 0-∞ , AUC 0-t , and C max of LY01015 to Opdivo ® were 94.49% (90.29-98.88%), 94.92% (88.73-101.54%), and 96.55% (93.32-99.90%), respectively, falling within the conventional bioequivalence criteria of 80.00-125.00%. The safety and immunogenicity were also comparable between the two groups., Conclusions: LY01015 demonstrated highly similar pharmacokinetics to nivolumab in healthy Chinese male subjects. Both drugs exhibited comparable safety and immunogenicity profiles., Trial Registration: This trial is registered at the Chinese Clinical Trial Registry website ( https://www.chictr.org.cn/ #ChiCTR2200064771)., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Mismatch repair deficiency (dMMR) is found in approximately 15% of non-metastatic colon cancers (CCs) and is characterized by a defective DNA mismatch repair system, resulting in hypermutated and highly immunogenic tumors. Although patients with dMMR CC have limited benefit from chemotherapy, these tumors have been shown to respond exceptionally well to neoadjuvant anti-PD-1 plus anti-CTLA-4, with high rates of pathologic responses. Here, based on data from melanoma studies, we postulated a high efficacy and favorable toxicity profile of anti-PD-1 plus anti-LAG-3. In the NICHE-3 study, a total of 59 patients with locally advanced dMMR CC were treated with two 4-weekly cycles of nivolumab (480 mg) plus relatlimab (480 mg) before surgery. Pathologic response was observed in 57 of 59 (97%; 95% confidence interval (CI): 88-100%) patients, meeting the primary endpoint. Responses included 54 (92%; 95% CI: 81-97%) major pathologic responses (≤10% residual viable tumor) and 40 (68%; 95% CI: 54-79%) pathologic complete responses. With a median follow-up of 8 months (range, 2-19), one patient had recurrence of disease. The treatment displayed an acceptable safety profile, with all-grade and grade 3-4 immune-related adverse events (irAEs) occurring in 80% and 10% of patients, respectively. The most common irAEs were infusion-related reactions (29%), thyroid dysfunction (22%) and fatigue (20%). In conclusion, our results show that neoadjuvant nivolumab/relatlimab induces high rates of pathologic responses and that further investigation of this treatment in larger studies is warranted. These data add to the body of evidence in support of neoadjuvant immunotherapy regimens in dMMR CC. ClinicalTrials.gov identifier: NCT03026140 ., Competing Interests: Competing interests J.B.A.G.H. is an advisor to Achilles Therapeutics, AstraZeneca, BioNTech, Bristol Myers Squibb, Curevac, Gadeta, Imcyse, Immunocore, Iovance Therapeutics, Ipsen, Merck Serono, Merck Sharp & Dohme, Molecular Partners, Neogene Therapeutics, Novartis, Pfizer, PokeAcel, Roche, Sanofi, Sastra Cell Therapy, Third Rock Ventures and T-Knife and has received research grants unrelated to this study from Amgen, Asher Bio, BioNTech US, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis and Sastra Cell Therapy. J.B.A.G.H. owns stock in Neogene Therapeutics. All grants were paid to the institutions. T.N.S. is a venture partner at Third Rock Ventures. T.N.S. is founder of, advisor to and stockholder in Asher Bio, Cell Control and Neogene Therapeutics. T.N.S. is advisor to and stockholder in Allogene Therapeutics, Merus and Scenic Biotech. M.C. is advisor to Bristol Myers Squibb, Kineta, Merck Sharp & Dohme, NOUSCOM and Roche/Genentech and has received research grants unrelated to this study from Agenus, Merck Sharp & Dohme and Roche/Genentech. All grants were paid to the institutions. The other authors declare no competing interests., (© 2024. The Author(s).)

Mucosal malignant melanoma (MMM) is a rare subtype of malignant melanoma with a more aggressive biological behavior than cutaneous melanoma (CM). Owing to its rarity, it is necessary to accumulate information on treatments, especially in Asians, in whom MMM occurs more frequently than in Caucasians. In this study, we investigated the efficacy and adverse events (AEs) of nivolumab plus ipilimumab therapy (NIVO+IPI) versus immune checkpoint inhibitor (ICI) monotherapy (PD-1) in Japanese patients with MMM. We reviewed patients with advanced or recurrent MMM who received ICIs as first-line systematic therapy between February 2012 and February 2024 at the Shizuoka Cancer Center. We enrolled a total of 57 patients: 10 (17.5%) were treated with NIVO+IPI, and 47 (82.5%) were treated with PD-1 as first-line systemic therapy. Objective response rates (ORR) did not differ significantly between the NIVO+IPI and PD-1 groups (40.0% vs 27.7%; p = 0.176). There was also no statistically significant difference in progression-free survival (PFS) (median PFS time: 4.3 months vs 9.9 months, log-rank test, p = 0.578) or overall survival (OS) (median OS time: 33.1 months vs. 22.8 months, log-rank test, p = 0.697) between the two groups. However, regarding AEs, grade ≥3 AEs leading to discontinuation of first-line treatment occurred in 80% of patients in the NIVO+IPI group and in 22.6% of patients in the PD-1 group (p = 0.002). No difference was found in the efficacy of NIVO+IPI therapy and anti-PD-1 antibody monotherapy as the first-line treatment for MMM in Japanese patients, but an increase in AEs was observed with combination therapy. This study suggests that patients with MMM may receive less benefit from NIVO+IPI than from PD-1., (© 2024 The Author(s). The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Most patients with Primary Mediastinal B-Cell Lymphoma (PMBCL) are cured by rituximab and doxorubicin-based immunochemotherapy, with or without radiotherapy. In cases with relapsed and refractory (RR) disease the prognosis was historically poor. Recently, immune checkpoint-based strategies have been shown to be highly effective in patients with RR-PMBCL. We report the case of a 23-year-old woman who, due to recurring episodes of symptomatic chemotherapy-induced sinus bradycardia, was unable to receive the planned six courses of immunochemotherapy, mediastinal radiotherapy, and autologous transplantation, leading to the early initiation of a chemo-free strategy. The patient maintains a continuous complete remission at a four-year follow-up after only two cycles of immunochemotherapy followed by nivolumab plus brentuximab vedotin (BV) and pembrolizumab consolidation. Beyond describing an underreported complication of anticancer treatments, the favorable clinical outcome suggests that in PMBCL, a minimal load of chemotherapy, integrated by early PD-1 blockade, with or without BV, may be sufficient to achieve long-term disease control and cure at least in some patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The real-world efficacy, prognostic factors, and adverse events of second-line nivolumab monotherapy and subsequent third-line therapy for unresectable or metastatic esophageal cancer have not been fully evaluated., Methods: This multi-institutional retrospective cohort study evaluated 184 consecutive patients treated with second-line nivolumab monotherapy for esophageal cancer between March 2021 and December 2022. We assessed tumor response, adverse events, long-term survival, and prognostic factors., Results: Among 128 patients with measurable lesions, the response rate was 23% and the disease control rate for all enrolled patients was 45%. The incidence of grade 3 or higher adverse events was 14%, but no treatment-related deaths presented. Median progression-free survival was 5.1 months and overall survival was 14 months, respectively. C-reactive protein level and performance status were identified as significant prognostic factors of overall survival through Cox proportional hazards analysis. The group with two favorable prognostic factors showed better overall survival than the groups with either one or zero prognostic factors (median overall survival: 22, 15, and 4.4 months, respectively). Among 69 patients who received third-line taxane anticancer agents, the progression-free survival was 6.7 months., Conclusions: Our study demonstrated that the real-world outcomes of second-line nivolumab monotherapy were comparable to those of previous randomized clinical trials in terms of tumor response, safety, and long-term survival. Furthermore, a good performance status and low C-reactive protein levels may identify patients who are likely to benefit from therapy. Third-line chemotherapy after nivolumab treatment may have an enhanced effect; however, further prospective studies are required to confirm this finding., (© 2024. Japanese Society of Gastroenterology.)

Background: Nivolumab plus ipilimumab (NIVO+IPI) has demonstrated superior overall survival (OS) and durable response benefits versus sunitinib (SUN) with long-term follow-up in patients with advanced renal cell carcinoma (aRCC). We report updated analyses with 8 years of median follow-up from CheckMate 214., Patients and Methods: Patients with aRCC (N = 1096) were randomized to NIVO 3 mg/kg plus IPI 1 mg/kg Q3W × four doses, followed by NIVO (3 mg/kg or 240 mg Q2W or 480 mg Q4W); or SUN (50 mg) once daily for 4 weeks on, 2 weeks off. The endpoints included OS, independent radiology review committee (IRRC)-assessed progression-free survival (PFS), and IRRC-assessed objective response rate (ORR) in intermediate/poor-risk (I/P; primary), intent-to-treat (ITT; secondary), and favorable-risk (FAV; exploratory) patients., Results: With 8 years (99.1 months) of median follow-up, the hazard ratio [HR; 95% confidence interval (CI)] for OS with NIVO+IPI versus SUN was 0.72 (0.62-0.83) in ITT patients, 0.69 (0.59-0.81) in I/P patients, and 0.82 (0.60-1.13) in FAV patients. PFS probabilities at 90 months were 22.8% versus 10.8% (ITT), 25.4% versus 8.5% (I/P), and 12.7% versus 17.0% (FAV), respectively. ORR with NIVO+IPI versus SUN was 39.5% versus 33.0% (ITT), 42.4% versus 27.5% (I/P), and 29.6% versus 51.6% (FAV). Rates of complete response were higher with NIVO+IPI versus SUN in all International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups (ITT, 12.0% versus 3.5%; I/P, 11.8% versus 2.6%; FAV, 12.8% versus 6.5%). The median duration of response (95% CI) with NIVO+IPI versus SUN was 76.2 versus 25.1 months [59.1 months-not estimable (NE) versus 19.8-33.2 months] in ITT patients, 82.8 versus 19.8 months (54.1 months-NE versus 16.4-26.4 months) in I/P patients, and 61.5 versus 33.2 months (27.8 months-NE versus 24.8-51.4 months) in FAV patients. The incidence of treatment-related adverse events was consistent with previous reports. Exploratory post hoc analyses are reported for FAV patients, those receiving subsequent therapy based on their response status, clinical subpopulations, and adverse events over time., Conclusions: Superior survival, durable response benefits, and a manageable safety profile were maintained with NIVO+IPI versus SUN at 8 years, the longest phase III follow-up for a first-line checkpoint inhibitor combination therapy in aRCC., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aims: Nivolumab is approved as adjuvant treatment in subjects with resected oesophageal or gastroesophageal junction cancer (EC/GEJC) based on results from the pivotal CheckMate 577 trial. We present a model-based clinical pharmacology profiling and benefit-risk assessment of nivolumab as adjuvant treatment in subjects with resected EC/GEJC supporting a less frequent dosing regimen., Methods: Population pharmacokinetic (popPK) analysis was conducted to characterize nivolumab pharmacokinetics (PK) using clinical data from 1493 subjects from seven monotherapy clinical studies across multiple solid tumours. The exposure-response (E-R) analyses included data from 756 patients from CheckMate 577. E-R relationships for efficacy and safety were characterized by evaluating the relationship between nivolumab exposure and disease-free survival (DFS) for efficacy; and time to first occurrence of Grade ≥2 immune-mediated adverse events (Gr2 + IMAEs) for safety., Results: Nivolumab exposure was found to be associated with both DFS and risk of Gr2 + IMAEs. However, the hazard ratios (HRs) (95% confidence interval [CI]) at the 5th and 95th percentiles of nivolumab exposure were similar for DFS and Gr2 + IMAEs, indicating flat E-R relationships within the exposure range produced by the studied regimen. Model-predicted probability of DFS and Gr2 + IMAEs were similar between the two regimens of 240 mg every 2 weeks or 480 mg every 4 weeks for 16 weeks followed by 480 mg Q4W up to 1 year., Conclusions: The analyses demonstrated a flat E-R relationship over the range of exposures produced by the studied regimen and supported the approval of an alternative dosing regimen with less frequent dosing in patients with adjuvant EC/GEJC., (© 2024 British Pharmacological Society.)

Purpose: Nivolumab is approved at various doses, including 3 mg/kg, 240 mg and 480 mg flat doses at various dosing intervals. The concept of low-dose immunotherapy is gaining traction in recent years. However, there is a need to better understand the pharmacokinetics and clinical outcomes at lower doses., Methods: Patients were either administered 40 mg flat dose or 3 mg/kg Q2W/Q3W, depending on affordability as per prevailing hospital practice. All patients were hospitalized on day 1 and pharmacokinetic samples were collected at 0, 0.5, 1.0, 6.0, 24.0, 72.0 h and day 14 following administration of the first dose of nivolumab. Plasma nivolumab levels were measured by ELISA. Patients were followed up for response and toxicity., Results: Twenty five patients were included in the study. Fourteen received nivolumab at conventional dose (3 mg/kg), while 11 patients received low-dose (40 mg flat). The geometric means of dose normalized C max and AUC 0-t were comparable between those who received conventional dose and low-dose of nivolumab (0.28 versus 0.23 µg/mL/mg and 0.0014 versus 0.0011 d/mL respectively). Nineteen patients were evaluable for response. ORR among patients who received conventional dose was 5/11 (45.5%) whereas it was 4/9 (44.4%) in the low-dose cohort. All 14 (100%) patients in conventional dosing group and 7/11 patients (63.64%) in low-dose group had treatment emergent adverse events. Grade ≥ 3 toxicities were observed in 4/14 patients in conventional dose group and none in low-dose group., Conclusion: Low-dose nivolumab leads to lower exposure in patients as compared with conventional dose, but low-dose was better tolerated, while response rates were comparable to conventional dose., (© 2024. The Author(s).)

While some literature has provided limited information about the potential cardiovascular risk and immune-related adverse events (irAEs) risk associated with PD-1/PD-L1 inhibitors in the treatment of Head and Neck Squamous Cell Carcinoma (HNSCC), the exact relevance is still uncertain. To assess the pharmacovigilance (PV), constituent ratio, severity, and reaction outcomes of major adverse cardiovascular events (MACE) and immune-related adverse events (irAEs) related to PD-1/PD-L1 inhibitors for HNSCC reported to the United States Food and Drug Administration Adverse Event Reporting System (FAERS). We analyzed reports of cardiovascular adverse events and irAEs associated with drug therapy for HNSCC submitted to FAERS from the 1st quarter 2015 to the 3rd quarter of 2023. Three PD-1/PD-L1 inhibitors were identified: nivolumab, pembrolizumab and durvalumab. Our primary composite endpoint was the PV of MACE and irAEs related to PD-1/PD-L1 inhibitors in the treatment of HNSCC, and the secondary endpoint was PV of other cardiovascular events. The software implemented was STATA 17.0 MP. 19,372 suspected drug-adverse event reports related to drug treatment in patients with HNSCC were identified, of which 916 reports were cardiovascular events, including 555 reports of MACE and 361 reports of other cardiovascular events. The PV signal regarding MACE was detected in durvalumab (PRR  = 2.12, 95% CI: 1.24-3.61; χ2  = 7.71; ROR  = 2.19, 95% CI: 1.24-3.86; IC  = 1.01; IC025  = 0.07) but not in nivolumab and pembrolizumab. The constituent ratio of MACE in all adverse events caused by nivolumab (OR  = 0.38, 95% CI: 0.19-0.73) and pembrolizumab (OR  = 0.48, 95% CI: 0.23-0.99) was significantly decreased, compared with durvalumab. A PV signal about other cardiovascular events was detected in durvalumab (PRR  = 3.04, 95% CI: 1.73-5.31; χ2  = 16.13; ROR  = 3.15, 95% CI: 1.74-5.70; IC  = 1.46; IC025  = 0.48), but it was not detected in nivolumab or pembrolizumab. The constituent ratio of other cardiovascular events in all adverse events caused by nivolumab (OR  = 0.25, 95% CI: 0.13-0.48) and pembrolizumab (OR  = 0.40, 95% CI: 0.20-0.80) was significantly decreased, compared with durvalumab. The constituent ratio of other cardiovascular events in all adverse events caused by nivolumab (OR  = 0.61, 95% CI: 0.38-0.99) was significantly decreased, compared with pembrolizumab. There were 40 cases of hypertension. A PV signal about hypertension was detected in pembrolizumab (PRR  = 3.72, 95% CI: 1.87-7.43; χ2  = 15.99; ROR  = 3.75, 95% CI: 1.87-7.51; IC  = 1.53, IC025  = 0.45), but it was not detected in nivolumab. The constituent ratio of hypertension in all adverse events caused by nivolumab (OR  = 0.09, 95% CI: 0.09-0.39) was significantly decreased, compared with pembrolizumab. There were 737 cases of irAEs. A PV signal about irAEs was detected in nivolumab (PPR  = 1.27, 95% CI: 1.05-1.53; χ2  = 6.38; ROR  = 1.28, 95% CI: 1.06-1.56; IC  = 0.29, IC025  = -0.00) and pembrolizumab (PPR  = 2.20, 95% CI: 1.79-2.71; χ2  = 56.55; ROR  = 2.31, 95% CI: 1.84-2.88; IC  = 1.03; IC025  = 0.68), but it was not detected in durvalumab. The constituent ratio of irAEs in all adverse events caused by nivolumab (OR  = 0.58, 95% CI: 0.44-0.76) significantly decreased, compared with pembrolizumab. By comparing the PV signals, constituent ratio, severity, and reaction outcome of the three drugs, we suppose that nivolumab can be used as the safest PD-1/PD-L1 inhibitor for HNSCC., (© 2024. The Author(s).)

Background: The aim of this study is to investigate the real-world efficacy and safety of nivolumab in combination with chemotherapy for patients with advanced human epidermal growth factor receptor 2 (HER2)-negative gastric cancer (GC)., Methods: We enrolled patients diagnosed with unresectable advanced or metastatic GC who received nivolumab plus chemotherapy as first-line systemic treatment. The combined positive score (CPS), indicating the number of programmed cell death-ligand 1 (PD-L1)-stained cells, was utilized. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Adverse events (AEs) were graded, and treatment was ceased upon disease progression or intolerance., Results: A total of 27 patients were included in the study, comprising 15 patients with CPS ≥ 5 and 12 patients with CPS < 5. The objective response rate (ORR) was 55.6%, with a disease control rate (DCR) of 74.1%. Patients in the CPS ≥ 5 group exhibited higher ORR and DCR compared to those in the CPS < 5 group. Median PFS and OS were 6.1 months and 14.6 months, respectively; patients with CPS ≥ 5 showed a trend towards better PFS and OS than those with CPS < 5. Most AEs were grade 1-2, with a few instances of grade 3-4 toxicities reported, including neutropenia, thrombocytopenia, diarrhea, and anemia. There were no grade 5 AEs reported in our cohort. Furthermore, 64.7% of patients received subsequent anticancer treatment following disease progression on nivolumab plus chemotherapy., Conclusions: The results of our study demonstrate the efficacy and safety of nivolumab plus chemotherapy in real-world practice support its adoption as a new standard first-line treatment for patients with advanced HER2-negative GC, particularly those with CPS ≥ 5., (© 2024. The Author(s).)

PD-1/PD-L1 inhibitors have increasingly been associated with the occurrence of subacute cutaneous lupus erythematosus (SCLE), but the clinical characteristics and outcomes remain under-explored. Literature on PD-1/PD-L1 inhibitors induced SCLE was retrieved from Chinese and English databases until June 31, 2024, and clinical data of patients were extracted for retrospective analysis. Twenty-nine patients participated, with a median age of 63 years (range 43, 80). The most frequently reported drugs were Nivolumab (51.7%) and pembrolizumab (31.0%). The median time from treatment initiation to SCLE onset was 3 months (range 0.5, 47). Cutaneous manifestations presented primarily as papulosquamous lesions (65.5%) and erythema annulare (31.0%), predominantly occurring on the trunk (51.7%) and arms (51.7%). Serological analysis revealed positive anti-Ro antibodies in 91.7% of patients, positive antinuclear antibodies in 75.0%, and positive anti-La antibodies in 50.0%. Skin biopsies showed interface dermatitis in 65.5% of cases and lymphocyte infiltration in 82.8%. Treatment with topical corticosteroids, systemic corticosteroids, and hydroxychloroquine led to gradual improvement or resolution of the rash, with a median recovery time of 1 month (range 0.5, 11). As the use of PD-1/PD-L1 inhibitors in oncology increases, SCLE should be recognized as a rare cutaneous adverse effect. Histological and serological evaluations play a critical role in diagnosing SCLE. Typically, SCLE resolves on its own with appropriate local and systemic treatment., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Immunotherapy has emerged as a promising treatment option due to its favorable toxicity profile. However, selecting the most appropriate immunotherapeutic agent for neoadjuvant use-aimed at curative intent in early-stage NSCLC-based on efficacy and safety remains a critical question. This review aims to compare the efficacy and safety profiles of nivolumab and pembrolizumab when used as neoadjuvant treatments in NSCLC. A systematic review was conducted across PubMed, Scopus, Wiley Online Library, ProQuest Dissertations and Theses Global, and Google Scholar, utilizing the search terms "Nivolumab OR Pembrolizumab AND Neoadjuvant Immunotherapy AND non-small cell lung cancer." Out of 1444 retrieved studies, 4 retrospective studies met the inclusion criteria by providing comparative data on nivolumab and pembrolizumab within the same study cohorts. Despite the critical risk of bias and the evidence quality ranging from moderate to very low across these studies, both nivolumab and pembrolizumab demonstrated efficacy rates exceeding 30% and maintained favorable safety profiles. There is no observed superiority between nivolumab and pembrolizumab in terms of efficacy and safety for the neoadjuvant treatment of early-stage NSCLC.

Background: Incorporating brentuximab vedotin into the treatment of advanced-stage classic Hodgkin's lymphoma improves outcomes in adult and pediatric patients. However, brentuximab vedotin increases the toxic effects of treatment in adults, more than half of pediatric patients who receive the drug undergo consolidative radiation, and relapse remains a challenge. Programmed death 1 blockade is effective in Hodgkin's lymphoma, including in preliminary studies involving previously untreated patients., Methods: We conducted a phase 3, multicenter, open-label, randomized trial involving patients at least 12 years of age with stage III or IV newly diagnosed Hodgkin's lymphoma. Patients were randomly assigned to receive brentuximab vedotin with doxorubicin, vinblastine, and dacarbazine (BV+AVD) or nivolumab with doxorubicin, vinblastine, and dacarbazine (N+AVD). Prespecified patients could receive radiation therapy directed to residual metabolically active lesions. The primary end point was progression-free survival, defined as the time from randomization to the first observation of progressive disease or death from any cause., Results: Of 994 patients who underwent randomization, 970 were included in the intention-to-treat population for efficacy analyses. At the second planned interim analysis, with a median follow-up of 12.1 months, the threshold for efficacy was crossed, indicating that N+AVD significantly improved progression-free survival as compared with BV+AVD (hazard ratio for disease progression or death, 0.48; 99% confidence interval [CI], 0.27 to 0.87; two-sided P = 0.001). Owing to the short follow-up time, we repeated the analysis with longer follow-up; with a median follow-up of 2.1 years (range, 0 to 4.2 years), the 2-year progression-free survival was 92% (95% CI, 89 to 94) with N+AVD, as compared with 83% (95% CI, 79 to 86) with BV+AVD (hazard ratio for disease progression or death, 0.45; 95% CI, 0.30 to 0.65). Overall, 7 patients received radiation therapy. Immune-related adverse events were infrequent with nivolumab; brentuximab vedotin was associated with more treatment discontinuation., Conclusions: N+AVD resulted in longer progression-free survival than BV+AVD in adolescents and adults with stage III or IV advanced-stage classic Hodgkin's lymphoma and had a better side-effect profile. (Funded by the National Cancer Institute of the National Institutes of Health and others; S1826 ClinicalTrials.gov number, NCT03907488.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Anti-programmed cell death 1 antibodies (PD-1 Abs) are widely used for advanced melanoma, but information on the efficacy of anti-PD-1 Abs is limited in the Asian population. There remains an unmet need to improve the therapeutic effects of anti-PD-1 Ab-treatment, particularly in patients with melanoma who are refractory to anti-PD-1 Abs. The aim of this study was to evaluate anti-PD-1 Ab-treatment in combination with TM5614 (a plasminogen activator inhibitor-1 inhibitor) in patients with unresectable melanoma., Methods: The TM5614-MM study was a multicentre, open-label, single-arm, phase II clinical trial to evaluate the efficacy and safety of nivolumab in combination with TM5614 in patients with advanced, unresectable malignant melanoma recruited at seven Japanese institutes between 13 September 2021 and 31 March 2023. Patients with metastatic or unresectable melanoma previously treated with anti-PD-1 Abs were enrolled. Nivolumab 480 mg was administered intravenously every 4 weeks for 8 weeks, while TM5614 was administered orally at a dose of 120 mg (0-4 weeks) and 180 mg once daily (5-8 weeks). The primary endpoint was the overall response rate after 8 weeks of concomitant use of TM5614., Results: Thirty-nine patients were enrolled, and 34 patients were included in the anti-PD-1 Ab-refractory cohort. The overall response rate at 8 weeks was 25.9% (95% confidence interval 12.9-44.9%, P = 0.027) in 27 patients who were anti-PD-1 Ab-refractory based on investigator assessment in the protocol per set cohort. Seven patients discontinued treatment owing to progressive disease or adverse events. Treatment-related grade 3 or higher adverse events occurred in 3 of 39 patients (7.7%) in the intention-to-treat cohort., Conclusions: TM5614 in combination with nivolumab is well tolerated and effective in anti-PD-1 Ab-refractory unresectable melanoma., Competing Interests: Conflicts of interest T.M. declares research funding from Astellas Pharma Inc., Daiichi-Sankyo Biotech Co. Ltd., and Kowa Company, and holds stocks from Renascience Inc., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Given the broad implementation of immune checkpoint inhibitors (ICI) for cancer therapy, we encounter a variety of immune-related adverse events (irAE) including immune-related blood eosinophilia. Eosinophilia demonstrated a potential positive predictive marker for a beneficial clinical response to ICI. However, there are reports of eosinophil-induced adverse events (Eo-irAE) with organ dysfunction requiring initiation of oral glucocorticoid therapy and discontinuation of ICI.We aim to assess the efficacy and safety of interleukin (IL) 5-axis inhibition in Eo-irAE secondary to ICI therapy.We present three cases of Eo-irAE referred to our allergy and clinical immunology unit at Hadassah Hebrew University Medical Center following therapy with pembrolizumab and nivolumab, monoclonal antibodies that target the programmed cell death 1 (PD-1) receptor, for two cases of melanoma and one metastatic non-small cell lung carcinoma. Following informed consent and committee approval, two patients were treated with 1-3 doses of mepolizumab, 100 mg, monoclonal IgG1 kappa anti-IL-5 antibody, and one patient received up-to-date 9 doses of benralizumab, 30 mg, monoclonal IgG1 kappa antibody directed against the alpha chain of the interleukin-5 receptor, both administered subcutaneously. Patients were carefully followed and treatment response was assessed by physical examinations and laboratory tests.Hypereosinophilia at the level of 2300-8000 K/UL was observed 8-12 months following therapy accompanied by symptoms of dyspnea, arthralgia, myalgia, fasciitis, 'morphea'-like lesions, fatigue, abdominal discomfort, pruritus, and chest pain. ICI discontinuation did not improve symptoms, two patients were resistant to glucocorticoids and therefore biological treatment was initiated to inhibit the IL5 axis. Patients demonstrated rapid clinical response and a decrease in peripheral blood eosinophil levels with long-term symptoms remission. There were no signals of negative impacts, such as tumor progression following IL5 axis inhibition.Eosinophilia secondary to ICI therapy can lead to organ dysfunction. Discontinuation of ICI might not be effective and symptoms may be refractory to steroid therapy hence targeted inhibition of the IL5 axis should be considered., Competing Interests: Competing interests: No, there are no competing interests., (© 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.)

Purpose: Combined immunotherapy (ipilimumab + nivolumab) has improved survival in stage IV melanoma patients, making Health-related Quality of Life (HrQoL) crucial due to potential immune-related adverse events (irAEs). Previous studies treated HrQoL as secondary/explorative endpoint, and no specific HrQoL questionnaire for melanoma patients on immune checkpoint inhibitor (ICI) therapy exists. This study aimed to gather specific HrQoL data during combined ICI therapy, tracking changes during and after treatment, and examining associations with gender, irAEs, and treatment response., Methods: 35 melanoma patients (22 males, 13 females) undergoing combined ICI were surveyed using the Short-form 36 questionnaire (SF-36), the Inflammatory Bowel Disease Questionnaire - Deutsch (IBDQ-D), and the distress thermometer (DT). HrQoL was evaluated during treatment, after six months, and at the onset of autoimmune colitis., Results: irAEs occurred in 51.4% of patients, with colitis being the most common (26.1%). 45.7% had progressive disease. SF-36 showed stable HrQoL during treatment and follow-up. Women had worse HrQoL on the physical component scale than men (p = 0.019). Patients with progression showed worse HrQoL over time in physical (p = 0.015) and mental health scales (p = 0.04). IBDQ-D showed constant HrQoL throughout treatment and follow-up. Distress on DT remained constant, with women reporting higher levels of distress., Conclusion: HrQoL remained stable during and after therapy. Female gender and disease progression negatively impacted HrQoL. The development of irAEs was not associated with HrQoL, though this may not apply to severe irAEs like colitis, which were not assessed., (© 2024. The Author(s).)

Background: Immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor receptor tyrosine kinase inhibitors are cornerstones of first-line treatment for advanced renal cell carcinoma; however, optimal treatment sequencing after progression is unknown. This study aimed to assess clinical outcomes of tivozanib-nivolumab versus tivozanib monotherapy in patients with metastatic renal cell carcinoma who have progressed following one or two lines of therapy in the post-ICI setting., Methods: TiNivo-2 is a multicentre, randomised, open-label, phase 3 trial at 190 sites across 16 countries, in Australia, Europe, North America, and South America. Patients with advanced renal cell carcinoma and progression during or after one to two previous lines of therapy (including one ICI) were randomised 1:1 to tivozanib (0·89 mg per day, orally) plus nivolumab (480 mg every 4 weeks, intravenously) or tivozanib (1·34 mg per day, orally). Randomisation was stratified by immediate previous therapy (ICI or non-ICI) and International Metastatic Renal Cell Carcinoma Database Consortium risk category. The primary endpoint was progression-free survival (PFS), defined as the time from randomisation to first documentation of objective progressive disease according to RECIST 1·1 or death from any cause, whichever came first, by independent radiology review. Efficacy was evaluated in the intention-to-treat population, and safety was assessed in patients who received one or more doses of the study drug. This trial was registered on ClinicalTrials.gov (NCT04987203) and is active and not recruiting., Findings: From Nov 4, 2021, to June 16, 2023, 343 patients were randomly assigned to tivozanib-nivolumab (n=171) or tivozanib monotherapy (n=172). Median follow-up was 12·0 months. Median PFS was 5·7 months (95% CI 4·0-7·4) with tivozanib-nivolumab and 7·4 months (5·6-9·2) with tivozanib monotherapy (hazard ratio 1·10, 95% CI 0·84-1·43; p=0·49). Among those with an ICI as their immediate previous therapy (n=244), median PFS was 7·4 months (95% CI 5·6-9·6) with tivozanib-nivolumab and 9·2 months (7·4-10·0) with tivozanib monotherapy. With non-ICIs as the most recent therapy, lower median PFS was observed, with no difference between groups (tivozanib-nivolumab 3·7 months [95% CI 2·7-5·4] and with tivozanib monotherapy 3·7 months [1·9-7·2]). Serious adverse events occurred in 54 (32%) of 168 patients receiving tivozanib-nivolumab and 64 (37%) of 171 patients receiving tivozanib monotherapy. One (<1%) treatment-related death occurred (tivozanib group)., Interpretation: These data further support that ICI rechallenge should be discouraged in patients with advanced renal cell carcinoma. Furthermore, these data suggest that tivozanib monotherapy has efficacy in the post-ICI setting., Funding: Aveo Pharmaceuticals., Competing Interests: Declaration of interests TKC reports institutional and personal paid or unpaid support for research, advisory board participation, consultancy, and honoraria within the past 5 years from Alkermes, Arcus Bio, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVIA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Neomorph, Nuscan and Precede Bio, Novartis, Oncohost, Pfizer, Roche, Sanofi Aventis, Scholar Rock, Surface Oncology, Takeda, and Tempest and equity in Tempest, Pionyr, Osel, Precede Bio, CureResponse, InnDura Therapeutics, and Primium. LA reports consulting fees from Bristol Myers Squibb, Ipsen, Roche, Novartis, Pfizer, Astellas, Merck, MSD, Janssen, Eisai, and Amgen and support for travel expenses from Bristol Myers Squibb, MSD, Ipsen, and Pfizer. PB reports grants or contracts from Roche, Bristol Myers Squibb, MSD, AstraZeneca, Pfizer, Exelixis, Ipsen, Merck, Gilead, Janssen, AAA Pharmaceutical, and Bayer; consulting fees from Astellas, Bayer, Bristol Myers Squibb, Ipsen, Janssen, MSD, Novartis, Pfizer, Merck, Gilead, AAA Pharmaceutical, Eisai, and AstraZeneca; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas, Bayer, Bristol Myers Squibb, Ipsen, Janssen, MSD, Novartis, Pfizer, Merck, Gilead, AAA Pharmaceutical, Eisai, and AstraZeneca; and reports participation on a data safety monitoring board or advisory board for Astellas, Bayer, Bristol Myers Squibb, Ipsen, Janssen, MSD, Novartis, Pfizer, Merck, Gilead, AAA Pharmaceutical, Eisai, and AstraZeneca. SE reports consulting fees from MSD, AstraZeneca, Eisai, Janssen, Bristol Myers Squibb, and Kephren and support for attending meetings and travel from MSD, Chugai, Pfizer, and Janssen. JM-C reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Ipsen, Pfizer, Roche, Bayer, Sanofi, Janssen, Astellas, Eisai, Adacap, Lilly, Novartis, Bristol Myers Squibb, MSD, Adium, and Asofarma; support for attending meetings and travel from Ipsen, Pfizer, Bristol Myers Squibb, and MSD; and participation on a data safety monitoring board or advisory board for Ipsen, Pfizer, Astellas, Eisai, Bristol Myers Squibb, and MSD. BG reports research funding grants from AbbVie, Accutar Biotechnology, Arcus Biosciences, Arvinas, AstraZeneca, AVEO Oncology, CRISPR Therapeutics, Eikon Therapeutics, Exelixis, Roche and Genentech, Flare Therapeutics, Harbour BioMed, IDEAYA Biosciences, Janssen, Janux Therapeutics, Jubilant Therapeutics, Kineta, Kinnate BioPharma, Loxo, Mink Therapeutics, Nuvation Bio, Profound Bio, Takeda Therapeutics, Teon Therapeutics, Tmunity Therapeutics, Xencor, and Zenshine and consulting fees from AbbVie, Adaptimmune, Adicent Therapeutics, AIQ Global, Amgen, Arcus Biosciences, Arvinas, AstraZeneca, AVEO Oncology, Bayer, Bicycle Therapeutics, Eisai, EMD Serono, Exelixis, Janssen, Merck, Novartis, Pfizer, Rondo Therapeutics, Sanofi–Aventis, Seagen, and Xencor. PB reports honoraria from UroToday; consulting or advising fees from Bayer, Bristol Myers Squibb, Pfizer, EMD Serono, Eisai, Caris Life Sciences, AstraZeneca, Exelixis, Aveo, Merck, Ipson, and Dendreon; speakers bureau funding from AstraZeneca, Caris Life Sciences, Bayer, Pfizer and Astellas, and Merck; and research funding from Exelixis, Aveo, Blue Earth, Pfizer, and Merck. AB reports honoraria from Gilead Sciences, Cardinal Health, Eisai, and Natera; consulting or advising fees from EMD Serono, Seattle Genetics, and Bristol Myers Squibb and Pfizer; speakers bureau funds from Eisai; and research funding from Merck, EMD Serono, Natera, Astellas Pharma, Bristol Myers Squibb and Celgene, Genentech and Roche, and Aveo. MTB reports consulting fees, payment or honoraria, and participation on a data safety monitoring board or advisory board from Bristol Myers Squibb. HM reports honoraria from EMD Serono and Pfizer; research funding from Bristol Myers Squibb, Amgen, Genentech, Seattle Genetics, Arcus Bioscience, Apollomics, Nektar, RevImmune, HUYA Bioscience International, Aveo, Xencor, and Pfizer; and travel accommodations or expenses from Aveo, Seagen, Bayer, and Genentech. RR reports honoraria from Ipsen, MSD Oncology, AstraZeneca, Bristol Myers Squibb, Pfizer, Advanced Accelerator Applications, and Eisai; consulting or advisory fees from Astellas Pharma, Pfizer, Ipsen, and MSD; and travel accommodations or expenses from Ipsen, MSD Oncology, and Janssen. RRM reports consulting or advisory roles for Janssen, Novartis, Tempus, Exelixis, Pfizer, Bristol Myers Squibb, Astellas Medivation, Dendreon, Bayer, Sanofi, Merck, Vividion, Calithera, AstraZeneca, Myovant, Caris Life Sciences, Sorrento Therapeutics, Aveo, Seattle Genetics, Telix, Eli Lilly, Blue Earth Diagnostics, Ambrx, Arcus Biosciences, Sumitomo Pharma Oncology, Eisai, and NeoMorph and research funding from Bayer, Tempus, AstraZeneca, Exelixis, Bristol Myers Squibb, Oncternal Therapeutics, and Artera. AC-R reports honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from OncLive and MJH Life Sciences, ASCO Direct, Exelixis, Medical Oncology Association of Southern California, EPG Health, Eisai Co, Aveo, and Seagen. HH reports grants or contracts for clinical trial support from Merck, Bristol Myers Squibb, Eisai, Agenus, Hoosier, and Aveo and advisory consulting fees from Eisai, Aveo, Pfizer, and Bristol Myers Squibb. DYCH reports consultancy fees from Pfizer, Novartis, Bristol Myers Squibb, Janssen, Astellas Pharma, Ipsen, Eisai, and Merck and research funding from Pfizer, Novartis, Exelixis, Bristol Myers Squibb, and Ipsen. EB reports funding for the provision of study materials, medical writing, or article processing charges from Aveo Oncology and stock or stock options from Autolus. KEB reports grants funding from Bristol Myers Squibb–Lung Cancer Foundation of America–International Association for the Study of Lung Cancer, Aravive, Pionyr, and Arsenal Bio; consulting fees from Aravive, Aveo, Alpine Bioscience, Arcus, AstraZeneca, Adicet, Bristol Myers Squibb, Exelixis, Eisai, Merck, Nimbus, and Xencor; and honoraria funding from Merck. BAM reports grants to his institution from Aveo, Bristol Myers Squibb, Exelixis, Gilead, and Pfizer; consulting fees from Arcus, Bristol Myers Squibb, Exelixis, Gilead, Lily, and Pfizer; payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Targeted Oncology, Dava Oncology, Aptitude Health, and Curio; and patents planned, issued, or pending with Gilead. RJM reports consulting fees from Aveo, Merck, Exelixis, and Takeda, grants or contracts from Pfizer, Genentech and Roche, Eisai, Merck, Bristol Myers Squibb, and Exelixis; and data safety monitoring and advisory board participation fees from Incyte. RI reports no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Real-world data on health-related quality of life (HRQoL) in advanced urothelial carcinoma (aUC) receiving immune checkpoint inhibitors (ICIs) are limited. This study included 42 patients with aUC who received second-line or later pembrolizumab (n = 19), maintenance avelumab followed by first-line chemotherapy (n = 13), or adjuvant nivolumab after radical surgery (n = 10). Time-course changes in the domains and scales related to HRQoL were evaluated using the EORTC QLQ-C30, FACT-G, and SF-8 questionnaires during ICI therapy. Anchor-based approaches for minimally important differences were determined as 'improved', 'stable', and 'deteriorated'. We found significant improvements after the start of pembrolizumab treatment on many scales. Almost none of the scales changed significantly in the avelumab and nivolumab groups. Approximately 80% of the pembrolizumab group had deteriorated social/family well-being in FACT-G. Approximately 60% of the patients in the avelumab group had deteriorated general health and vitality in SF-8. In the nivolumab group, none of the scales deteriorated in > 50% of the patients. Deterioration of physical function in the SF-8 was associated with occurrence of treatment-related adverse events ≥ grade 2 during ICI therapy (P = 0.013). Our findings demonstrated that majority of patients with aUC who received ICI therapy had a stable HRQoL, which was consistent with evidence from clinical trials., (© 2024. The Author(s).)

Background: Immune checkpoint inhibitors have demonstrated efficacy against various cancers; however, there is a rising incidence of immune-related colitis. Some cases of immune-related colitis prove resistant to treatment, even with the administration of glucocorticoids or infliximab, and there is currently no established standard treatment for such cases., Case: The patient, a 73-year-old male, had undergone combination therapy for malignant pleural mesothelioma for 2 years, utilizing both ipilimumab (a CTLA-4 inhibitor) and nivolumab (a PD-1 inhibitor). Unfortunately, the treatment led to side effects, specifically immune-related adverse event (irAE) enterocolitis. Steroid and infliximab treatment failed to improve the patient's condition. Treatment with tacrolimus was attempted, but the patient remained unresponsive. Subsequently, 45 mg of upadacitinib, a Janus kinase (JAK) inhibitor, was administered. Symptoms improved rapidly following upadacitinib administration, and endoscopy also revealed positive results. With the increasing incidence of immune-related colitis, some patients have become resistant to treatment with glucocorticoids and infliximab. In this case, the irAE enterocolitis was improved by upadacitinib administration., Conclusion: In cases where immune-related colitis proves resistant to treatment with glucocorticoids, infliximab, or tacrolimus, upadacitinib represents a potential option as a JAK inhibitor., (© 2024 The Author(s). Cancer Reports published by Wiley Periodicals LLC.)

Abstract: Targeted immunotherapy became the most advanced approach for cancer treatment. Programmed death-1 (PD-1) expressed on activated T cells can reverse immune suppression and cause T-cell activation. Nivolumab, a PD-1 immune checkpoint inhibitor antibody that is a fully human immunoglobulin G4, blocks PD-1 and promotes antitumor immunity. Cabozantinib (tyrosine kinase inhibitor) inhibits the tyrosine kinase activity of vascular endothelial growth factor receptors 1, 2, and 3. As a result of enhancing immune response in normal tissues, immune-related adverse events can occur. Thyroid dysfunction is a common form of immune-related adverse event and seen on 18 F-FDG PET/CT scans post therapy., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Combination therapy with ipilimumab and nivolumab is indicated for many types of cancers; however, several patients experience immune-related adverse events (irAEs). We herein report a case of cytokine release syndrome (CRS) in a 63-year-old woman with stage IV left clear cell renal cell carcinoma. Our patient developed CRS while taking prednisolone, 43 days after the start of ipilimumab and nivolumab administration. The patient was treated with steroid pulse therapy, which improved the symptoms of shock and respiratory failure. Increased vascular permeability and relative adrenal insufficiency are considered to be the main pathogeneses. The early administration of high-dose steroids is crucial as a replacement for corticosteroids.

Purpose: Proteinuria can cause interindividual variability in the pharmacokinetics of therapeutic antibodies and may affect therapeutic efficacy. Here, we measured the serum and urinary concentrations of bevacizumab (BV) and nivolumab (NIVO) in patients with proteinuria and reported a case series of these patients., Methods: Thirty-two cancer patients who received BV every 3 weeks or NIVO every 2 weeks between November 2020 and September 2021 at Kyoto University Hospital were enrolled in this study. The serum and urinary concentrations of BV and NIVO were measured using liquid chromatography-tandem mass spectrometry., Results: We divided the BV-treated patients and the NIVO-treated patients into two groups based on the urine protein-creatinine ratio (UPCR): UPCR 1 g/g or higher (BV, n = 9; NIVO, n = 3) and UPCR less than 1 g/g (BV, n = 14; NIVO, n = 6). Serum concentrations of the therapeutic antibodies adjusted by their doses were significantly lower in both BV- and NIVO-treated patients with UPCR 1 g/g or higher compared to those with less than 1 g/g. In patients with UPCR 1 g/g or higher, urinary concentrations of the therapeutic antibodies adjusted by their serum concentrations and urinary creatinine concentrations tended to increase., Conclusion: This case-series study suggests a possibility of reduction in serum concentrations of BV and NIVO in patients with proteinuria by urinary excretion of these drugs., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

A 74-year-old Japanese male with lung squamous cell carcinoma received his first dose of immune checkpoint inhibitors (ICIs): ipilimumab and nivolumab. He developed acute kidney injury (AKI) and was admitted to our department. We diagnosed kidney immune-related adverse effects (irAE), and a kidney biopsy revealed acute tubulointerstitial nephritis. We started oral prednisolone (PSL) and his AKI immediately improved. The patient maintained stable findings after PSL was tapered off. However, seven months after the ICI administration, he developed rapid progressive glomerular nephritis and was admitted to our department again. The second kidney biopsy showed findings consistent with anti-glomerular basement membrane glomerulonephritis. Although the patient was treated with pulse methylprednisolone followed by oral PSL and plasma exchange, he became dependent on maintenance hemodialysis. To our knowledge, no case report has described two different types of biopsy-proven nephritis. In cases of suspected relapsing kidney irAEs, both a relapse of previous nephritis and the development of another type of nephritis should be considered., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Background: Different combination therapies using anti - PD-1 / PD-L1 or CTLA-4 immune checkpoint inhibition (ICI) are widely used in patients with metastatic renal cell carcinoma (mRCC). In the absents of established biomarkers, immune-related adverse events (irAEs) have been discussed as potential predictors of response., Methods: In this retrospective cohort study, data of 134 patients with mRCC undergoing ICI treatment (Nivolumab, Ipilimumab and Nivolumab, Pembrolizumab and Axitinib or Avelumab and Axitinib) between 2015 and 2021 were analyzed. To examine the utility of irAEs as predictors of overall survival (OS) and progression-free survival (PFS), separate Kaplan-Meier analyses and Cox proportional regression analyses were applied. Landmark analysis was conducted after 12 weeks to reduce immortal time bias., Result: irAEs were observed in 85 patients (63.4%). Cutaneous (n = 52, 38.8%), endocrine (n = 33, 24.6%) and hepatic (n = 19, 14.2%) irAEs were most commonly observed. In Kaplan-Meier analysis, patients experiencing irAEs showed favorable median PFS (15 months, 95% CI, 9.91-20.09) compared to the non-irAE group (5 months, 95% CI, 3.56-6.44, P < .001). The median OS was 25 months (95% CI, 16.79-33.21) in the non-irAE group, while it was not reached in the irAE group (P = .002). In multivariable analysis, the presence of any irAE was associated with favorable PFS (HR 0.46 [95% CI, 0.26-0.82] P = .008) and OS (HR: 0.28 [95% CI, 0.12-0.63] P = .002), respectively. Landmark analysis after 12 weeks showed mixed results depending on the classification of the irAE group at the landmark time., Conclusion: The presence of irAEs under ICI therapy in patients with mRCC is associated with better PFS and OS. Thus, manageable irAEs should not be cause for premature discontinuation of ICI therapy, as they seem to indicate favorable outcomes. Considering the time-dependent nature of irAEs is crucial estimating their value as predictive markers., Competing Interests: Disclosure MS has nothing to disclose. LMK received fees for advisory roles and lectures from BMS, Ipsen, Merck Healthcare, MSD, Roche. MB received fees for advisory roles and lectures from AAA, Amgen, Apogepha, Astellas, AstraZeneca, Bayer, BMS, Eisai, EUSA-Pharma, Exelixis, Gilead, Ipsen, Janssen Cilag, Lilly, Merck Healthcare, MSD, Novartis, Pfizer, Roche, Sanofi and travel expenses from Astra Zeneca, Bayer, Janssen Cilag, Ipsen, Merck Healthcare. AJS has nothing to disclose. KT has nothing to disclose. KS received fees for advisory roles and lectures from AAA, Amgen, Apogepha, Astellas, AstraZeneca, Bayer, BMS, Eisai, EUSA-Pharma, Fosanis, Ipsen, Janssen Cilag, Merck Healthcare, MSD, Novartis, Pfizer, Roche and travel expenses from Sanofi-Aventis, Astra Zeneca, Astellas, Bayer, Janssen Cilag, Ipsen, Merck Healthcare., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Platinum-based chemotherapy (CTX) has historically been the primary treatment for advanced urothelial cancer (aUC), with limited alternative options. The therapeutic landscape experienced a paradigm shift following the results of the EV-302 and Checkmate-901 trials, which led to the approval of Enfortumab vedotin plus pembrolizumab (EV-P) as the preferred first-line treatment, and nivolumab plus CTX for those unable to receive the preferred regimen. Currently, further investigations are underway to explore PD-1 and PD-L1 inhibitors in the initial treatment of aUC., Patients and Methods: We conducted a systematic search across PubMed, Embase, and the Cochrane Library for randomized controlled trials (RCTs) comparing immune checkpoint inhibitors (ICI)-CTX combinations versus CTX alone as first-line treatment for advanced UC. Employing a random-effects model, we pooled hazard ratios (HR) with 95% confidence intervals (CI)., Results: Our analysis encompassed 3 RCTs, involving 2162 participants, with 51.16% randomized to combination therapy with platinum-based CTX. Compared to CTX alone, immune-chemotherapy significantly improved overall survival (HR 0.84; 95% CI 0.75-0.93; P < .01), progression-free survival (HR 0.78; 95% CI 0.70-0.86; P < .01), and objective response rate (RR 1.20; 95% CI 1.06-1.36; P < .01), while elevating the risk of immune-related adverse events (P-value = .02)., Conclusion: In this meta-analysis of RCTs, ICI plus CTX demonstrated a significant association with improved survival at the expense of an increased risk of immune-related adverse events. Therefore, our findings suggest that this combination should be considered as an initial treatment for aUC in platinum-eligible patients who cannot receive EV-P., Competing Interests: Disclosure None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Immune checkpoint inhibitors are humanized antibodies that inhibit downregulatory receptors on T cells, enhancing the antitumor activity of these cells. However, they have been associated with a wide range of systemic immune-related adverse events, including renal toxicities, among others. Most renal immune-related adverse events are acute interstitial nephritis causing acute kidney injury. Recently, immune checkpoint inhibitors-associated glomerular diseases, including IgA nephropathy, have been reported in adults. Most of the adult cases with glomerular involvement had also concomitant acute interstitial nephritis and acute kidney injury. We present the first pediatric case of IgA nephropathy without acute kidney injury during nivolumab treatment., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Recently, immune checkpoint inhibitors (ICIs) have been used to treat several cancer types. ICIs have been reported to cause a wide variety of immune-related adverse events, including endocrine, neurologic, gastrointestinal, and cutaneous disorders. Thrombotic thrombocytopenic purpura (TTP) is an autoimmune hematologic disorder characterized by the presence of autoantibodies against a disintegrin and metalloprotease with thrombospondin-1, member 13. Several previous cases of TTP were thought to have been caused by ICI treatment. We herein report a rare case of TTP that developed after long-term treatment with an ICI (nivolumab) for gastric tube cancer.

A woman in her 50s presented to the hospital with new-onset jaundice and ascites. Her medical history included a melanoma of the right shoulder, diagnosed 8 months before, for which she had received four cycles of ipilimumab and nivolumab. Due to the oncological history and previous immunotherapy, an immune-checkpoint-inhibitor (ICI)-induced hepatitis was suspected, and a high-dose corticosteroid treatment was initiated. However, as there was no improvement in the liver function tests, a percutaneous liver biopsy was performed for further diagnostic clarification. Histological analysis ultimately identified a hepatic sinusoidal obstruction syndrome (SOS) as the underlying cause of liver dysfunction and portal hypertension. ICI-related hepatic SOS represents an extremely rare adverse event related to immunotherapy that should be considered in all patients with treatment-refractory ICI-related hepatotoxicity and clinical signs of portal hypertension., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In non-small cell lung cancer (NSCLC), chemoradiotherapy (CRT) yields pathological complete response (pCR) rates of approximately 30%. We investigated using ipilimumab plus nivolumab (IPI-NIVO) with neoadjuvant CRT in resectable, and borderline resectable NSCLC., Methods: This single-arm, phase-II trial enrolled operable T3-4N0-2 patients with NSCLC without oncogenic drivers. Primary study endpoints were safety, major pathological response (MPR) and pCR. Treatment encompassed platinum-doublet concurrent CRT, IPI 1 mg/kg intravenous and NIVO 360 mg intravenous on day-1, followed by chemotherapy plus NIVO 360 mg 3 weeks later. Thoracic radiotherapy was 50 or 60 Gy, in once-daily doses of 2 Gy. Resections were 6 weeks post-radiotherapy., Results: In a total of 30 patients in the intention-to-treat (ITT) population, grades 3-4 treatment-related adverse events (TRAEs) occurred in 70%, one TRAE grade 5 late-onset pneumonitis on day 96 post-surgery (1/30, 3.3%) occurred, and one non-TRAE COVID-19 death (1/30, 3.3%). pCR and MPR were achieved in 50% (15/30) and 63% (19/30) of the ITT; and in 58% (15/26) and 73% (19/26) of the 26 patients who underwent surgery, respectively. Postoperative melanoma was seen in one non-pCR patient. The R0 rate was 100% (26/26), and no patient failed surgery due to TRAEs. In peripheral blood, proliferative CD8 + T cells were increased, while proliferative regulatory T cells (Tregs) were not. On-treatment, pCR-positives had higher CD8 + CD39 + T cells and lower HLA-DR + Tregs., Conclusions: Neoadjuvant IPI-NIVO-CRT in T3-4N0-2 NSCLC showed acceptable safety with pCR and MPR in 58% and 73% of operated patients, respectively. No patient failed surgery due to TRAEs., Trial Registration Number: NCT04245514., Competing Interests: Competing interests: The authors have disclosed the following conflicts of interest: DEO-L received grants from Janssen and Curium, honoraria from EANM, EAU, ESMO, and Curium, travel support from EANM, ESMO, EAU, and Bayer, and serves on a Bayer advisory board. CD received institutional fees for advisory roles with BMS, AstraZeneca, and MSD. SMSH has research contracts with several pharmaceutical companies and received honoraria from Janssen. IB’s institution received support from BMS, AstraZeneca, and Boehringer Ingelheim, and he received honoraria from AstraZeneca, MSD, and BMS. FLS received a research grant from ViewRay and honoraria from AstraZeneca. SS’s institution received grants from Varian, ViewRay, and AstraZeneca; he received consulting fees and honoraria from AstraZeneca and MSD, and serves on advisory boards for AstraZeneca and MSD. TDdG’s institution received grants from Idera Pharmaceuticals, consulting fees from LAVA Therapeutics and Mendus, and she holds stock in LAVA Therapeutics. All other authors have declared no conflicts of interest., (© 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.)

Background: In this open-label, randomized, non-comparative, multicenter phase II study (Alliance A091401) we report on three expansion cohorts treated with nivolumab (N) with and without ipilimumab (N+I) and provide a multi-omic correlative analysis of actionable biomarkers., Methods: Patients were randomized (non-comparative) to receive either N or N+I. The primary endpoint was a 6-month confirmed response rate (CRR) defined by Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included treatment-related adverse events (TRAEs), progression-free survival, and overall survival. Multi-omic correlative analyses were conducted using samples from both the primary and expansion cohorts., Results: A total of 66 patients were evaluated for the primary endpoint with disease including gastrointestinal stromal tumor (GIST, n=18), undifferentiated pleomorphic sarcoma (UPS, n=24), and dedifferentiated liposarcoma (DDLPS, n=24). Neither N nor N+I achieved a complete or partial response in the GIST expansion cohort. In DDLPS and UPS, the primary response endpoint of CRR was met with N+I (both 16.6%, 2/12) but not with N alone (both 8.3%, 1/12). In the GIST cohort, TRAE was higher with N+I treatment, halting enrollment as required per protocol. In a correlative analysis of patients for the expansion cohort and the original cohort (n=86), traditional biomarkers of immunotherapy response were not correlated with response in any histological subtype. Markers of genomic instability including the presence of gene fusions and increased subclonal mutations correlated with improved clinical outcomes., Conclusions: This expansion cohort reaffirms the outcomes of A091401. There remains a pressing need to determine the role of and predictive biomarkers for immunotherapy in sarcoma., Trial Registration Number: NCT02500797., Competing Interests: Competing interests: JLC: Foundation Medicine (personal fees), Tempus (employment); BVT: Daiichi Sankyo Inc (personal fees), Deciphera Pharmaceuticals (personal fees), Advenchen (personal fees), Putnam (personal fees), Boxer Capital LLC (personal fees), Acuta Capital Partners, LLC (personal fees), Aadi (personal fees), Race Oncology (personal fees), Hinge Bio, Inc (personal fees), Kronos Bio, Inc, (personal fees) Sonata Therapeutics, Inc. (personal fees), Total Health Conference (personal fees), Adaptimmune (other support), Boehringer Ingelheim (consulting/licensing), Accuronix Therapeutics (patent), Polaris (non-paid member of Scientific/Safety Board); DAL: AADI Bioscience (consulting), MatchTx, LLC (patents); all other authors declare no competing interests., (© 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.)

Immune checkpoint inhibitors (ICI) are promising therapeutic agents for relapsed or refractory classical Hodgkin's lymphoma (RRcHL). This retrospective study evaluated patients with RRcHL registered in the clinical research program Tohoku-Hematology-Forum-26, between 2016 and 2020, and treated with ICI in 14 centers in Northeast Japan. We analyzed the usage, efficacy, and safety of ICI therapy (ICIT). Among a total of 27 patients with RRcHL, 21 and nine were treated with nivolumab and/or pembrolizumab, respectively. The best response was complete response (CR), partial response (PR), stable disease (SD), and progressive disease in 11 (40.8%), seven (25.9%), eight (29.6%), and one (3.7%) patient, respectively. In all patients undergoing ICIT, the 2-year progression-free survival and 2-year overall survival (OS) were 48.6% and 87.4%, respectively. The 2-year OS for patients with CR, PR, and SD were 100%, 68.6%, and 87.5%, respectively. A total of 36 events of immune-related adverse events (irAEs) or immune-related like adverse events (irlAEs) were observed in 19 of the 27 patients (70.4%). Two thirds of these irAEs or irlAEs were grade 1-2 and controllable. During the observation period, ICIT was discontinued in 22 of 27 (81.4%) patients due to CR, inadequate response, irAE and patient circumstances in five (22.7%), seven (31.8%), eight (36.4%) and two patients (9.1%), respectively. Therapy-related mortality-associated irAE were observed in only one patient during ICIT. These results suggest that ICIT for RRcHL is effective and safe in real-world settings. The optimal timing of induction and duration of ICIT remains to be established.

Introduction: The development of immune checkpoint inhibitors (ICIs) represents one of the most significant advancements in cancer treatment over the past decade. Nivolumab, a widely used ICI, has been incorporated into the therapeutic regimens for various cancers. As with any drug, this drug also has side effects, including class-specific immune-related adverse effects (irAEs). Although irAEs are not rare, their diagnosis can be challenging. This study examines the emergency department (ED) visits of patients undergoing nivolumab therapy, focusing on diagnostic challenges, evaluating the management, and outcomes of irAEs in the ED setting., Material and Methods: A retrospective cohort study was conducted on adult patients who received nivolumab therapy for any cancer between April 1, 2018, and March 31, 2023, at a large, urban tertiary care center. In this study, we evaluated the ED visits of patients receiving nivolumab. In addition to previous studies, we evaluated irAEs in detail (percentage, recognizability, risk factors, reasons for late recognition, and outcome). Patient data were collected from electronic medical records and patient's medical files. The anamnesis, laboratory, and imaging results, ED management, and consultation notes were examined separately for each ED visit. Logistic regression models were employed to identify significant univariable predictors of ED visits and irAEs., Results: A total of 199 patients were included in the study, all of whom had metastatic cancer. Of these, 154 patients (77.4%) received nivolumab therapy for non-small cell lung cancer. Most patients (71.9%, n = 143) had at least one additional comorbidity. One hundred and eleven patients (55.8%) presented to the ED. Hypertension (OR: 2.425, 95% CI: 1.226-4.795, p = 0.011) and chronic obstructive pulmonary disease (OR: 2.489, 95% CI: 1.133-5.468, p = 0.023) were identified as risk factors for ED visits. A total of 21 irAEs were diagnosed (14 in ED, 6 in the oncology clinic, and 1 in the inpatient ward). Univariate analysis found no significant association between irAE diagnosis and any specific factors., Conclusion: A significant proportion of the patients treated with nivolumab for advanced cancer present to ED for ICI-related adverse events, although most cases were not attributable to irAEs. Due to the vague symptomatology of irAEs, their recognition and diagnosis in the ED can be challenging. Close collaboration between ED physicians and oncologists is paramount to the management of patients with cancer in the ED., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Immune checkpoint inhibitors (ICIs) have efficacy in several solid tumors but limited efficacy in glioblastoma (GBM). This study evaluated the safety of anti-CTLA-4 and anti-PD-1 ICIs alone or in combination in newly diagnosed GBM after completion of standard radiochemotherapy with the subsequent intent to test combinatorial ICIs in this setting., Methods: The primary endpoint was dose-limiting toxicity (DLT) for adults with unifocal, supratentorial newly diagnosed GBM after resection and chemoradiation. Ipilimumab and nivolumab were tested separately and in combination with a planned expansion cohort dependent upon DLT results., Results: Thirty-two patients were enrolled at 9 institutions: 6 to each DLT assessment cohort and 14 to the expansion cohort. Median age: 55 years, 67.7% male, 83.9% White. Treatment was well tolerated with 16% Grade 4 events; the combination did not have unexpectedly increased toxicity, with no Grade 5 events. One DLT was seen in each single-agent treatment; none were observed in the combination, leading to expanded accrual of the combined treatment. The median follow-up was 19.6 months. For all patients receiving combination treatment, median overall survival (OS) and progression-free survival (PFS) were 20.7 and 16.1 months, respectively., Conclusions: IPI and NIVO are safe and tolerable with toxicities similar to those noted with other cancers when given in combination with adjuvant temozolomide for newly diagnosed GBM. Combination IPI + NIVO is not substantially more toxic than single agents. These results support a subsequent efficacy trial to test the combination of ICIs in Phase II/III for patients with newly diagnosed GBM., Clinicaltrials.gov Registration: NCT02311920., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

In Japan, cancer immunotherapy using immune checkpoint inhibitors(ICIs)has become a new treatment modality in cancer chemotherapy in the 2010s, and is now widely approved for many types of cancer. Today, combination cancer immunotherapy utilizing ICIs is being developed, with many cancer types. The first approved ICI combination in Japan consists of nivolumab, an anti-PD-1 antibody, and ipilimumab, an anti-CTLA-4 antibody. In the combination therapy, ipilimumab is administered at different doses, intervals, and frequencies depending on the cancer type. ICI combination therapy has been reported to be more effective than ICI monotherapy, but also be associated with more severe adverse events. Therefore, optimal dosing strategies for ipilimumab were explored considering both treatment efficacy and adverse event profiles. In the study of 64 cases with multiple cancer, higher efficacy of ICI combined therapy was expected in cases with irAEs, and there were cases with long-lasting efficacy even after early discontinuation of ipilimumab due to irAEs. And the high dose(3 mg/kg)of ipilimumab was suggested to be an independent risk factor for CTCAE Grade 3 or higher for severe irAEs.

Competing Interests: The authors have no conflicts of interest to declare.

Background: Plinabulin is a GEF-H1 releasing agent with an immune-enhancing function. We report results from a multicenter Phase I/II study (NCT03575793) assessing plinabulin in combination with nivolumab and ipilimumab for the treatment of recurrent SCLC., Methods: In Phase I, patients were enrolled using a 3 + 3 design to determine dose-limiting toxicities (DLTs) and recommended Phase 2 dose (RP2D). Patients received nivolumab (1 mg/kg), ipilimumab (3 mg/kg), and plinabulin (in escalating doses) on day 1 of each 21-day cycle for 4 cycles followed by maintenance with plinabulin and nivolumab. In phase II, patients with recurrent PD(L)1 inhibitor resistant SCLC were enrolled. The primary objective was median progression-free survival (PFS)., Results: Between 9/2018 and 2/2023, 39 patients were enrolled, and 36 patients received study treatment and were evaluable for safety (16 in Phase I; 20 in Phase II). In the phase I dose-escalation, there were 2 DLTs; grade 3 altered mental status lasting <24 h and grade 3 infusion reaction. The Plinabulin RP2D was determined to be 30 mg/m 2 . Common TRAEs were vomiting (44 %), nausea (42 %), and infusion reaction (36 %); 6 % of patients had a ≥grade 3 TRAE. Five patients (14 %) had ≥grade 3 irAEs; there were no cases of immune-related pneumonitis. In the efficacy analysis in 27 patients, the median PFS was 1.6 months (95 % CI 1.2 to 2.7) and the trial did not meet the pre-specified target median PFS of 3.5 months. Four patients treated at 30 mg/m 2 had PR (confirmed 1, unconfirmed 3); 5 patients had SD with a CBR of 33 %. Two of 8 patients treated in phase I at the lower 20 mg/m 2 dose had confirmed PR, with 1 patient on the drug regimen for >90 cycles. The median OS and follow-up time were 5.5 months and 2.5 months respectively., Conclusions: Plinabulin in combination with nivolumab and ipilimumab was tolerable at the dose of 30 mg/m 2 . While the clinical responses in PD-1 resistant SCLC were limited, some patients had a long duration of response. The number of ≥grade 3 irAE with the combination were lower than expected., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Cabozantinib and nivolumab (CaboNivo) alone or with ipilimumab (CaboNivoIpi) have shown promising efficacy and safety in patients with metastatic urothelial carcinoma (mUC), metastatic renal cell carcinoma (mRCC), and rare genitourinary (GU) tumors in a dose-escalation phase I study. We report the final data analysis of the safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the phase I patients and seven expansion cohorts., Methods: This is an investigator-initiated, multicenter, phase I trial. CaboNivo doublet expansion cohorts included (1) mUC, (2) mRCC, and (3) adenocarcinoma of the bladder/urachal; CaboNivoIpi triplet expansion cohorts included (1) mUC, (2) mRCC, (3) penile cancer, and (4) squamous cell carcinoma of the bladder and other rare GU tumors (ClinicalTrials.gov identifier: NCT02496208)., Results: The study enrolled 120 patients treated with CaboNivo (n = 64) or CaboNivoIpi (n = 56), with a median follow-up of 49.2 months. In 108 evaluable patients (CaboNivo n = 59; CaboNivoIpi n = 49), the ORR was 38% (complete response rate 11%) and the median duration of response was 20 months. The ORR was 42.4% for mUC, 62.5% for mRCC (n = 16), 85.7% for squamous cell carcinoma of the bladder (n = 7), 44.4% for penile cancer (n = 9), and 50.0% for renal medullary carcinoma (n = 2). Grade ≥ 3 treatment-related adverse events occurred in 84% of CaboNivo patients and 80% of CaboNivoIpi patients., Conclusion: CaboNivo and CaboNivoIpi demonstrated clinical activity and safety in patients with multiple GU malignancies, especially clear cell RCC, urothelial carcinoma, and rare GU tumors such as squamous cell carcinoma of the bladder, small cell carcinoma of the bladder, adenocarcinoma of the bladder, renal medullary carcinoma, and penile cancer.

Introduction: The phase 2 RAMONA study demonstrated that second-line nivolumab ± ipilimumab immunotherapy was feasible and effective in older patients with advanced esophageal squamous cell cancer (ESCC). Here, we presented results from functional status (FS) and quality-of-life (QoL) analyses., Materials and Methods: Patients aged ≥65 years with advanced ESCC and disease progression following first-line therapy were enrolled for study treatment with nivolumab ± ipilimumab. Geriatric assessments (GA) consisting of G8 and GoGo/SlowGo evaluation, and quality of life (QoL) assessments with EORTC QLQ-C30 questionnaires were conducted at baseline and during the treatment. A post hoc analysis was performed to compare therapy efficacy, toxicity, and QoL between age groups (≥70 years vs. <70 years) and functionality groups (G8 > 14 vs. ≤14 and GoGo vs. SlowGo)., Results: In 66 treated patients with a median age of 70.5 years, older patients had non-inferior overall survival and tumor response compared to younger patients, with no increased treatment-related adverse events. Fitter patients (G8 > 14, GoGo) had a clinically, yet not statistically significant, survival advantage than less fit patients (G8 ≤ 14, SlowGo) patients. Moreover, FS by G8 and GoGo/SlowGo significantly correlated with QoL. Overall, QoL was impaired at baseline but remained stable in all scales over the course of immunotherapy., Discussion: The administration of nivolumab ± ipilimumab second-line immunotherapy in older patients with ESCC did not show age-dependent effects and maintained QoL. GA could identify functional deficits and limitations of QoL and should be implemented in the context of immunotherapy., Clinicaltrials: gov: NCT03416244., Competing Interests: Declaration of Competing Interest NMB reports research funding and receipt of equipment from Deutsche Forschungsgemeinschaft. RDH reports advisory for Amgen, Astra Zeneca, Bristol Myers Squibb, Boehringer, Daichi, Lilly, Merck, MSD, Pierre Fabre, Roche, and Servier; honoraria for lectures and presentations from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer, Daichi, Lilly, medac, Merck, MSD, Pierre Fabre, Roche, Saladax, Sanofi, and Servier; and consulting fees from Amgen, Astra Zeneca, Bayer, BMS, Boehringer, Daichi, Lilly, medac, Merck, MSD, Pierre Fabre, Roche, Saladax, Sanofi, and Servier. AV reports consultancy and advisory role for AstraZeneca, Amgen, BeiGene, Böhringer Mannheim, BMS, BTG, Daichi-Sankyo, EISAI, Incyte, Ipsen, MSD, PierreFabre, Roche, Servier, Sirtex, Tahio and Terumo. MdW reports research funding from Pfizer, Abbvie, Novartis, Astellas, Bristol Myers Squibb, AstraZeneca and MorphoSys; speaker's honoraria from AstraZeneca and Janssen; travel or accommodation expenses from Astellas and Janssen. RJ reports consulting fees from Roche and Bayer; payments for lectures and presentations from Dr. Falk Pharma and Bristol Myers Squibb; for writing of manuscripts from Boston Scientific and Springer Nature; advisory for Heidelberg University Hospital; and leading the Endoscopy section of the German Society of Gastroenterology. GS reports consulting fees from Servier, Pharmacosmos, Bristol Myers Squibb, Amgen and travel support from Daichi-Sankyo. PTP reports consulting fees from Bristol Myers Squibb, AstraZeneca, and MSD. TL is Scientific Head at CROLLL GmbH. HB is an employee of a commercial provider of clinical statistics and programming services (Staburo GmbH, Munich). MPE reports funding for conducting the trial from AIO-Studien-gGmbH which is the regulatory sponsor of the trial, and advisory for Bristol Myers Squibb. NH reports advisory for Bristol Myers Squibb. All remaining authors declare no conflicts of interests., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: To investigate the risk of developing diabetes and ketoacidosis in clinical patients with immune checkpoint inhibitors (ICIs)., Methods: We looked in the FDA Adverse Event Reporting System for reports of ICIs-associated diabetes mellitus (DM) and ketoacidosis between January 2004 and March 2022. We explored the signals using fourfold table-based proportional imbalance algorithms. Patient characteristics, country distribution, and outcomes of adverse reactions were described. Kruskal-Wallis test was used to compare the time of onset and prognosis of adverse reactions., Results: A total of 2110 reports of ICIs-related DM were included in the study. The largest number of reports was from Japan (752, 35.64%), followed by the United States and France (624, 29.57%; 183, 8.67%). Seven drugs detected signals of DM and ketoacidosis according to 4 proportional imbalance algorithms: nivolumab, pembrolizumab, cemiplimab, dostarlimab, atezolizumab, avelumab, and durvalumab. Diabetes and ketoacidosis generally occurred early in the course of ICIs treatment, the median time to event onset was 144.5 (interquartile range 27-199) days. ICIs-related diabetes and ketoacidosis events resulted in 934 major medical events (44.3%), 524 hospitalizations (24.8%), 60 life-threatening events (2.8%), 42 deaths (2.0%), and 39 disability events (1.8%)., Conclusion: The study reveals the risk and characteristics of diabetes and ketoacidosis associated with ICIs, which may provide evidence for postmarketing evaluation. Careful consideration should be given to the possibility of an increased risk of diabetes and ketoacidosis after using ICIs, and careful monitoring for diabetes and ketoacidosis is recommended., Competing Interests: Disclosure The authors have no conflicts of interest to disclose., (Copyright © 2024 AACE. Published by Elsevier Inc. All rights reserved.)

Background: Nivolumab, an immune checkpoint inhibitor used to treat several malignancies, is associated with immune-related adverse events (IrAEs). Original dosing for melanoma was 3 mg/kg (maximum 240 mg) every 2 weeks (Q2W). Based on simulation studies depicting similar efficacy and toxicity to original dosing, extended interval dosing of 6 mg/kg (maximum 480 mg) every 4 weeks (Q4W) was introduced., Objective: This study will compare safety between Q2W and Q4W dosing at BC Cancer in melanoma patients., Methods: Retrospective chart review for reported incidence, onset, and severity of IrAEs in melanoma patients treated with nivolumab Q2W and Q4W dosing was completed. Fisher's test was conducted for first incidence IrAEs using Microsoft Excel., Results: Seventy-one patients were identified (Q2W n  = 35, Q4W n  = 36). Baseline characteristics were similar in both groups. No statistically significant difference was found in incidence of IrAEs between Q2W and Q4W dosing (Q2W 40% vs Q4W 50%, p  = 0.477). Rash was most common (Q2W 79% vs Q4W 50%) followed by hypothyroidism (Q2W 33% vs Q4W 20%). Median onset of IrAEs seemed later with Q4W dosing (Q2W cycle 1 vs Q4W cycle 4). Regardless of dosing, most IrAEs were grade 1-2 in severity (Q2W 100% vs Q4W 89%)., Conclusion: Q4W dosing is associated with comparable incidence and potentially later onset of IrAEs compared to Q2W dosing. Most IrAEs in both dosing groups were similar and mild. Therefore, Q4W dosing offers a safe alternative to Q2W dosing while providing benefits including decreased workload for staff, decreased clinic visits, and viral exposure by patients., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Therapy with immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of metastatic melanoma but is also associated with various immune-related adverse events (AE), including pulmonary toxicity. Herein, we describe the case of a 60-year-old female with metastasized melanoma with BRAF mutation under combination immunotherapy with ipilimumab and nivolumab, who presented with a persistent, nonproductive cough for the last two months. Her CT-scan showed de novo bronchial inflammation and wall thickening in all lung fields. Initial treatment with antimicrobial treatment and inhalation corticosteroids did not resolve her symptoms, nor the radiologic abnormalities. Additional testing with transbronchial cryobiopsy showed a histologic picture of diffuse ill-formed granulomas and the presence of moderate chronic active inflammation of the respiratory epithelium, consistent with medication-related bronchiolitis. Bronchiolitis, as present in this case, has rarely been reported as an immune-related AE. A thorough diagnostic workup is mandatory as it remains a diagnosis of exclusion. Management consists of discontinuing ICIs and administering systemic corticosteroids. The addition of immunosuppressive agents (e, infliximab, cyclophosphamide, or mycophenolate mofetil) can be considered in refractory cases. In our case, clinical and radiologic resolution was achieved after discontinuing the ICI and treatment with high-dose prednisone. This case shows that although bronchiolitis is a rare immune-related side effect of ICIs, oncologists, and pulmonologists should always be aware of this relatively easily treatable AE., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)