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Background: Patients treated with immune checkpoint inhibitors (ICIs) may experience pseudoprogression, which can be classified as progressive disease (PD) by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 and could lead to inappropriate treatment discontinuation. Immune-response criteria were developed to better capture novel response patterns seen with ICIs., Methods: We pooled data from 1765 patients with 12 types of advanced solid tumors treated with avelumab (an anti-programmed death ligand 1 (PD-L1) monoclonal antibody) monotherapy in the JAVELIN Solid Tumor and JAVELIN Merkel 200 trials, conducted a comparative analysis of tumor assessments by investigators according to RECIST 1.1 and immune-related RECIST (irRECIST), and evaluated the correlation between progression-free survival (PFS) and overall survival (OS)., Results: In total, 147 patients (8.3%) had a best overall response (BOR) of PD by RECIST 1.1 but had immune-related disease control by irRECIST (defined as immune-related BOR (irBOR) of immune-related stable disease or better). This discordance was seen irrespective of PD-L1 status and observed across all tumor types. Overall, PFS and immune-related PFS showed similar imputed rank correlations with OS., Conclusions: The use of irRECIST identified a subset of patients with a BOR of PD by RECIST 1.1 but an irBOR of immune-related disease control by irRECIST with a distinctive survival curve, thereby providing more clinically relevant information than RECIST 1.1 alone. However, as a surrogate endpoint for OS in the whole population, immune-related PFS by irRECIST did not show improved predictive value compared with PFS by RECIST 1.1., Competing Interests: Competing interests: JLG has received research funding from Astellas Medivation, Bavarian Nordic, Bristol Myers Squibb, EMD Serono, an affiliate of Merck KGaA, NantBioScience, and Pfizer. SPD has provided consultancy or advisory services for Amgen, GlaxoSmithKline, Immune Design, Incyte, EMD Serono, an affiliate of Merck KGaA, and Nektar Therapeutics, and received travel expenses from Adaptimmune, EMD Serono, an affiliate of Merck KGaA, and Nektar Therapeutics. JM is an employee of EMD Serono Research & Development Institute, Billerica, Massachusetts, USA, an affiliate of Merck KGaA. SPE is an employee of Merck Serono Ltd., Feltham, UK, an affiliate of Merck KGaA. MB is an employee of Merck. All other authors report no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Adverse events (AEs) of special interest that arise during treatment with immune checkpoint inhibitors, including immune-related AEs (irAEs), have been reported to be associated with improved clinical outcomes. We analyzed patients treated with avelumab from the JAVELIN Solid Tumor and Merkel 200 trials, examining the association between AEs and efficacy while adjusting for confounding factors such as treatment duration and event order., Methods: We analyzed efficacy and safety data from 1783 patients treated with the programmed death ligand 1 inhibitor avelumab who were enrolled in expansion cohorts of the JAVELIN Solid Tumor and Merkel 200 trials. To analyze the association between irAEs and efficacy with regard to survival, we used a time-dependent Cox model with time-varying indicators for irAEs, as well as multistate models that accounted for competing risks and time inhomogeneity., Results: 295 patients (16.5%) experienced irAEs and 454 patients (25.5%) experienced infusion-related reactions. There was a reduced risk of death in patients who experienced irAEs compared with those who did not (HR 0.71, 95% CI 0.59 to 0.85) using the time-dependent Cox model. The multistate model did not suggest that the occurrence of irAEs could predict response; however, it predicted a higher chance of irAEs occurring after a response. No association was observed between response and infusion-related reactions., Conclusions: Patients who experience irAEs showed improved survival. Although irAEs are not predictors for response to immune checkpoint inhibitors, increased vigilance for irAEs is needed after treatment with avelumab., Trial Registration Numbers: NCT01772004 and NCT02155647., Competing Interests: Competing interests: KK has received research grants from EMD Serono (an affiliate of Merck KGaA, Darmstadt, Germany) and Merck & Co; has served on advisory boards for EMD Serono and Merck & Co; and has received an honorarium from Merck & Co. JM, MB and JW are employees of EMD Serono Research & Development Institute (an affiliate of Merck KGaA, Darmstadt, Germany). VK was an employee of EMD Serono (an affiliate of Merck KGaA, Darmstadt, Germany) at the time this analysis was conducted. IS is an employee of Merck KGaA, Darmstadt, Germany. SPD reports serving as a consultant or advisor for Amgen, EMD Serono (an affiliate of Merck KGaA, Darmstadt, Germany), GlaxoSmithKline, Immunocore, Immune Design, Incyte, Merck & Co, and Nektar; has received research grants from Amgen, Bristol Myers Squibb, Deciphera, EMD Serono, Incyte, Merck & Co, and Nektar; and has received reimbursement for travel and accommodation expenses from Adaptimmune, EMD Serono, Immunocore and Nektar. AR and JLG are employees of the National Cancer Institute, which has a cooperative research and development agreement with EMD Serono (an affiliate of Merck KGaA, Darmstadt, Germany)., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Anti-programmed cell death ligand 1 (PD-L1)/programmed cell death 1 antibodies have shown clinical activity in platinum-treated metastatic urothelial carcinoma, resulting in regulatory approval of several agents, including avelumab (anti-PD-L1). We report ≥2-year follow-up data for avelumab treatment and exploratory subgroup analyses in patients with urothelial carcinoma., Methods: Patients with previously treated advanced/metastatic urothelial carcinoma, pooled from two cohorts of the phase Ib JAVELIN Solid Tumor trial, received avelumab 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity or withdrawal. End points included best overall response and progression-free survival (PFS) per RECIST V.1.1, overall survival (OS) and safety. Post hoc analyses included objective response rates (ORRs) in subgroups defined by established high-risk/poor-prognosis characteristics and association between time to response and outcome., Results: 249 patients received avelumab; efficacy was assessed in 242 postplatinum patients. Median follow-up was 31.9 months (range 24-43), and median treatment duration was 2.8 months (range 0.5-42.8). The confirmed ORR was 16.5% (95% CI 12.1% to 21.8%; complete response in 4.1% and partial response in 12.4%). Median duration of response was 20.5 months (95% CI 9.7 months to not estimable). Median PFS was 1.6 months (95% CI 1.4 to 2.7 months) and the 12-month PFS rate was 16.8% (95% CI 11.9% to 22.4%). Median OS was 7.0 months (95% CI 5.9 to 8.5 months) and the 24-month OS rate was 20.1% (95% CI 15.2% to 25.4%). In post hoc exploratory analyses, avelumab showed antitumor activity in high-risk subgroups, including elderly patients and those with renal insufficiency or upper tract disease; ORRs were numerically lower in patients with liver metastases or low albumin levels. Objective response achieved by 3 months versus later was associated with longer OS (median not reached (95% CI 18.9 months to not estimable) vs 7.1 months (95% CI 5.2 to 9.0 months)). Safety findings were consistent with previously reported 6-month analyses., Conclusions: After ≥2 years of follow-up, avelumab showed prolonged efficacy and acceptable safety in patients with platinum-treated advanced/metastatic urothelial carcinoma, including high-risk subgroups. Survival appeared longer in patients who responded within 3 months. Long-term safety findings were consistent with earlier reports with avelumab treatment in this patient population., Competing Interests: Competing interests: ABA has no relationships to disclose. JAE has no relationships to disclose. JRI has received research funding from Aileron Therapeutics, ARMO BioSciences, AstraZeneca, BioMed Valley Discoveries, Bristol Myers Squibb, Calithera Biosciences, Celldex, eFFECTOR Therapeutics, Genentech/Roche, GlaxoSmithKline, Immunocore, Janssen Oncology, MedImmune, Merck and Co., Novartis, Pfizer, Phosplatin Therapeutics, Roche, and TESARO. MA has no relationships to disclose. MSG reports having stocks and other ownership interests in Caremission and WCCT Global; has received research funding from AbbVie, Acetylon, Aduro Biotech, Advaxis, Amgen, Array BioPharma, BeiGene, BioLineRx, Calithera Biosciences, CanBas, Celgene, Celldex, Corcept Therapeutics, CtyomX Therapeutics, Deciphera, Driver Group, Endocyte, ESSA, Five Prime Therapeutics, FujiFilm, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, Halozyme, Hengrui Therapeutics, Inanovate, Incyte, Lilly, Lilly/ImClone, MabVax, Macrogenics, MedImmune, Merck KGaA (Darmstadt, Germany), Merrimack, Millennum, Minneamrita Therapeutics, Nektar, Novartis, Novita Pharmaceuticals, OncoMed, Pfizer, Phoenix Biotech, Plexxikon, Proderm IQ, Samumed, Seattle Genetics, Sirtex Medical, Strategia Therapeutics, Syndax, SynDevRx, TESARO, Tokai Pharmaceuticals, Tolero Pharmaceuticals, Toray Industries, TRACON Pharma, Trovagene, and Verastem; and reports patents, royalties or other intellectual property for patient-on-patient selection for clinical trials. RA has no relationships to disclose. TG has received research funding from Ferring Pharmaceuticals. LD has no relationships to disclose. K-WL has received research funding from Array BioPharma, ASLAN Pharmaceuticals, AstraZeneca/MedImmune, Five Prime Therapeutics, Green Cross Corp., LSK BioPharma, MacroGenics, Merck KGaA (Darmstadt, Germany), MSD, Ono Pharmaceutical, Pfizer, and Pharmacyclics. MHT reports serving as a consultant or advisor for ArQule, Array BioPharma, Bayer, Blueprint Medicines, Bristol Myers Squibb, Eisai, Loxo, and Novartis; and is a member of a speaker’s bureau for Bristol Myers Squibb, and Eisai. PS reports serving as a consultant or advisor for Blueprint Medicines, Eisai, Ellipses Pharma, Epizyme, Ipsen, Lilly, Loxo, PIQUR Therapeutics, and Plexxikon; and has received research funding from Blueprint Medicines, Boehringer Ingelheim, CoBioRes, Eisai, Exelixis, G1 Therapeutics, Lilly, Novartis, PharmaMar, and Plexxikon. DW reports serving as a consultant or advisor for Merck and Co.; and has received reimbursement for travel, accommodation and expenses from Merck and Co. AR has received honoraria from Bristol Myers Squibb, Ipsen, Merck KGaA (Darmstadt, Germany), MSD, Novartis, and Pfizer; reports serving as a consultant or advisor for Bristol Myers Squibb, Ipsen, Novartis, Pfizer, and Roche; has received research funding from Novartis and Pfizer; and has received reimbursement for travel, accommodation and expenses from Bristol Myers Squibb, MSD, Novartis, and Pfizer. JM reports employment at EMD Serono Research & Development Institute, Inc.; a business of Merck KGaA, Darmstadt, Germany. GP reports employment at EMD Serono, Inc.; a business of Merck KGaA, Darmstadt, Germany. MR reports employment at EMD Serono Research & Development Institute, Inc.; a business of Merck KGaA, Darmstadt, Germany. JLG has received research funding from Astellas/Medivation, Bavarian Nordic, Bristol Myers Squibb, EMD Serono (a business of Merck KGaA, Darmstadt, Germany), Incyte, Janssen, Merck & Co, Immunity Bio, and Pfizer. MRP is a member of a speaker’s bureau for Celgene, Exelixis, Genentech/Roche, and Taiho Pharmaceutical., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)