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Background: Belzutifan is a first-in-class hypoxia-inducible factor subunit 2α (HIF-2α) inhibitor approved at a dose of 120 mg once daily for certain adults with VHL disease and adults with advanced renal cell carcinoma (RCC) following therapy with a programmed cell death protein 1 (PD-1) [or programmed death ligand 1 (PD-L1)] inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor. However, whether the belzutifan dose could be optimized is unclear., Patients and Methods: The phase II LITESPARK-013 study (NCT04489771) enrolled patients with advanced clear cell RCC whose disease progressed after one to three prior systemic therapies, including an anti-PD-(L)1 regimen. Patients were randomly assigned 1 : 1 to receive belzutifan 120 or 200 mg once daily. The primary endpoint was the objective response rate (ORR) per RECIST version 1.1. The secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety., Results: Overall, 154 patients were enrolled (120 mg: n = 76; 200 mg: n = 78). The median follow-up was 20.1 months (range 14.8-28.4). The ORR was 23.7% versus 23.1% for the 120 mg and 200 mg groups, respectively [P = 0.5312; -0.5%, 95% confidence interval (CI) -14.0% to 12.9%]. The median DOR was not reached for the 120 mg arm and was 16.1 months (2.1+ to 23.5+) for the 200 mg arm. No between-group differences were observed for PFS [hazard ratio (HR) 0.94, 95% CI 0.63-1.40] or OS (medians not reached; HR 1.11, 95% CI 0.65-1.90). Grade 3 or 4 treatment-related adverse events were observed in 35 patients (46.1%) in the 120 mg group and 36 patients (46.2%) in the 200 mg group., Conclusions: The efficacy of belzutifan was similar between the 120 mg dose and the 200 mg dose for previously treated clear cell RCC. Safety at both doses was consistent with the known safety profile of belzutifan. These results further support 120 mg once daily as the preferred dose for belzutifan., (Copyright © 2024. Published by Elsevier Ltd.)

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.)

Purpose: A clinically meaningful attribute of some immune-oncology (IO) regimens is potential durable clinical benefit during a treatment-free interval. We characterize treatment-free survival (TFS) with and without ongoing toxicity in trials of frontline IO-VEGF tyrosine kinase inhibitor (TKI) combinations in patients with advanced renal cell carcinoma (aRCC)., Experimental Design: Individual patient data were pooled by treatment arm from randomized trials submitted to the FDA evaluating IO-TKI combination in treatment-naïve aRCC with at least 30 months of median follow-up. OS, TFS, TFS with and without toxicity, and time to all protocol therapy cessation were assessed. TFS was estimated by 30-month restricted mean times, defined as area between Kaplan-Meier curves for two time-to-event endpoints originating at randomization: time to all protocol therapy cessation and time to subsequent systemic therapy initiation or death., Results: Three trials met criteria for analysis; 1,183 patients received IO-TKI versus 1,184 on control arms receiving TKI alone (sunitinib, SUN). IO-TKI and SUN groups spent 9% {2.7 months [95% confidence interval (CI), 1.8-3.5]} and 10% [2.9 months (95% CI, 2.1-3.8)] of the 30-month period alive and treatment-free, respectively. Mean TFS without grade ≥3 toxicity was 1.7 and 2.3 months in IO-TKI and SUN groups, respectively., Conclusions: In this post hoc partitioned survival analysis, TFS and TFS without toxicity appeared similar in the IO-TKI group compared with the SUN group. These findings may reflect contin-uation of TKI until progression per protocol design in all trials and discontinuation of IO after 2 years in two trials. See related commentary by Stadler and Karrison, p. 3098., (©2024 American Association for Cancer Research.)

Background: Immunotherapy can be associated with prolonged disease control even after cessation of treatment without the need for further cancer-directed therapy. Treatment-related adverse events (TRAEs) can also persist after discontinuation of therapy. Treatment-free survival (TFS) with and without toxicity as a component of a partitioned survival model can characterize patient survival time, which is not captured by standard outcome measures., Methods: Data from 1096 patients with advanced renal cell carcinoma treated with first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) in the CheckMate 214 trial were analyzed. TFS was defined as the area between two Kaplan-Meier curves for time from randomization to protocol therapy discontinuation and time from randomization to subsequent systemic therapy initiation or death, estimated as the difference in 60-month restricted mean times with confidence intervals (CIs) obtained using bootstrap sampling. Time on protocol therapy and TFS were further characterized as time with and without grade 2+ and 3+TRAEs. Survival functions were estimated in subgroups including International Metastatic Renal Cell Carcinoma Database Consortium risk groups using the Kaplan-Meier method., Results: At 5 years from randomization, 48% of patients treated with NIVO+IPI and 37% of patients treated with SUN were alive. In the intent-to-treat population, 18% of the NIVO+IPI-treated and 5% of SUN-treated patients are surviving treatment-free. For favorable-risk patients, the 60-month mean TFS was 14.4 months for NIVO+IPI versus 5.5 months for SUN (difference 8.9 months (95% CI 4.9 to 12.8)). TFS for NIVO+IPI versus SUN with grade 2+TRAEs was 5.0 and 2.1 months, respectively, and with grade 3+TRAEs was 1.2 and 0.3 months, respectively. For intermediate/poor-risk patients, the 60-month mean TFS was 10.1 months for NIVO+IPI versus 4.1 months for SUN (difference 6.1 months (95% CI 4.2 to 7.9)). TFS for NIVO+IPI versus SUN with grade 2+TRAEs was 4.0 versus 2.0 months, respectively, and 0.6 versus 0.3 months with grade 3+TRAEs., Conclusions: Although overall survival was similar, favorable-risk patients treated with NIVO+IPI spent more time surviving treatment-free with and without toxicity versus SUN after 60 months of follow-up. Intermediate/poor-risk patients treated with NIVO+IPI had longer survival and longer TFS without toxicity versus SUN., Trial Registration Number: NCT02231749., Competing Interests: Competing interests: CMM reports no conflicts of interest. OAJ reports no conflicts of interest. TP reports consulting or advisory roles with Bristol Myers Squibb (BMS), AstraZeneca, Ipsen, Pfizer, Novartis, Seagen, Roche, Exelixis, MSD, Merck Serono, Astellas Pharma, Johnson & Johnson, Eisai, MashupMD, Merck, and Incyte; travel, accommodations, expenses from Pfizer, MSD, AstraZeneca, Roche, and Ipsen; honoraria from AstraZeneca, Eisai, Merck, Novartis, Pfizer, Roche, Astellas Pharma, BMS GmbH & Co. KG, Exelixis, Incyte, Ipsen, Seagen, Merck Serono, Johnson & Johnson/Janssen, and MashupMD; and research funding from AstraZeneca, Roche, BMS, Exelixis, Ipsen, MSD, Novartis, Pfizer, Seagen, Merck Serono, Astellas Pharma, Johnson & Johnson, and Eisai. RJM reports consulting or advisory roles with Eisai, Exelixis, Merck, Genentech/Roche, Incyte, Pfizer, AstraZeneca, EMD Serono, Calithera Biosciences, and AVEO; travel, accommodations, and expenses from BMS; and research funding to institution from Pfizer, BMS, Eisai, Novartis, Genentech/Roche, Exelixis, Merck, and AVEO. NMT reports stock and other ownership interests with Amgen, Arcturus, Arcus Biosciences, BioCryst Pharmaceuticals, Corvus Pharmaceuticals, Johnson & Johnson/Janssen, Merck, Surface Oncology, Vanguard Health Care ETF, Xencor, First Trust Amex Biotech (FBT), Nuvation Bio, Revolution Medicines, and Spdr S&P Pharmaceuticals ETF; honoraria from BMS, Exelixis, Eisai Medical Research, Neoleukin Therapeutics, Merck Sharp & Dohme, Intellisphere, Oncorena, AstraZeneca/Merck, and Nektar Therapeutics; consulting or advisory roles with Oncorena, Merck Sharp & Dohme, BMS Foundation, and Nektar; and research funding to institution from Exelixis, BMS, Nektar, Arrowhead Pharmaceuticals, Novartis, and Calithera Biosciences. C-HL reports research funding to institution from BMS, Calithera, Eisai, Eli Lilly, Exelixis, Merck, and Pfizer; consulting or advisory roles with Amgen, BMS, Exelixis, Eisai, Merck, Pfizer, and EMD Serono; and honoraria from AiCME, Intellisphere, and Research to Practice. YT reports consulting or advisory roles with Eisai, MSD, Ono Pharmaceutical, and Taiho Pharmaceutical; honoraria from Astellas Pharma, BMS Japan, Chugai Pharma, Ono Pharmaceutical, Takeda, Merck, Pfizer, and MSD; and research funding to institution from Astellas Pharma, AstraZeneca, Chugai Pharma, Eisai, MSD, Ono Pharmaceutical, Pfizer, and Takeda. MHV reports consulting or advisory roles with Novartis, GSK, Exelixis, Merck, Corvus, Calithera, and AVEO; travel, accommodations, and expenses from Takeda, Novartis; research funding with BMS and Roche/Genentech. ERP reports consulting or advisory roles with Seattle Genetics/Astellas, AstraZeneca, AVEO, BMS/Medarex, Calithera Biosciences, EMD Serono, Exelixis, IMV, Janssen, MEI Pharma, Merck, Signatera, Pfizer, and Regeneron; and research funding to institution from BMS, Merck Sharp & Dohme, Astellas, and Genentech/Roche. TKC reports institutional and/or personal, paid and/or unpaid support for research, advisory boards, consultancy, and/or honoraria past 5 years, ongoing or not, from: Alkermes, Arcus Bio, AstraZeneca, Aravive, AVEO, Bayer, BMS, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Neomorph, Nuscan/PrecedeBio, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (Peerview, OncLive, MJH, CCO and others), outside the submitted work. Institutional patents filed on molecular alterations and immunotherapy response/toxicity, and ctDNA. Equity: Tempest, Pionyr, Osel, Precede Bio, CureResponse, InnDura Therapeutics, Primium. Committees: NCCN, GU Steering Committee, ASCO (BOD 6-2024-, ESMO, ACCRU, KidneyCan. Medical writing and editorial assistance support may have been funded by Communications companies in part. No speaker’s bureau. Mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components. The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter. TKC is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan Mass Challenge, Hinda and Arthur Marcus Fund and Loker Pinard Funds for Kidney Cancer Research at DFCI. BIR reports consulting or advisory roles with Pfizer, Merck, BMS, AVEO, Surface Oncology, Corvus Pharmaceuticals, Aravive, Arrowhead Pharmaceuticals, Eisai, Genentech, Alkermes, NiKang Therapeutics, EUSA Pharma, Athenex, Debiopharm Group, and HiberCell; leadership roles with MJH Life Sciences and MashupMD; travel, accommodations, and expenses from Pfizer, BMS, and Merck; stock and other ownership interests with PTC Therapeutics; and research funding to institution from Pfizer, Roche/ Genentech, BMS, Merck, AstraZeneca/MedImmune, Incyte, Arrowhead Pharmaceuticals, Seagen, Surface Oncology, Dragonfly Therapeutics, Aravive, Exelixis, AVEO, Arcus Biosciences, HiberCell, Stata, ADC Therapeutics, Dracen, Janssen, Adela, Pionyr, VasGene Therapeutics, Gilead Sciences, Point Therapeutics, and Daiichi Sankyo/UCB Japan. HJH reports consulting or advisory roles with BMS, Pfizer, Exelixis, Bayer, Novartis, Merck, ARMO BioSciences, Corvus Pharmaceuticals, Surface Oncology, and Lilly; travel, accommodations, and expenses from BMS, Merck, Pfizer, Lilly, and Novartis; honoraria from BMS; and research funding to institution from BMS, Merck, Aravive, and Surface Oncology. BE reports consulting or advisory roles with Pfizer, BMS, Ipsen, AVEO, and Oncorena; travel, accommodations, and expenses from BMS, Ipsen, and MSD; honoraria from Pfizer, BMS, Ipsen, and Oncorena; and research funding to institution from BMS. LA reports consulting or advisory roles to institution with Astellas, BMS, Eisai, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche; non-financial interests with Pfizer, BMS, Ipsen, Roche, Exelixis, AVEO, AstraZeneca, MSD, ASCO, Kidney Foundation, and ESMO. LR reports employment with BMS and stock and other ownership interests with BMS. MBA reports consulting or advisory roles with Genentech, Novartis, BMS, Merck, Exelixis, Eisai, Agenus, Werewolf Pharma, Surface Oncology, Pyxis, Fathom Biotechnology, AVEO, Cota Healthcare, Idera, Ellipses Pharma, AstraZeneca, PACT Pharma, Pfizer, Scholar Rock, Asher Biotherapeutics, Takeda, Sanofi, Simcha Therapeutics, GlaxoSmithKline, Oncorena, and Pliant; stock and other ownership interests with Werewolf Pharma and Pyxis; and research funding to institution from BMS and Merck. MMR reports consulting or advisory roles (institution) with Ipsen and Debiopharm; personal fees from BMS and Tolmar Pharmaceuticals; grants from Novartis, Pfizer, Ipsen, TerSera, Merck, Ferring, Pierre Fabre, Roche, AstraZeneca, Bayer, and BMS. DFM reports consulting or advisory roles with BMS, Merck, Genentech/Roche, Pfizer, Exelixis, Novartis, Array BioPharma, Peloton Therapeutics, EMD Serono, Jounce Therapeutics, Alkermes, Lilly, Eisai, Calithera Biosciences, Iovance Biotherapeutics, Werewolf Therapeutics, Synthekine, AVEO, Sanofi, and Xilio Therapeutics; other relationship with Beth Israel Deaconess Medical Center; research funding to institution from BMS, Merck, Genentech, Novartis, and Alkermes; and uncompensated relationships with X4 Pharma and AVEO., (© 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 of Review: The aim of this study is to provide an update on mitral valve prolapse (MVP) and mitral annular disjunction (MAD) and who may be at risk for ventricular arrhythmias and sudden cardiac death., Recent Findings: MVP is generally considered a benign condition. However, a small subset of patients may be at risk for life-threatening ventricular arrhythmias. Among the risk factors identified in adults include patients with bileaflet mitral valves, myxomatous changes, myocardial fibrosis, and the presence of MAD. Advances in multimodal imaging have allowed for improved identification of fibrosis, anatomical valve derangements, and the amount of MAD. Recent guidelines have suggested that patients with MVP with or without MAD may be at risk for life-threatening arrhythmias if they have had prior ventricular arrhythmias, ventricular dysfunction, or unexplained syncope. Yet, extrapolation of adult data to a pediatric cohort with similar MVP and MAD at this juncture is challenging. There is, however, early evidence that some pediatric patients with significant myocardial fibrosis or abnormal tissue Doppler may be at risk for ventricular tachycardia., Summary: Mitral valve prolapse and mitral annular disjunction at times coexist and at other times can be seen as isolated entities. While the incidence of arrhythmic MVP is quite rare, there is increasing evidence that certain select adults with MVP may be at risk for ventricular tachycardia and sudden cardiac death. Future multicenter studies are needed to better understand the natural history of arrhythmic mitral valve disease and how early disease manifestation in children may impact findings now being reported in young adults., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Regulatory approval of immune checkpoint inhibitors (ICIs) was based on results of large, randomized clinical trials, resulting in limited outcomes data in patient cohorts typically underrepresented in such trials. The objective of this study was to evaluate the efficacy and safety of ICIs in these unique patient cohorts. This is a multicenter, retrospective analysis of real-world data at six academic and community clinics in the United States from 1 January 2011 to 1 April 2018. Patients were included if they had received at least one cycle of ICI treatment. Unique patient cohorts included age > 75 years, non-White race, positive smoking history, ECOG performance status (PS) ≥ 2, BMI ≥ 30 kg/m 2 , autoimmune diseases (AIDs), chronic viral infections (CVI), extensive prior lines of therapy (LOTs), or >three metastatic sites. Immune-related adverse events (irAEs), overall survival (OS), and time to treatment failure were evaluated in the entire cohort and in NSCLC patients treated with PD-(L)1 monotherapy. Outcomes and their association with unique patient cohorts were compared on univariate analysis and multivariate analysis to those without a particular characteristic in the entire NSCLC PD-(L)1 monotherapy cohorts. In total, 1453 patients were included: 56.5%-smokers, 30.4%-non-White, 22.8%-elderly, 20.8%-ECOG PS ≥ 2, 15.7%-history of AIDs, and 4.7%-history of CVI. The common ICIs were nivolumab (37.1%) and pembrolizumab (22.2%). Black patients, compared to White patients, experienced fewer irAEs (OR 0.54, p < 0.001). An ECOG PS of ≥2 (HR = 2.01, p < 0.001) and an increased number of previous LOTs were associated with poor OS (the median OS of 26.2 vs. 16.2 vs. 9.6 months for one vs. two vs. three prior LOTs, p < 0.001). The above results were confirmed in anti-PD-(L)1 monotherapy non-small cell lung cancer patients (n = 384). Overall, ICIs were safe and efficacious in these typically underrepresented patient cohorts. We noted ECOG PS ≥ 2 and an increased prior LOTs were associated with poor ICI efficacy, and Black patients, compared to White patients, experienced fewer irAEs.

Background: As part of a partitioned survival analysis, treatment-free survival (TFS) can characterize the overall survival time patients spend between the cessation of immunotherapy and the start of subsequent therapy; both with and without toxicity. Significant TFS was reported for the nivolumab/ipilimumab arms of the CheckMate 067 and 214 trials for patients with advanced melanoma or renal cell carcinoma (aRCC), respectively, where immunotherapy was often halted for toxicity rather than a predefined treatment endpoint. We therefore sought to assess TFS in the HCRN GU16-260 trial, which was designed to reduce toxicity and cap immunotherapy duration., Methods: Data were analyzed from 128 patients with clear-cell aRCC treated with first-line nivolumab monotherapy for up to 2 years. Salvage nivolumab/ipilimumab for up to 1 year was provided to eligible patients with disease progression at any point or stable disease at 48 weeks (29% of patients). TFS was defined as the area between Kaplan-Meier curves for a time from registration to protocol therapy cessation and for a time from registration to subsequent systemic therapy initiation or death, estimated from 36-month mean times. The time on or off protocol treatment with grade 3+treatment-related adverse events (TRAEs) was also captured., Results: At 36 months from enrollment, 68.3% of patients were alive: 96.8% of International Metastatic RCC Database Consortium (IMDC) favorable-risk patients and 56.6% of those with intermediate/poor-risk, respectively. The 36-month mean time on protocol therapy was 11.5 months including 0.6 months with grade 3+TRAEs (16.0 months for favorable-risk patients and 9.6 months for intermediated/poor-risk patients). The 36-month mean TFS for the whole population was 9.4 months (12.9 months including 1.5 months with grade 3+TRAEs for favorable-risk and 8.0 months including 1.0 months with grade 3+TRAEs for intermediate/poor-risk). At 36 months, 65.6% of favorable-risk patients and 27.1% of intermediate/poor-risk patients were alive and subsequent systemic treatment-free., Conclusions: Nivolumab monotherapy with salvage nivolumab/ipilimumab in non-responders is an active treatment approach in treatment-naïve patients with aRCC and, similar to nivolumab/ipilimumab in CheckMate 214, results in substantial TFS and toxicity-free TFS. TFS was greatest in patients with favorable-risk disease, supporting the use of an immunotherapy-only regimen in this population., Competing Interests: Competing interests: MBA has/had an advisory role for Bristol-Myers Squibb, Merck, Novartis, Eisai, Exelixis, Aveo, Pfizer, Werewolf, Fathom, Pyxis Oncology, PACT, Elpis, X4Pharma, ValoHealth, ScholarRock, Surface, Takeda, Simcha, Roche, SAB Bio, Pliant Therapeutics, Atreca, OncoRena, Sanofi and GSK and has served as a consultant: Bristol-Myers Squibb, Merck, Novartis, Pfizer, Roche, Agenus, Asher Bio, and AstraZeneca. He reports research support to his institution from Bristol-Myers Squibb and Merck. He holds stock/stock options in Pyxis Oncology, Werewolf and Elpis. OAJ—none. NBH is a paid consultant to BMS, Eisai, Exelixis, Merck and Roche Genentech. DFM has acted as a paid consultant for and/or as a member of the advisory boards of BMS, Pfizer, Merck, Alkermes, Inc, EMD Serono, Eli Lilly and Company, Iovance, Eisai Inc., Werewolf Technologies, Calithera Biosciences, Synthekine, Inc., Johnson served on speakers bureaus for Bristol Myers Squibb and Merck; received institutional research funding from Bristol Myers Squibb, Pfizer, Merck, AstraZeneca, Astellas, Aravive, and Surface Oncology; has received reimbursement for travel and accommodations expenses from Bristol Myers Squibb, Pfizer, Eisai, and Exelixis. MH has served on Advisory Boards for Bristol Myers Squibb, CRISPR Therapeutics, Exelixis, Nektar Therapeutics, Janssen and has received research support to his institution from Alpine, Achilles Therapeutics, Apexigen, Arrowhead, Astellas, AstraZeneca, Bayer, Bristol Myer Squibb, CRISPR Therapeutics, Corvus, Eli Lilly, Endocyte, Fate Therapeutics, Genentech, Genmab, GSK, Innocrin, Iovance, KSQ, Merck, Nektar Therapeutics, Novartis, Pfizer, Progenics, Sanofi Aventis, SeaGen, Tmunity, Torque, Unum. He also reports Spouse salary from Gamida Cell, Arvinas. DJP holds stock in Bristol-Myers Squibb and Merck. DE reports research funding to institution from Bristol-Myers Squibb, Cardiff Oncology, Mink Therapeutics, Novartis, Puma Biotechnology, and Sanofi, as well as discounted research sequencing from Foundation Medicine and honorarium from OncLive. PJC—none. HH has acted as a paid consultant for and/or as a member of the advisory boards of Exelixis, BMS, Pfizer, Merck, Corvus, Armo Biosciences, Eisai, Eli Lilly, Surface Oncology, Aveo and Novartis and has received grants to his institution from Merck, Bristol-Myers Squibb, Surface Oncology and Aravive for work performed as outside of the current study. MMR reports research funding to institution from AstraZeneca, Bayer, Biotheranostics, Bristol-Myers Squibb, DebioPharm, Ipsen, Novartis, Pfizer, Roche, TerSera Therapeutics, all outside of the current study, and a consulting or advisory role for AstraZeneca, Bristol-Myers Squibb, DebioPharm, Ipsen, TerSera Therapeutics, Tolmar Pharmaceuticals., (© 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: Nivolumab plus ipilimumab has demonstrated improved survival for treatment-naïve advanced clear cell renal cell carcinoma (RCC). A series of clinical trials evaluated the effect of salvage nivolumab plus ipilimumab in patients without an objective response to nivolumab. Given the size and heterogeneity of these studies, we performed a pooled analysis to better inform the activity of nivolumab plus ipilimumab after nivolumab., Patients and Methods: Eligible patients included those with advanced clear cell RCC having received no prior immunotherapy. The primary objective was confirmed objective response rate (ORR) by investigator-assessment. Secondary objectives included progression-free survival (PFS) and overall survival (OS)., Results: The analysis included 410 patients with clear cell RCC, of whom 340 (82.9%) had IMDC intermediate/poor risk disease, and 137 (33.4%) had prior treatment. The 16-18-week ORR to nivolumab prior to nivolumab plus ipilimumab was 22.7% (n = 93), and best ORR to nivolumab was 25.1% (n = 103). Two hundred and thirty (56.1%) patients treated with nivolumab received nivolumab plus ipilimumab at a median of 16 weeks (IQR 9-19) after initiation of nivolumab [27.0% (n = 62) with stable disease and 73.0% (n = 168) with progressive disease to nivolumab]. The ORR to nivolumab plus ipilimumab was 12.6% (n = 29). Six-month PFS on nivolumab plus ipilimumab was 37% (95% CI, 27-47). Median follow-up was 34.3 months and 3-year OS was 59% (95% CI, 53-64) from nivolumab start., Conclusion: A small subset of patients lacking a response to nivolumab derive benefit from salvage nivolumab plus ipilimumab. When possible, both drugs should be given in concomitantly, rather in an adaptive fashion., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Tivozanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) with efficacy in advanced renal cell carcinoma (RCC). Long-term exploratory analyses from the TIVO-3 trial in relapsed/refractory (R/R) RCC including patients (26%) with prior immuno-oncology (IO) therapy are reported., Methods: Patients with R/R advanced RCC that progressed with 2 or 3 prior systemic therapies (≥1 VEGFR TKI) were randomized to tivozanib 1.5 mg QD or sorafenib 400 mg BID, stratified by IMDC risk and previous therapy. Safety, investigator-assessed long-term progression-free survival (LT-PFS), and serial overall survival (OS) were assessed., Results: Mean time on treatment was 11.0 months with tivozanib (n = 175) and 6.3 months with sorafenib (n = 175). Fewer grade ≥3 treatment-related adverse events occurred with tivozanib (46%) than sorafenib (55%). Dose modification rates were lower with tivozanib than sorafenib across age/prior IO subgroups; prior IO therapy did not impact dose reductions or discontinuations in either arm. Landmark LT-PFS rates were higher with tivozanib (3 years: 12.3% vs 2.4%; 4 years: 7.6% vs 0%). After 22.8 months mean follow-up, the OS HR was 0.89 (95% CI, 0.70-1.14); when conditioned on 12-month landmark PFS, tivozanib showed significant OS improvement over sorafenib (HR, 0.45; 95% CI, 0.22-0.91; 2-sided P = .0221)., Conclusions: Tivozanib demonstrated a consistent safety profile and long-term survival benefit in patients with R/R advanced RCC who were alive and progression free at 12 months. These post hoc exploratory analyses of LT-PFS and conditional OS support a clinically meaningful improvement with tivozanib versus sorafenib in this advanced RCC population., (© The Author(s) 2024. Published by Oxford University Press.)

Purpose: Programmed cell death protein 1 (PD-1) expression on CD8+TIM-3-LAG-3- tumor-infiltrating cells predicts positive response to PD-1 blockade in metastatic clear-cell renal cell carcinoma (mccRCC). Because inhibition of PD-1 signaling in regulatory T cells (Treg) augments their immunosuppressive function, we hypothesized that PD-1 expression on tumor-infiltrating Tregs would predict resistance to PD-1 inhibitors., Experimental Design: PD-1+ Tregs were phenotyped using multiparametric immunofluorescence in ccRCC tissues from the CheckMate-025 trial (nivolumab: n = 91; everolimus: n = 90). Expression of CD8, PD-1, TIM-3, and LAG-3 was previously determined (Ficial and colleagues, 2021). Clinical endpoints included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR)., Results: In the nivolumab (but not everolimus) arm, high percentage of PD-1+ Tregs was associated with shorter PFS (3.19 vs. 5.78 months; P = 0.021), shorter OS (18.1 vs. 27.7 months; P = 0.013) and marginally lower ORR (12.5% vs. 31.3%; P = 0.059). An integrated biomarker (PD-1 Treg/CD8 ratio) was developed by calculating the ratio between percentage of PD-1+Tregs (marker of resistance) and percentage of CD8+PD-1+TIM-3-LAG-3- cells (marker of response). In the nivolumab (but not everolimus) arm, patients with high PD-1 Treg/CD8 ratio experienced shorter PFS (3.48 vs. 9.23 months; P < 0.001), shorter OS (18.14 vs. 38.21 months; P < 0.001), and lower ORR (15.69% vs. 40.00%; P = 0.009). Compared with the individual biomarkers, the PD-1 Treg/CD8 ratio showed improved ability to predict outcomes to nivolumab versus everolimus., Conclusions: PD-1 expression on Tregs is associated with resistance to PD-1 blockade in mccRCC, suggesting that targeting Tregs may synergize with PD-1 inhibition. A model that integrates PD-1 expression on Tregs and CD8+TIM-3-LAG-3- cells has higher predictive value., (©2023 American Association for Cancer Research.)

This Q&A answers questions regarding ASCO's recent Systemic Therapy for Melanoma guideline.

Background: Tobacco use is associated with adverse outcomes among patients diagnosed with cancer. Socioeconomic determinants influence access and utilization of tobacco treatment; little is known about the relationship between neighborhood socioeconomic disadvantage (NSD) and tobacco assessment, assistance, and cessation among patients diagnosed with cancer., Methods: A modified Cancer Patient Tobacco Use Questionnaire (C-TUQ) was administered to patients enrolled in nine ECOG-ACRIN clinical trials. We examined associations of NSD with (1) smoking status, (2) receiving tobacco cessation assessment and support, and (3) cessation behaviors. NSD was classified by tertiles of the Area Deprivation Index. Associations between NSD and tobacco variables were evaluated using logistic regression., Results: A total of 740 patients completing the C-TUQ were 70% male, 94% White, 3% Hispanic, mean age 58.8 years. Cancer diagnoses included leukemia 263 (36%), lymphoma 141 (19%), prostate 131 (18%), breast 79 (11%), melanoma 69 (9%), myeloma 53 (7%), and head and neck 4 (0.5%). A total of 402 (54%) never smoked, 257 (35%) had formerly smoked, and 81 (11%) were currently smoking. Patients in high disadvantaged neighborhoods were approximately four times more likely to report current smoking (odds ratio [OR], 3.57; 95% CI, 1.69-7.54; p = .0009), and more likely to report being asked about smoking (OR, 4.24; 95% CI, 1.64-10.98; p = .0029), but less likely to report receiving counseling (OR, 0.11; 95% CI, 0.02-0.58; p = .0086) versus those in the least disadvantaged neighborhoods., Conclusions: Greater neighborhood socioeconomic disadvantage was associated with smoking but less cessation support. Increased cessation support in cancer care is needed, particularly for patients from disadvantaged neighborhoods., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Melanoma brain metastases (MBM) are clinically challenging to treat and exhibit variable responses to immune checkpoint therapies. Prior research suggests that MBM exhibit poor tumor immune responses and are enriched in oxidative phosphorylation. Here, we report results from a multi-omic analysis of a large, real-world melanoma cohort. MBM exhibited lower interferon-gamma (IFNγ) scores and T cell-inflamed scores compared to primary cutaneous melanoma (PCM) or extracranial metastases (ECM), which was independent of tumor mutational burden. Among MBM, there were fewer computationally inferred immune cell infiltrates, which correlated with lower TNF and IL12B mRNA levels. Ingenuity pathway analysis (IPA) revealed suppression of inflammatory responses and dendritic cell maturation pathways. MBM also demonstrated a higher frequency of pathogenic PTEN mutations and angiogenic signaling. Oxidative phosphorylation (OXPHOS) was enriched in MBM and negatively correlated with NK cell and B cell-associated transcriptomic signatures. Modulating metabolic or angiogenic pathways in MBM may improve responses to immunotherapy in this difficult-to-treat patient subset., (© 2023. The Author(s).)

Previous analyses of KEYNOTE-426, an open-label, phase 3 randomized study, showed superior efficacy of first-line pembrolizumab plus axitinib to sunitinib in advanced clear cell renal cell carcinoma (ccRCC). We report results of the final protocol-prespecified analysis of KEYNOTE-426. Patients received pembrolizumab 200 mg intravenously every 3 wk plus axitinib 5 mg orally twice daily or sunitinib 50 mg orally once daily (4 wk per 6-wk cycle). The dual primary endpoints were overall survival (OS) and progression-free survival (PFS) as per RECIST v1.1 by a blinded independent central review. The secondary endpoints included objective response rate (ORR) and duration of response (DOR). The median study follow-up was 43 (range, 36-51) mo. Benefit with pembrolizumab plus axitinib versus sunitinib was maintained for OS (hazard ratio [HR], 0.73 [95% confidence interval {CI}, 0.60-0.88]), PFS (HR, 0.68 [95% CI, 0.58-0.80]), and ORR (60% vs 40%). The median DOR was 24 (range, 1.4+ to 43+) versus 15 (range, 2.3-43+) mo in the pembrolizumab plus axitinib versus the sunitinib arm. No new safety signals emerged. These results support pembrolizumab plus axitinib as a standard of care for patients with previously untreated advanced ccRCC. PATIENT SUMMARY: Extended results of KEYNOTE-426 support pembrolizumab plus axitinib as the standard of care for advanced clear cell renal cell carcinoma., (Copyright © 2023. Published by Elsevier B.V.)

Background: While cigarette smoking has declined among the U.S. general population, sale and use of non-cigarette alternative tobacco products (ATP; e.g., e-cigarettes, cigars) and dual use of cigarettes/ATPs are rising. Little is known about ATP use patterns in cancer survivors enrolled in clinical trials. We investigated prevalence of tobacco product use, and factors associated with past 30-day use, among patients with cancer in national trials., Methods: Cancer survivors (N = 756) enrolled in 9 ECOG-ACRIN clinical trials (2017-2021) completed a modified Cancer Patient Tobacco Use Questionnaire (C-TUQ) which assessed baseline cigarette and ATP use since cancer diagnosis and in the past 30 days., Results: Patients were on average 59 years old, 70% male, and the mean time since cancer diagnosis was 26 months. Since diagnosis, cigarettes (21%) were the most common tobacco product used, followed by smokeless tobacco use (5%), cigars (4%), and e-cigarettes (2%). In the past 30 days, 12% of patients reported smoking cigarettes, 4% cigars, 4% using smokeless tobacco, and 2% e-cigarettes. Since cancer diagnosis, 5.5% of the sample reported multiple tobacco product use, and 3.0% reported multiple product use in the past 30 days. Males (vs. females; OR 4.33; P = 0 < 0.01) and individuals not living with another person who smokes (vs. living with; OR, 8.07; P = 0 < 0.01) were more likely to use ATPs only versus cigarettes only in the past 30 days., Conclusions: Among patients with cancer, cigarettes were the most prevalent tobacco product reported., Impact: Regardless, ATPs and multiple tobacco product use should be routinely assessed in cancer care settings., (©2023 American Association for Cancer Research.)

Purpose: To provide guidance to clinicians regarding the use of systemic therapy for melanoma., Methods: American Society of Clinical Oncology convened an Expert Panel and conducted an updated systematic review of the literature., Results: The updated review identified 21 additional randomized trials., Updated Recommendations: Neoadjuvant pembrolizumab was newly recommended for patients with resectable stage IIIB to IV cutaneous melanoma. For patients with resected cutaneous melanoma, adjuvant nivolumab or pembrolizumab was newly recommended for stage IIB-C disease and adjuvant nivolumab plus ipilimumab was added as a potential option for stage IV disease. For patients with unresectable or metastatic cutaneous melanoma, nivolumab plus relatlimab was added as a potential option regardless of BRAF mutation status and nivolumab plus ipilimumab followed by nivolumab was preferred over BRAF/MEK inhibitor therapy. Talimogene laherparepvec is no longer recommended as an option for patients with BRAF wild-type disease who have progressed on anti-PD-1 therapy. Ipilimumab- and ipilimumab-containing regimens are no longer recommended for patients with BRAF -mutated disease after progression on other therapies.This full update incorporates the new recommendations for uveal melanoma published in the 2022 Rapid Recommendation Update.Additional information is available at www.asco.org/melanoma-guidelines.

Background: The prespecified on-treatment analysis of ASCEND-ND (NCT02876835) raised concerns about a higher relative risk of cancer-related adverse events (AEs) with daprodustat vs darbepoetin in patients with anaemia of CKD. This concern was not observed in dialysis patients in ASCEND-D (NCT02879305)., Methods: ASCEND-ND randomized 3872 patients to daprodustat or darbepoetin. ASCEND-D randomized 2964 patients to daprodustat or conventional erythropoiesis-stimulating agents (ESAs). In both studies ESA comparators used different dosing intervals (3/week, 1/week, every 2 or every 4 weeks). The prespecified on-treatment approach examined relative risks for cancer AEs up to the last dose date + 1 day. In these analyses, owing to different dosing intervals between arms, Cox models were used to estimate the daprodustat effect by various follow-up periods (censoring at last dose date, last dose date + dosing intervals, or end of study)., Results: In ASCEND-ND, the safety of daprodustat vs darbepoetin on cancer-related AEs depended on the duration of follow-up after last dose date: hazard ratio (HR) 1.04 [95% confidence interval (CI) 0.77, 1.40] at end of study [HR 1.12 (95% CI 0.81, 1.56) for last dose date + dosing interval; HR 1.50 (95% CI 1.04, 2.15) for last dose date + 1 day]. In ASCEND-D, no excess risk of cancer-related AEs was observed with any model examined., Conclusions: Prespecified on-treatment analyses for cancer-related AEs appeared to result in biased risk estimates in ASCEND-ND by preferentially under-counting events from patients assigned to darbepoetin. Analyses accounting for longer darbepoetin dosing intervals, or extending follow-up, resulted in attenuation of effect estimates towards neutrality, similar to ASCEND-D, where ESA comparator dosing intervals are closer to daprodustat., Trial Registration: The ASCEND-ND trial is registered with ClinicalTrials.gov (NCT02876835); the ASCEND-D trial is registered with ClinicalTrials.gov (NCT02879305)., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Background: Immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) are often managed via immunosuppressive agents (ISAs); however, their impact on ICI efficacy is not well studied. The impact of the use of ISAs on ICI efficacy in patients with advanced melanoma was therefore investigated., Methods: This is a real-world, multicenter, retrospective cohort study of patients with advanced melanoma who received ICIs (n = 370). Overall survival (OS) and time to treatment failure (TTF) from the time of ICI initiation were compared among patients in subgroups of interest by unadjusted and 12-week landmark sensitivity-adjusted analyses. The association of irAEs and their management with OS and TTF were evaluated using univariate and multivariable Cox proportional hazards regression models., Results: Overall, irAEs of any grade and of grade ≥3 occurred in 57% and 23% of patients, respectively. Thirty-seven percent of patients received steroids, and 3% received other ISAs. Median OS was longest among patients receiving both (not reached [NR]), shorter among those receiving only systemic steroids (SSs) (84.2 months; 95% CI, 40.2 months to NR), and shortest among those who did not experience irAEs (10.3 months; 95% CI, 6-20.1 months) (p < .001). Longer OS was significantly associated with the occurrence of irAEs and the use of SSs with or without ISAs upon multivariable-adjusted analysis (p < .001). Similar results were noted with anti-programmed death 1 (PD-1) monotherapy and combination anti-PD-1 plus anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) therapy, and with 12-week landmark sensitivity analysis (p = .01)., Conclusions: These findings in patients with melanoma who were treated with ICIs suggest that the use of SSs or ISAs for the management of irAEs is not associated with inferior disease outcomes, which supports the use of these agents when necessary., (© 2023 American Cancer Society.)

Background: We report updated data for avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma from the third interim analysis of the phase III JAVELIN Renal 101 trial., Patients and Methods: Progression-free survival (PFS), objective response rate (ORR), and duration of response per investigator assessment (RECIST version 1.1) and overall survival (OS) were evaluated in the overall population and in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups; safety was also assessed., Results: Overall, median OS [95% confidence interval (CI)] was not reached [42.2 months-not estimable (NE)] with avelumab plus axitinib versus 37.8 months (31.4-NE) with sunitinib [hazard ratio (HR) 0.79, 95% CI 0.643-0.969; one-sided P = 0.0116], and median PFS (95% CI) was 13.9 months (11.1-16.6 months) versus 8.5 months (8.2-9.7 months), respectively (HR 0.67, 95% CI 0.568-0.785; one-sided P < 0.0001). In patients with IMDC favorable-, intermediate-, poor-, or intermediate plus poor-risk disease, respectively, HRs (95% CI) for OS with avelumab plus axitinib versus sunitinib were 0.66 (0.356-1.223), 0.84 (0.649-1.084), 0.60 (0.399-0.912), and 0.79 (0.636-0.983), and HRs (95% CIs) for PFS were 0.71 (0.490-1.016), 0.71 (0.578-0.866), 0.45 (0.304-0.678), and 0.66 (0.550-0.787), respectively. ORRs, complete response rates, and durations of response favored avelumab plus axitinib overall and across all risk groups. In the avelumab plus axitinib arm, 81.1% had a grade ≥3 treatment-emergent adverse event (TEAE), and incidences of TEAEs and immune-related AEs were highest <6 months after randomization., Conclusions: Avelumab plus axitinib continues to show improved efficacy versus sunitinib and a tolerable safety profile overall and across IMDC risk groups. The OS trend favors avelumab plus axitinib versus sunitinib, but data remain immature; follow-up is ongoing., Trial Registration: ClinicalTrials.govNCT02684006; https://clinicaltrials.gov/ct2/show/NCT02684006., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

With multiple PD-(L)1 inhibitors approved across dozens of indications by the US Food and Drug Administration, the number of patients exposed to these agents in adjuvant, first-line metastatic, second-line metastatic, and refractory treatment settings is increasing rapidly. Although some patients will experience durable benefit, many have either no clinical response or see their disease progress following an initial response to therapy. There is a significant need to identify therapeutic approaches to overcome resistance and confer clinical benefits for these patients. PD-1 pathway blockade has the longest history of use in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). Therefore, these settings also have the most extensive clinical experience with resistance. In 2021, six non-profit organizations representing patients with these diseases undertook a year-long effort, culminating in a 2-day workshop (including academic, industry, and regulatory participants) to understand the challenges associated with developing effective therapies for patients previously exposed to anti-PD-(L)1 agents and outline recommendations for designing clinical trials in this setting. This manuscript presents key discussion themes and positions reached through this effort, with a specific focus on the topics of eligibility criteria, comparators, and endpoints, as well as tumor-specific trial design options for combination therapies designed to treat patients with melanoma, NSCLC, or RCC after prior PD-(L)1 pathway blockade., Competing Interests: Competing interests: TZ reports grants or contracts from Acerta, Novartis, Merrimack, Abbvie/StemCentrx, Merck, Regeneron, Mirati Therapeutics, Janssen, AstraZeneca, Pfizer, OmniSeq, Personal Genome Diagnostics, Astellas, Eli Lilly, Exelixis, BMS, and Tempus; advisory board/consulting fees from Merck, Exelixis, Sanofi-Aventis, Janssen, AstraZeneca, Pfizer, Amgen, BMS, Pharmacyclics, SeaGen, Calithera, QED Therapeutics, Eisai, Aveo, Eli Lilly, Aravive, and Bayer; honoraria from MJH Associates, Vaniam, Aptitude Health, Peerview, Clinical Care Options, KCA, SIU, and ASCO; all unrelated to submitted work. DB reports grants from BMS, Exelixis, AVEO Pfizer, Eisai, EMD Serono, leadership or fiduciary role in KCCure (President), NCI GU Steering Committee, and Alliance Cooperative Group GU Committee, all outside the submitted work. WS reports support for the present manuscript from LUNGevity Foundation paid to her company WSCollaborative. Outside the submitted publication, she reports consulting fees from LUNGevity Foundation, National Brain Tumor Society, Ovarian Cancer Research Alliance, Cholangiocarcinoma Foundation, Pfizer, Daiichi Sankyo, Target Cancer Foundation, CancerCare, Childhood Cancer Coalition, and TriSalus Life Sciences paid to her company; honoraria from American Institutes of Cancer Research; leadership or fiduciary role in Rising Tide Foundation for Clinical Cancer Research; and owns stock in TriSalus Life Sciences. EB reports grants from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, EMD Serono, Genentech, Johnson&Johnson, Merck (MSD), and Natera outside the submitted work. RJS reports grants from Merck, loyalty to Up-to-date, consulting fees from AstraZeneca, Merck, BMS, Novartis, Eisai, Pfizer, and Iovance; and participation on a data safety monitoring/advisory board for Yale and Duke Universities, all outside the submitted work. MBA reports grants from the NCI (P30CA051008, R21CA270585, P50CA101942, R01CA231291, and DoD (KC170216), consultant fees from BMS, Merck, Novartis, Eisai, Aveo, Pfizer, Werewolf, Fathom, Pyxis Oncology, PACT, Elpis, X4Pharma, ValoHealth, ScholarRock, Surface, Takeda, Roche, SAB Bio, Exelixis, Iovance, COTA, Idera, Agenus, Asher Bio, AstraZeneca, Calithera, SeaGen, Sanofi, OncoRena, and GSK; honoraria from Medscape, OncLive, PRIME, Clinical Education Alliance, LivDerm, and ASCO; participation on a data safety monitoring board or advisory board for Novartis, BMS, Pfizer, SIMCHA, Genentech/Roche, and Melanoma Research Foundation; and owns stock in Werewolf, Pyxis Oncology, and Elpis, all outside the submitted work. PMF reports research funding to his affiliated institution from AstraZeneca, BMS, Corvus, Kyowa, Novartis, and Regeneron; consultant fees from Amgen, AstraZeneca, BMS, Daiichi, F-Star, G1, Genentech, Janssen, Iteos, Merck, Sanofi, Novartis, and Surface; and participation on a data safety monitoring board for Polaris, outside the submitted work. GF owns stock in Bristol Myers Squibb and works for BMS. MSH is the CEO of the Melanoma Research Alliance. SE is an employee of Merck&Co. The remaining authors report no conflicts of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: COVID-19 particularly impacted patients with co-morbid conditions, including cancer. Patients with melanoma have not been specifically studied in large numbers. Here, we sought to identify factors that associated with COVID-19 severity among patients with melanoma, particularly assessing outcomes of patients on active targeted or immune therapy., Methods: Using the COVID-19 and Cancer Consortium (CCC19) registry, we identified 307 patients with melanoma diagnosed with COVID-19. We used multivariable models to assess demographic, cancer-related, and treatment-related factors associated with COVID-19 severity on a 6-level ordinal severity scale. We assessed whether treatment was associated with increased cardiac or pulmonary dysfunction among hospitalized patients and assessed mortality among patients with a history of melanoma compared with other cancer survivors., Results: Of 307 patients, 52 received immunotherapy (17%), and 32 targeted therapy (10%) in the previous 3 months. Using multivariable analyses, these treatments were not associated with COVID-19 severity (immunotherapy OR 0.51, 95% CI 0.19 - 1.39; targeted therapy OR 1.89, 95% CI 0.64 - 5.55). Among hospitalized patients, no signals of increased cardiac or pulmonary organ dysfunction, as measured by troponin, brain natriuretic peptide, and oxygenation were noted. Patients with a history of melanoma had similar 90-day mortality compared with other cancer survivors (OR 1.21, 95% CI 0.62 - 2.35)., Conclusions: Melanoma therapies did not appear to be associated with increased severity of COVID-19 or worsening organ dysfunction. Patients with history of melanoma had similar 90-day survival following COVID-19 compared with other cancer survivors., (© 2023. The Author(s).)

Background: In phase III TIVO-3 trial, tivozanib improved progression-free survival (PFS) compared to sorafenib for patients with metastatic renal cell carcinoma (mRCC). However, the effectiveness of this drug after exposure to other selective VEGFR agents has not yet been defined. Herein, we characterize the clinical efficacy of tivozanib in patients with mRCC previously treated with axitinib., Methods: We identified patients from the intention to treat (ITT) population, in the TIVO-3 trial, who received treatment with axitinib before enrolment in the study and evaluated PFS, response rate (RR), and safety., Results: Out of 350 patients, 172 (83:89, tivozanib:sorafenib) had received prior treatment with axitinib in TIVO-3. In this subgroup, PFS was 5.5 months with tivozanib and 3.7 months with sorafenib (HR 0.68). RR was 13% and 8% favoring tivozanib., Conclusions: Tivozanib is active in the treatment of patients with mRCC who have progressed on prior therapies, including axitinib., (© The Author(s) 2022. Published by Oxford University Press.)

Background: Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown., Methods: In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated., Results: At a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group., Conclusions: Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.)., (Copyright © 2023 Massachusetts Medical Society.)

Advanced renal cell carcinoma is a biologically heterogeneous disease with multiple treatment options that largely involve immunotherapy and/or anti-angiogenic therapies. The choice of initial and subsequent therapy depends on both clinical and biological considerations. Here, we describe the application of recent data to clinical practice., Competing Interests: Competing interests: BIR has research funding to institution from: Pfizer, Hoffman-LaRoche, Incyte, AstraZeneca, Seattle Genetics, Arrowhead Pharmaceuticals, Immunomedics, BMS, Mirati Therapeutics, Merck, Surface Oncology, Aravive, Exelixis, Jannsen, Pionyr, AVEO. Consulting from: BMS, Pfizer, GNE/Roche, Aveo, Synthorx, Merck, Corvus, Surface Oncology, Aravive, Alkermes, Arrowhead, Shionogi, Eisai, Nikang Therapeutics, EUSA, Athenex, Allogene Therapeutics, Debiopharm; and stock ownership in PTC therapeutics. JB has/had an advisory role for Arrowhead Pharmaceuticals, Eisai, Johnson and Johnson, Exelixis, and Calithera. In addition, he has patents for HIF2 biomarkers and mechanisms of resistance pending. MBA has/had an advisory role for Bristol-Myers Squibb, Merck, Novartis, Eisai, Aveo, Pfizer, Werewolf, Fathom, Pyxis Oncology, Elpis, X4Pharma, ValoHealth, Sanofi, ScholarRock, Surface, Takeda, Simcha, Roche, SAB Biom OncoRena and GSK and has served as a consultant to: Bristol-Myers Squibb, Merck, Novartis, Pfizer, Roche, Exelixis, Agenus, Asher Bio, AstraZeneca, Calithera, and SeaGen. He reports research support to his institution from Bristol-Myers Squibb, Merck and Pfizer. He holds stock/stock options in Pyxis Oncology, Werewolf and Elpis., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: To determine the efficacy and toxicity of nivolumab monotherapy in treatment-naïve patients with non-clear cell renal cell carcinoma (nccRCC) and the efficacy of nivolumab/ipilimumab salvage therapy in patients with tumors unresponsive to initial nivolumab monotherapy., Methods: Eligible patients with treatment-naïve nccRCC received nivolumab until progressive disease (PD), toxicity, or completion of 96 weeks of treatment (Part A). Patients with PD prior to, or stable disease (SD) at 48 weeks (prolonged SD) were potentially eligible to receive salvage nivolumab/ipilimumab (Part B). Patients were required to submit tissue from a metastatic lesion obtained within 12 months prior to study entry and prior to Part B for correlative studies., Results: 35 patients with nccRCC were enrolled: 19 (54%) had papillary, 6 (17%) had chromophobe and 10 (29%) had unclassified histology. At median follow-up of 22.9 months, RECIST-defined objective response rate (ORR) was 5 of 35 (14.3% 95% CI 4.8% to 30.3%) (complete response (CR) 2 (5.7%) and partial response (PR) 3 (8.6%)). ORR by histology was: papillary-1/19 (5%); chromophobe-1/6 (17%); and unclassified-3/10 (30%). Nine patients (26%) had tumors with sarcomatoid features with 3 (33%) (2 unclassified and 1 papillary) responding. ORR was 0/18, 3/11 (27%) and 2/6 (33%) for patients with tumor progammed death ligand 1 (PD-L1) expression of <5%, ≥5% or not measured, respectively. Median progression-free survival was 4.0 (2.7-4.3) months. Two of five responders have progressed. Thirty-two patients had PD or prolonged SD and therefore, were potentially eligible for salvage nivolumab/ipilimumab (Part B), but 15 patients did not enroll due to grade 2-3 toxicity (6) on nivolumab, symptomatic disease progression (5), or other reasons including no biopsy tissue (4). In the 17 Part B patients, there was one PR (6%) (unclassified/non-sarcomatoid). Grade > 3 treatment-related adverse events were seen in 7/35 (20%) on nivolumab and 7/17 (41%) on salvage nivolumab/ipilimumab with one patient experiencing sudden death., Conclusions: Nivolumab monotherapy has limited activity in treatment-naïve nccRCC with most responses (4 of 5) seen in patients with sarcomatoid and/or unclassified tumors. Toxicity is consistent with prior nivolumab studies. Salvage treatment with nivolumab/ipilimumab was provided in half of these patients with minimal activity., Trial Registration Number: NCT03117309., Competing Interests: Competing interests: MBA, has/had an advisory role for Bristol-Myers Squibb, Merck, Novartis, Eisai, Aveo, Pfizer, Werewolf, Fathom, Pneuma, Leads, Pyxis Oncology, PACT, Elpis, X4Pharma, ValoHealth, ScholarRock, Surface, Takeda, Simcha, Roche, SAB Bio and GSK and has served as a consultant: Bristol-Myers Squibb, Merck, Novartis, Pfizer, Roche, Exelixis, Iovance, COTA, Idera, Agenus, Apexigen, Asher Bio, Neoleukin, AstraZeneca, Calithera, SeaGen, and Sanofi. He reports research support to his institution from Bristol-Myers Squibb, Merck and Pfizer. He holds stock/stock options in Pyxis Oncology, Werewolf and Elpis. NBH has/had an advisory role for Merck, Eisai, Aveo, and Roche. DFM has acted as a paid consultant for and/or as a member of the advisory boards of BMS, Pfizer, Merck, Alkermes, EMD Serono, Eli Lilly and Company, Iovance, Eisai, Werewolf Technologies, Calithera Biosciences, Synthekine, Johnson & Johnson, and Aveo. He has received support to his institution from BMS, Merck, Genentech, Pfizer, Exelixis, X4 Pharma, Alkermes, Checkmate Pharmaceuticals, and CRISPR Therapeutics for work performed outside of the current study. MAB has acted as a paid consultant for and/or as a member of the advisory boards of Exelixis, Bayer, BMS, Eisai, Pfizer, AstraZeneca, Janssen, Calithera Biosciences, Genomic Health, Nektar, EMD Serono, SeaGen, and Sanofi and has received grants to his institution from Merck, Xencor, Bayer, Bristol-Myers Squibb, Genentech/Roche, SeaGen, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Genome & Company, AAA, Peloton Therapeutics, and Pfizer for work performed outside of the current study. MS has consulted for Exelixis, Xencor, Janssen, Vaccitech, Bristol-Myers Squibb and reports research funding to his institution from Bellicum, Merck, Janssen, Medivation/Astellas, Advaxis, Harpoon, Bristol-Myers Squibb, Genocea, Lilly, Nektar, SeaGen, Xencor, Tmunity, Exelixis. JS serves on Advisory Boards for Eisai, Apexigen, Iovance, Covus. He reports research funding to his institution from Bristol Myers Squibb, PACT and Corvus. RA has consulted for Eisai, Bayer and Janssen Oncology and participated in Speakers' Bureaus for Astellas Pharma, Janssen Oncology, Bayer, Pfizer, Exelixis, Gilead Sciences, Aveo and Bristol-Myers Squibb. ERP reports consulting or advisory roles for Astellas, AstraZeneca, Aveo, Bristol Myers Squibb, Exelixis, Merck, Natera, Pfizer, Regeneron, SeaGen and research support to institution from Astella, Bristol Myers Squibb, Genentech and Merck. MCO has served in consulting or advisory roles for Eisai, Exelixis, Pfizer, Aveo, Merck, and Bristol-Myers Squibb; served on speakers’ bureaus for Bristol Myers Squibb; received institutional research funding from Bristol Myers Squibb, Pfizer, Merck, AstraZeneca, Astellas, Aravive, and Surface Oncology; has received reimbursement for travel and accommodations expenses from Bristol Myers Squibb, Pfizer, and Exelixis. MH has served on Advisory Boards for Bristol Myers Squibb, CRISPR Therapeutics, Exelixis, Nektar Therapeutics, Janssen and has received research support to his institution from Alpine, Achilles Therapeutics, Apexigen, Arrowhead, Astellas, AstraZeneca, Bayer, Bristol Myer Squibb, CRISPR Therapeutics, Corvus, Eli Lilly, Endocyte, Fate Therapeutics, Genentech, Genmab, GSK, Innocrin, Iovance, KSQ, Merck, Nektar Therapeutics, Novartis, Pfizer, Progenics, Sanofi Aventis, SeaGen, Tmunity, Torque, Unum He also reports Spouse salary from Gamida Cell, Arvinas. SS reports receiving commercial research grants from Bristol-Myers Squibb, AstraZeneca, Exelixis and Novartis; is a consultant/advisory board member for Merck, AstraZeneca, Bristol-Myers Squibb, CRISPR Therapeutics AG, AACR, and NCI; and receives royalties from Biogenex. CW reports receiving research funding from Pharmacyclics and being an equity holder of BionTech. DB reports personal fees from LM Education and Exchange, Adnovate Strategies, MDedge, Cancer Network, Cancer Expert Now, OncLive, Catenion, AVEO, and grants and personal fees from Exelixis, outside the submitted work. DE reports research funding to institution from Bristol-Myers Squibb, Cardiff Oncology, and Puma Biotechnology, as well as discounted research sequencing from Foundation Medicine and honorarium from OncLive. HH has acted as a paid consultant for and/or as a member of the advisory boards of Exelixis, BMS, Pfizer, Merck, Corvus, Armo Biosciences, Eisai, Eli Lilly, Surface Oncology, Aveo and Novartis and has received grants to his institution from Merck, Bristol-Myers Squibb, Surface Oncology and Aravive for work performed as outside of the current study., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immunotherapy offers deep and durable disease control to some patients, but many tumors do not respond to treatment with single-agent immune checkpoint inhibitors (ICIs). One strategy to enhance responses to immunotherapy is via combinations with signal transduction inhibitors, such as antiangiogenic therapies, which not only directly target cancer cells but also could potentially favorably modulate the tumor immune microenvironment. Combination strategies with ICIs have demonstrated enhanced antitumor activity compared with tumor-targeted or antiangiogenic therapy alone in randomized trials in a variety of solid tumor settings, leading to regulatory approval from the US Food and Drug Administration and agencies in other countries for the treatment of endometrial cancer, kidney cancer, melanoma, and hepatocellular carcinoma. Despite improved survival and response rates for some patients when antiangiogenic or targeted therapies are administered with ICIs, many patients continue to progress after combination treatment and urgently need new strategies to address this manifestation of resistance to immunotherapy. Previously, the Society for Immunotherapy of Cancer (SITC) published consensus definitions for resistance to single-agent anti-PD-(L)1. To provide guidance for clinical trial design and to support analyses of emerging molecular and immune profiling data surrounding mechanisms of resistance to ICI-based combinations, SITC convened a follow-up workshop in 2021 to develop consensus definitions for resistance to multiagent ICI combinations. This manuscript reports the consensus clinical definitions for combinations of anti-PD-(L)1 ICIs and targeted therapies. Definitions for resistance to ICIs in combination with chemotherapy and with other ICIs will be published in companion volumes to this paper., Competing Interests: Competing interests: MBA—Consulting fees: Aveo, Bristol Myers Squibb, Eisai, Exelixis, Genentech, Iovance, Merck, Novartis, Pfizer, Roche, Pyxis, Werewolf, Asher Bio, Calithera, Idera, Agenus, Apexigen, Neoleukin, Adagene, AstraZeneca, Elpis, ScholarRock, Surface, ValoHealth, Sanofi, Fathom; Ownership interest less than 5%: Werewolf, Pyxis, Elpis. DF—Salary and employment: Palleon Pharmaceuticals; Ownership interest less than 5%: Palleon Pharmaceuticals. DBJ—IP rights: MHC-II for use as immunotherapy biomarker, Abatacept as treatment for irAEs; Consulting fees: Bristol Myers Squibb, Catalyst, Iovance, Jansen, Mallinckrodt, Merck, Mosaic ImmunoIngineering, Novartis, Oncosec, Pfizer, Targovax; Contracted research: Bristol Myers Squibb, Incyte. JS—Consulting fees: Array, Nektar, Jazz, Iovance, Apexigen, Eisai; Contracted research: Bristol Myers Squibb, Amphivena, PACT. NIK—Consulting fees: Bristol Myers Squibb, Merck, Jounce, Iovance, Regeneron, Genzyme, NCCN (via Pfizer), Novartis, Nektar, Castle Biosciences, Instil Bio, Immunocore; Contracted research: Bristol Myers Squibb, Merck, Celgene, GSK, HUYA, Replimune, Novartis, Regeneron, Amgen; Data safety Montioring board: AstraZeneca, Incyte; Study steering committee: Nektar, Bristol Myers Squibb, Regeneron, Replimune; Ownership interest less than 5%: Bellicum Pharaceuticals, Asensus Surgical (formerly TransEnterix), Amarin. PAA—Consulting fees: Bristol Myers Squibb, Roche, Array, Novartis, Merck Serono, Pierre Fabre, Incyte, Medimmune, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandox, Immunocore, 4SC, Italfarmaco, Mektar, Boehringer Ingelheim, Eisai, Renegeron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, SeaGen, iTEOS, Medicenna; Contracted research: Bristol Myers Squibb, Genentech/Roche, Array, Sanofi. TAY—Consulting fees: AstraZeneca, Almac, Aduro, Artios, Athena, Atrin, Axiom, Bayer, Bristol Myers Squibb, Calithera, Clovis, Cybrexa, EMD Serono, F-Star, GLG, Guidepoint, Ignyta, I-Mab, ImmuneSensor, Jansen, Merck, Pfizer, Repare, Roche, Schrodinger, Seattle Genetics, Varian, Zai Labs, ZielBio; Contracted research: AstraZeneca, Artios, Bayer, Beigene, BioNTech, Bristol Myers Squibb, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech/Roche, Haihe, ImmuneSensor, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Kyowa, Merck, Novartis, Pfizer, Repare, Ribon Therapeutics, Regeneron, Rubius, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, Vivace. HK—Consulting fees: Iovance, Immunocore, Celldex, Array Biopharma, Merck, Elevate Bio, Instil Bio, Bristol Myers Squibb, Clinigen, Shionogi, Chemocentryx, Calithera, Signatero. RJS—Consulting fees: Asana Biosciences, AstraZeneca, Bristol Myers Squibb, Eisai, Iovance, Merck, Novartis, OncoSec, Pfizer, Replimune; Contracted research: Merck, Amgen. HT—Consulting fees: Genentech/Roche, Bristol Myers Squibb, Novartis, Merck, Pfizer, Eisai, Karyopharm, Boxer Capital; Contracted research: Genentech/Roche, Bristol Myers Squibb, Novartis, Merck, GSK. JLG—Nothing to disclose. SITC Staff: SMW, PI—Nothing to disclose., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immune-related adverse events (irAEs) associated with immune checkpoint inhibitor (ICI) therapy may vary substantially in their clinical presentation, including natural history, outcomes to treatment, and patterns. The application of clinical guidelines for irAE management can be challenging for practitioners due to a lack of common or consistently applied terminology. Furthermore, given the growing body of clinical experience and published data on irAEs, there is a greater appreciation for the heterogeneous natural histories, responses to treatment, and patterns of these toxicities, which is not currently reflected in irAE guidelines. Furthermore, there are no prospective trial data to inform the management of the distinct presentations of irAEs. Recognizing a need for uniform terminology for the natural history, response to treatment, and patterns of irAEs, the Society for Immunotherapy of Cancer (SITC) convened a consensus panel composed of leading international experts from academic medicine, industry, and regulatory agencies. Using a modified Delphi consensus process, the expert panel developed clinical definitions for irAE terminology used in the literature, encompassing terms related to irAE natural history (ie, re-emergent, chronic active, chronic inactive, delayed/late onset), response to treatment (ie, steroid unresponsive, steroid dependent), and patterns (ie, multisystem irAEs). SITC developed these definitions to support the adoption of a standardized vocabulary for irAEs, which will have implications for the uniform application of irAE clinical practice guidelines and to enable future irAE clinical trials., Competing Interests: Competing interests: JN—Consulting fees: AstraZeneca, Bristol Myers-Squibb, Roche/Genentech, Takeda, Pfizer, Daiichi Sankyo; Contracted research: AstraZeneca, Merck; Data Safety Monitoring Board: Daiichi Sankyo; NPI: 1710327721. LCC—Consulting fees: AbbVie; Contracted research: Bristol-Myers Squibb. CM—Nothing to Disclose. MBA—Consulting fees: Aveo, BMS, Eisai, Exelixis, Genentech, Iovance, Merck, Novartis, Pfizer, Roche, Pyxis, Werewolf, Asher Bio, Calithera, Idera, Agenus, Apexigen, Neoleukin, Adagene, AstraZeneca, Elpis, ScholarRock, Surface, ValoHealth, Sanofi, Fathom; Ownership Interest Less Than 5%: Werewolf, Pyxis, Elpis; NPI: 1306874201. JRB—Consulting fees: Amgen, BMS, Genentech/Roche, Eli Lilly, GlaxoSmithKline, Merck, Sanofi, Regeneron; Contracted research: AstraZeneca, BMS, Genentech/Roche, Merck, RAPT Therapeutics, Revolution Medicines; Data and Safety Monitoring Board/Committees: GlaxoSmithKline, Sanofi. SC—Consulting fees: Amgen, AstraZeneca, Ultrahuman, Oncovita; Fees for Non-CE Services: Amgen, AstraZeneca, BMS, Janssen, Merck, MSD, Novartis and Roche; Contracted Research: Amgen, Merck, Sanofi Aventis; As part of the Drug Development Department (DITEP) at Gustave Roussy, Principal/sub-Investigator of Clinical Trials Research Grants from, Non-financial support (drug supplied) from: Principal/sub-Investigator of Clinical Trials for: Abbvie, Adaptimmune, Adlai Nortye USA, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Astex Pharmaceuticals, Astra Zeneca Ab, Aveo, Basilea Pharmaceutica International, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, BicycleTx, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co, Clovis Oncology, Cullinan-Apollo, Curevac, Daiichi Sankyo, Debiopharm, Eisai, Eisai, Eli Lilly, Exelixis, Faron Pharmaceuticals, Forma Tharapeutics, Gamamabs, Genentech, Glaxosmithkline, H3 Biomedicine, Hoffmann La Roche Ag, Imcheck Therapeutics, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Iteos Belgium SA, Janssen Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncopeptides, Orion Pharma, Ose Pharma, Pfizer, Pharma Mar, Pierre Fabre, Medicament, Roche, Sanofi Aventis, Seattle Genetics, Sotio A.S, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Turning Point Therapeutics, XencorResearch Grants from Astrazeneca, BMS, Boehringer Ingelheim, GSK, INCA, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi, Non-financial support (drug supplied) from Astrazeneca, Bayer, BMS, Boringher Ingelheim, GSK, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche. DF—Salary: Palleon Pharmaceuticals; Ownership Interest Less Than 5 Percent: Palleon Pharmaceuticals. LMK—Salary: AstraZeneca; Ownership Interest Less Than 5 Percent: AstraZeneca. JM—Consulting fees: Novartis, Pfizer, Bristol-Myers Squibb, Takeda, Pharmacyclics, Audentes Pharmaceuticals, AstraZeneca, Deciphera, Ipsen, Boston, Biomedical, ImmunoCore, GlaxoSmithKline, Janssen, Myovant, Amgen, Boehringer, Cytokinetics. MCP— Employee of Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA, and own stock (less than 5%) in Merck & Co, Rahway, NJ, US. JR—Nothing to Disclose. CR—Consulting fees: BMS, Roche, Pierre Fabre, Novartis, Sanofi, MSD, Pfizer, AstraZeneca. ES—NPI: 1467480160. MES-A—Consulting fees: Avenue Therapeutics ChemoCentryx, Celgene (All unrelated to the topic of interest. KS—Nothing to Disclose. MT—Nothing to Disclose. JW—Royalty: Less than 2000 dollars from a TIL growth patent by Moffitt Cancer Center; IP Rights: Named on a PD-1 biomarker patent by Biodesix, and on a CTLA4 biomarker patent by Moffitt Cancer Center, and a TIL growth patent by Moffitt Cancer Center; Consulting fees: Ad Boards for: BMS, GSK, Merck, Genentech, Astra Zeneca, Pfizer, Celldex, Biond, Evaxion, Regeneron, Alkermes, Novartis, Incyte, Moderna, Cytomx, Ultimovacs and Sellas; NPI: 1053348706; Ownership Interest Less Than 5 Percent: Biond, Neximmune MESA: Consultant fees: Pfizer, Eli Lilly, BMS. SITC Staff—CG, AK, NL, SMW: Nothing to Disclose., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Programmed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory. PD-1 blockade can mediate tumor regression in a substantial proportion of patients with melanoma, but it is not known whether this is associated with extended survival or maintenance of response after treatment is discontinued., Patients and Methods: Patients with advanced melanoma (N = 107) enrolled between 2008 and 2012 received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation., Results: Median overall survival in nivolumab-treated patients (62% with two to five prior systemic therapies) was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively. Among 33 patients with objective tumor regressions (31%), the Kaplan-Meier estimated median response duration was 2 years. Seventeen patients discontinued therapy for reasons other than disease progression, and 12 (71%) of 17 maintained responses off-therapy for at least 16 weeks (range, 16 to 56+ weeks). Objective response and toxicity rates were similar to those reported previously; in an extended analysis of all 306 patients treated on this trial (including those with other cancer types), exposure-adjusted toxicity rates were not cumulative., Conclusion: Overall survival following nivolumab treatment in patients with advanced treatment-refractory melanoma compares favorably with that in literature studies of similar patient populations. Responses were durable and persisted after drug discontinuation. Long-term safety was acceptable. Ongoing randomized clinical trials will further assess the impact of nivolumab therapy on overall survival in patients with metastatic melanoma.

Purpose: Combination programmed cell death protein 1/cytotoxic T-cell lymphocyte-4-blockade and dual BRAF/MEK inhibition have each shown significant clinical benefit in patients with BRAFV600 -mutant metastatic melanoma, leading to broad regulatory approval. Little prospective data exist to guide the choice of either initial therapy or treatment sequence in this population. This study was conducted to determine which initial treatment or treatment sequence produced the best efficacy., Patients and Methods: In a phase III trial, patients with treatment-naive BRAFV600 -mutant metastatic melanoma were randomly assigned to receive either combination nivolumab/ipilimumab (arm A) or dabrafenib/trametinib (arm B) in step 1, and at disease progression were enrolled in step 2 to receive the alternate therapy, dabrafenib/trametinib (arm C) or nivolumab/ipilimumab (arm D). The primary end point was 2-year overall survival (OS). Secondary end points were 3-year OS, objective response rate, response duration, progression-free survival, crossover feasibility, and safety., Results: A total of 265 patients were enrolled, with 73 going onto step 2 (27 in arm C and 46 in arm D). The study was stopped early by the independent Data Safety Monitoring Committee because of a clinically significant end point being achieved. The 2-year OS for those starting on arm A was 71.8% (95% CI, 62.5 to 79.1) and arm B 51.5% (95% CI, 41.7 to 60.4; log-rank P = .010). Step 1 progression-free survival favored arm A ( P = .054). Objective response rates were arm A: 46.0%; arm B: 43.0%; arm C: 47.8%; and arm D: 29.6%. Median duration of response was not reached for arm A and 12.7 months for arm B ( P < .001). Crossover occurred in 52% of patients with documented disease progression. Grade ≥ 3 toxicities occurred with similar frequency between arms, and regimen toxicity profiles were as anticipated., Conclusion: Combination nivolumab/ipilimumab followed by BRAF and MEK inhibitor therapy, if necessary, should be the preferred treatment sequence for a large majority of patients.

Introduction: Tivozanib, vascular endothelial growth factor receptor inhibitor, met the primary endpoint of improved progression free survival compared to sorafenib in the phase 3 TIVO-3 study in patients with previously treated metastatic renal cell carcinoma. In this study we sought to understand the temporal characteristics of treatment related adverse events (TRAEs) and frequency and timing of the dose modifications., Materials and Methods: In this open label, randomized, phase 3 TIVO-3 study, previously treated patients with a diagnosis of metastatic renal cell carcinoma and with measurable disease were included. Patients were randomized to receive either tivozanib 1.5 mg orally once daily in 4-week cycles or sorafenib 400 mg orally twice daily continuously. Based on updated safety analysis data (cutoff date of August 15, 2019), time to onset of the most commonly reported TRAEs, duration of toxicity, rate of dose modifications was calculated for each treatment arm., Results: Overall, 350 patients were randomly assigned to receive tivozanib or sorafenib;173 patients from the tivozanib arm and 170 patients from the sorafenib arm were included in this analysis. Patients received a median of 11.9 cycles (336 days) and 6.7 cycles (192 days) of tivozanib and sorafenib, respectively. Dose reductions, interruptions and treatment discontinuations were 25%, 50%, and 21%, and 39%, 50%, and 30% in the tivozanib and sorafenib arms, respectively, with a longer time to onset of TRAEs in the tivozanib arm., Conclusion: Tivozanib was associated with less TRAEs, fewer dose modifications, a longer time to onset and a shorter duration of TRAEs compared to sorafenib., Competing Interests: Disclosure Zeynep B. Zengin, MD and Sumanta K. Pal, MD has no conflicts of interest that might be relevant to the contents of this manuscript. Vijay Kasturi, MD: Employed by AVEO Oncology. David F. McDermott, MD: Honorrari: BMS, Pfizer, Merck, Alkernes, EMD Serono, Eli Lilly and company, Iovance, Eisai, Werewolf Therapeutics, Calithera Biosciences. Research funding: BMS, Merck, Genentech, Pfizer, Exelexis, X4 Pharma, Alkermes. Bernard Escudier, MD: Advisory: Pfizer, BMS, Ipsen, Aveo, Eisai Thomas E. Hutson, DO, PharmD: Consultant/ Advisory Board and Speaker for: Aveo, Pfizer, Exelexis, BMS, EMD Serono, Eisai, Jansen, Gilead, and Astellas Camillo Porta, MD: Consulting and/or participation in Speakers’ Bureau: Angelini Pharma, AstraZeneca, Bristol Myers Squibb, Eisai, EUSA Pharma, General Electric, Ipsen, Janssen, Merck, Merck Sharp & Dohme, Novartis, Pfizer; Expert Testimony: EUSA Pharma and Pfizer; Protocol Steering Committee Member: Merck Sharp & Dohme, Bristol Myers Squibb, Eisai, EUSA Pharma; received travel support from Roche. Elena Verzoni, MD: Consulting and/or speakers’ Bureau: Bristol Myers Squibb, Eisai, Janssen, Merck, MSD, Ipsen Michael B. Atkins, MD: Consuting: Eisai, Aveo, Pfizer, Werewolf, Fathom, Pneuma, Leads, Pyxis Oncology, PACT, Elpis, X4Pharma, ValoHealth, ScholarRock, Surface, Takeda, Simcha, Bristol Myers Squibb, Merck, Novartis, Pfizer, Roche, Exelixis, Iovance, Idera, Agenus, Asher Bio, Neoleukin, AstraZeneca, Calithera, SeaGen, SAB Bio and Sanofi. Equity Interest: Werewolf, Pyxis Oncology. Brian Rini, MD: Research Funding to Institution: Pfizer, Hoffman-LaRoche, Incyte, AstraZeneca, Seattle Genetics, Arrowhead Pharmaceuticals, Immunomedics, BMS, Mirati Therapeutics, Merck, Surface Oncology, Dragonfly Therapeutics, Aravive, Exelixis, Jannsen; Consulting: BMS, Pfizer, GNE/Roche, Aveo, Synthorx, Compugen, Merck, Corvus, Surface Oncology, 3DMedicines, Aravive, Alkermes, Arrowhead, GSK, Shionogi, Eisai, Nikang Therapeutics; Stock: PTC therapeutics, (Copyright © 2022. Published by Elsevier Inc.)

Brain metastases are the most common brain malignancy. This review discusses the studies presented at the third annual meeting of the Melanoma Research Foundation in the context of other recent reports on the biology and treatment of melanoma brain metastases (MBM). Although symptomatic MBM patients were historically excluded from immunotherapy trials, efforts from clinicians and patient advocates have resulted in more inclusive and even dedicated clinical trials for MBM patients. The results of checkpoint inhibitor trials were discussed in conversation with current standards of care for MBM patients, including steroids, radiotherapy, and targeted therapy. Advances in the basic scientific understanding of MBM, including the role of astrocytes and metabolic adaptations to the brain microenvironment, are exposing new vulnerabilities which could be exploited for therapeutic purposes. Technical advances including single-cell omics and multiplex imaging are expanding our understanding of the MBM ecosystem and its response to therapy. This unprecedented level of spatial and temporal resolution is expected to dramatically advance the field in the coming years and render novel treatment approaches that might improve MBM patient outcomes., (© 2022 The Authors. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.)

Background: In the phase 3 KEYNOTE-426 (NCT02853331) trial, pembrolizumab + axitinib demonstrated improvement in overall survival, progression-free survival, and objective response rate over sunitinib monotherapy for advanced renal cell carcinoma (RCC)., Objective: To evaluate health-related quality of life (HRQoL) in KEYNOTE-426., Design, Setting, and Participants: A total of 861 patients were randomly assigned to receive pembrolizumab + axitinib (n = 432) or sunitinib (n = 429). HRQoL data were available for 429 patients treated with pembrolizumab + axitinib and 423 patients treated with sunitinib., Outcome Measurements and Statistical Analysis: HRQoL end points were measured using the European Organisation for the Research and Treatment of Cancer Core (EORTC) Quality of Life Questionnaire (QLQ-C30), EQ-5D visual analog rating scale (VAS), and Functional Assessment of Cancer Therapy Kidney Cancer Symptom Index-Disease-Related Symptoms (FKSI-DRS) questionnaires., Results and Limitations: Better or not different overall improvement rates from baseline between pembrolizumab + axitinib and sunitinib were observed for the FKSI-DRS (-0.79% improvement vs sunitinib; 95% confidence interval [CI] -7.2 to 5.6), QLQ-C30 (7.5% improvement vs sunitinib; 95% CI 1.0-14), and EQ-5D VAS (9.9% improvement vs sunitinib; 95% CI 3.2-17). For time to confirmed deterioration (TTcD) and time to first deterioration (TTfD), no differences were observed between arms for the QLQ-C30 (TTcD hazard ratio [HR] 1.0; 95% CI 0.82-1.3; TTfD HR 0.82; 95% CI 0.69-0.97) and EQ-5D VAS (TTcD HR 1.1; 95% CI 0.87-1.3; TTfD HR 0.98; 95% CI 0.83-1.2). TTfD was not different between treatment arms (HR 1.1; 95% CI 0.95-1.3) for the FKSI-DRS, but TTcD favored sunitinib (HR 1.4; 95% CI 1.1-1.7). Patients were assessed during the off-treatment period for sunitinib, which may have underestimated the negative impact of sunitinib on HRQoL., Conclusions: Overall, patient-reported outcome scales showed that results between the pembrolizumab + axitinib and sunitinib arms were not different, with the exception of TTcD by the FKSI-DRS., Patient Summary: Compared with sunitinib, pembrolizumab + axitinib delays disease progression and extends survival, while HRQoL outcomes were not different between groups., (Copyright © 2022. Published by Elsevier B.V.)

Purpose: PD-L1 expression on tumor cells (TC) is associated with response to anti-PD-1-based therapies in some tumor types, but its significance in clear cell renal cell carcinoma (ccRCC) is uncertain. We leveraged tumor heterogeneity to identify molecular correlates of TC PD-L1 expression in ccRCC and assessed their role in predicting response to anti-PD-1 monotherapy., Experimental Design: RNA sequencing was performed on paired TC PD-L1 positive and negative areas isolated from eight ccRCC tumors and transcriptomic features associated with PD-L1 status were identified. A cohort of 232 patients with metastatic ccRCC from the randomized CheckMate-025 (CM-025) trial was used to confirm the findings and correlate transcriptomic profiles with clinical outcomes., Results: In both the paired samples and the CM-025 cohort, TC PD-L1 expression was associated with combined overexpression of immune- and cell proliferation-related pathways, upregulation of T-cell activation signatures, and increased tumor-infiltrating immune cells. In the CM-025 cohort, TC PD-L1 expression was not associated with clinical outcomes. A molecular RCC subtype characterized by combined overexpression of immune- and cell proliferation-related pathways (previously defined by unsupervised clustering of transcriptomic data) was enriched in TC PD-L1 positive tumors and displayed longer progression-free survival (HR, 0.32; 95% confidence interval, 0.13-0.83) and higher objective response rate (30% vs. 0%, P = 0.04) on nivolumab compared with everolimus., Conclusions: Both TC-extrinsic (immune-related) and TC-intrinsic (cell proliferation-related) mechanisms are likely intertwined in the regulation of TC PD-L1 expression in ccRCC. The quantitation of these transcriptional programs may better predict benefit from anti-PD-1-based therapy compared with TC PD-L1 expression alone in ccRCC., (©2022 American Association for Cancer Research.)

The broad activity of agents blocking the programmed cell death protein 1 and its ligand (the PD-(L)1 axis) revolutionized oncology, offering long-term benefit to patients and even curative responses for tumors that were once associated with dismal prognosis. However, only a minority of patients experience durable clinical benefit with immune checkpoint inhibitor monotherapy in most disease settings. Spurred by preclinical and correlative studies to understand mechanisms of non-response to the PD-(L)1 antagonists and by combination studies in animal tumor models, many drug development programs were designed to combine anti-PD-(L)1 with a variety of approved and investigational chemotherapies, tumor-targeted therapies, antiangiogenic therapies, and other immunotherapies. Several immunotherapy combinations improved survival outcomes in a variety of indications including melanoma, lung, kidney, and liver cancer, among others. This immunotherapy renaissance, however, has led to many combinations being advanced to late-stage development without definitive predictive biomarkers, limited phase I and phase II data, or clinical trial designs that are not optimized for demonstrating the unique attributes of immune-related antitumor activity-for example, landmark progression-free survival and overall survival. The decision to activate a study at an individual site is investigator-driven, and generalized frameworks to evaluate the potential for phase III trials in immuno-oncology to yield positive data, particularly to increase the number of curative responses or otherwise advance the field have thus far been lacking. To assist in evaluating the potential value to patients and the immunotherapy field of phase III trials, the Society for Immunotherapy of Cancer (SITC) has developed a checklist for investigators, described in this manuscript. Although the checklist focuses on anti-PD-(L)1-based combinations, it may be applied to any regimen in which immune modulation is an important component of the antitumor effect., Competing Interests: Competing interests: MBA—Consulting Fees: Aveo, BMS, Eisai, Exelixis, Genentech, Iovance, Merck, Novartis, Pfizer, Roche, Pyxis, Werewolf, Asher Bio, Calithera, Idera, Agenus, Apexigen, Neoleukin, Adagene, AstraZeneca, Elpis, ScholarRock, Surface, ValoHealth, Sanofi, Fathom; Ownership Interest (less than 5%): Werewolf, Pyxis, Elpis. HA-S—Nothing to disclose. PAA—Consulting Fees: BMS, Roche, Array, Novartis, Merck Serono, Pierre Fabre, Incyte, Medimmune, AstraZeneca, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTEOS, Medicenna; Contracted Research: BMS, Roche-Genentech, Array, Sanofi. MRB—Consulting Fees: Novartis, Kite/Gilead, CRISPR Therapeutics, Autolus, Takeda, Agios, Iovance, Bluebird Bio, BMS; Fees for Non-CE Services: Agio, BMS, Incyte, Sanofi, Kite/Gilead; Contracted Research: Immatics, Novartis, Kite/Gilead, CRISPR Therapeutics, Autolus, TMUNITY. DSC—Ownership Interest (less than 5%): IGM Biosciences, Corvus. MD—Consulting Fees: Lava Therapeutics, Amgen, Janssen, Roche/Genentech. LAE—Consulting Fees: Genentech, F. Hoffmann-La Roche, Chugai, GPCR, Gilead, Immune Onc, Immutep, Shionogi, Mersana; Contracted Research: AbbVie, AstraZeneca, Bolt Therapeutics, Bristol Myers Squibb, Compugen, Corvus, CytomX, EMD Serono, Genentech, F. Hoffmann-La Roche, ImmuneOnc, Maxcyte, Merck, Next Cure, Silverback, Takeda, Tempest; Grants from Non-Industry Entities: HeritX Incorporated, NSABP Foundation, Translational Breast Cancer Research Consortium, Breast Cancer Research Foundation, National Cancer Institute, Department of Defense, Johns Hopkins University, University of California San Francisco, Cornell University, Dana Farber Cancer Institute. Royalties: Elsevier; IP Rights: Aduro Biotech. MSE—Nothing to Disclose. RLF—Consulting Fees: Achilles Therapeutics, Aduro Biotech, Bicara Therapeutics, BMS, Brooklyn Immunotherapeutic, Everest Clinical Research Corporation, F. Hoffman-La Roche, Genocea Biosciences, Hookipa Biotech GmbH, Instill Bio, Kowa Research Institute, Lifescience Dynamics Limited, MacroGenics, Merck, Mirati Therapeutics, Nanobiotix, Novasenta, Numab Therapeutics AG, OncoCyte Corporation, Pfizer, PPD Development, L.P., Rakuten Medical, Sanofi, Seagen, Vir Biotechnology, Zymeworks; Contracted Research: AstraZeneca/MedImmune, BMS, Merck, Novasenta, Tesaro; Stock: Novasenta. TFG—Contracted Research: AstraZeneca, BMS, Merck, Sillajen, Vascular Biogenics. JLG—Nothing to disclose. RSH—Consulting Fees: AbbVie Pharmaceuticals, ARMO Biosciences, AstraZeneca, Bayer HealthCare Pharmaceuticals, Bolt Biotherapeutics, BMS, Candel Therapeutics, Cybrexa Therapeutics, eFFECTOR Therapeutics, Eli Lilly and Company, EMD Serono, Foundation Medicine, Genentech/Roche, Genmab, Gilead, Halozyme Therapeutics, Heat Biologics, I-Mab Biopharma, Immunocore, Infinity Pharmaceuticals, Loxo Oncology, Merck and Company, Mirati Therapeutics, Nektar, Neon Therapeutics, NextCure, Novartis, Ocean Biomedical, Oncternal Therapeutics, Pfizer, Ribbon Therapeutics, Ventana Medical Systems, Sanofi, Seattle Genetics, Shire PLC, Spectrum Pharmaceuticals, STCube Pharmaceuticals, Symphogen, Takeda, Tesaro, Tocagen, WindMIL Therapeutics, Xencor; Contracted Research: AstraZeneca, Eli Lilly and Company, Genentech/Roche, Merck and Company; Board Member (non-executive/independent): Immunocore Holdings Limited, Junshi Pharmaceuticals. RWH—Stock: Black Diamond, Xilio. JL—Consulting Fees: Iovance, Boston Biomedical, Pfizer, BMS, GSK, Novartis, Incyte, Immunocore, YKT Global, iOnctura, Apple Tree, Roche, Pierre Fabre, AstraZeneca, EUSA Pharma, MSD, Ervaxx, Merck, Ipsen, Aptitude, Eisai, Calithera, Ultmovacs, Seagen; Contracted Research: BMS, MSD, Novartis, Pfizer, Achilles, Roche, Nektar, Covance, Immunocore, Pharmacyclics, Aveo. KAM—Consulting Fees: Iovance DMC, ImaginAb SAB, Checkmate Pharma DSMB, Xilio advisor, Werewolf advisor, all except ImaginAb less than 10k/year;Temporary higher consulting fees: ImaginAb (to provide one time extra consulting up to 25k). LM—Consulting Fees: Tethis spa; Fees for Non-CE Services: Roche. SSR—Consulting Fees: Amgen, BMS, Genentech/Roch, Merck, AstraZeneca, Takeda, Eisai, Daiichi Sankyo, Sanofi, GSK, Lilly; Contracted Research: Tesaro, Merck, AstraZeneca, Advaxis, BMS, Amgen, Takeda, Genmab, GSK. MMR—Consulting Fees: BMS, Tolmar, WebMD; Contracted Research: Novartis, Pfizer, Ipsen, TerSera, Merck, Pierre Fabre, Roche, AstraZeneca, BMS, Bayer, DebioPharm. BIR—Consulting Fees: BMS, Pfizer, GNE/Roche, Aveo, Synthorx, Compugen, Merck, Corvus, Surface Oncology, 3DMedicines, Aravive, Alkermes, Arrowhead, GSK, Shionogi, Eisai; Contracted Research: Pfizer, F. Hoffmann-La Roche, Incyte, AstraZeneca, Taris, Seattle Genetics, Arrowhead Pharmaceuticals, Immunomedics, Bristol Myers Squibb, Mirati Therapeutics, Merck, Surface Oncology, Dragonfly Therapeutics, Aravive, Exelixis; Ownership Interest (less than 5%): PTC therapeutics. MS—Consulting Fees: Adaptimmune, Pfizer, Kadmon, Pierre-Fabre, Biond, Nextcure, Incyte, Alligator, Bristol Myers, Ocellaris, Simcha, Rootpath, Numab, Evolveimmune, Biontech, Immunocore, Glaxo Smith Kline, Adagene, Asher, Kanaph, iTEOS, Genocea, Trillium, Sapience, Targovax, Molecular Partners, Ontario Institute for Cancer Research, Jazz Pharmaceuticals, Gilead, Innate pharma, Tessa, Stcube, Oncosec, Regeneron, AstraZeneca, Agenus, Idera, Apexigen, Verastem, Rubius, Genentech-Roche, Boston Pharmaceutical, Servier, Dragonfly, Boehringer Ingelheim, Nektar, Pieris, AbbVie, Zelluna, Seattle Genetics; Stock options: Adaptive Biotechnologies, Amphivena, Intensity, Actym, Evolveimmune, Nextcure, Repertoire, Oncohost, Rootpath, Asher; Stock: Johnson and Johnson, Glaxo-Smith Kline. SITC staff: SMW—Shares owned: Pacific Biosciences, Editas Medicine. ME, AK—Nothing to disclose., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Brain metastases are a challenging manifestation of renal cell carcinoma. We have a limited understanding of brain metastasis tumor and immune biology, drivers of resistance to systemic treatment, and their overall poor prognosis. Current data support a multimodal treatment strategy with radiation treatment and/or surgery. Nonetheless, the optimal approach for the management of brain metastases from renal cell carcinoma remains unclear. To improve patient care, the authors sought to standardize practical management strategies. They performed an unstructured literature review and elaborated on the current management strategies through an international group of experts from different disciplines assembled via the network of the International Kidney Cancer Coalition. Experts from different disciplines were administered a survey to answer questions related to current challenges and unmet patient needs. On the basis of the integrated approach of literature review and survey study results, the authors built algorithms for the management of single and multiple brain metastases in patients with renal cell carcinoma. The literature review, consensus statements, and algorithms presented in this report can serve as a framework guiding treatment decisions for patients. CA Cancer J Clin. 2022;72:454-489., (© 2022 The Authors. CA: A Cancer Journal for Clinicians published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Purpose: To determine the value of tumor cell programmed death-ligand 1 (PD-L1) expression as a predictive biomarker of nivolumab monotherapy efficacy in treatment-naive patients with clear cell renal cell carcinoma (ccRCC) and the efficacy of salvage nivolumab/ipilimumab in patients with tumors unresponsive to nivolumab monotherapy., Methods: Eligible patients with treatment-naive ccRCC received nivolumab until progressive disease (PD), toxicity, or completing 96 treatment weeks (part A). Patients with PD before or stable disease at 48 weeks could receive salvage nivolumab/ipilimumab (part B). The primary end point was improvement in 1-year progression-free survival in patients with tumor PD-L1 expression > 20% versus 0%., Results: One hundred twenty-three patients were enrolled. The objective response rate (ORR) was 34.1% (95% CI, 25.8 to 43.2). ORR by International Metastatic RCC Database Consortium category was favorable-risk 57.1%, intermediate-risk/poor-risk 25.0%, and by sarcomatoid features 36.4%. The ORR was 26.9%, 50.0%, and 75.0% for patients with the tumor PD-L1 expression of 0, 1-20, or > 20%, respectively (trend test P value = .002). The median duration of response was 27.6 (19.3 to not reached) months, with 26 of 42 responders including 17 of 20 with favorable-risk disease remaining progression-free. The 1-year progression-free survival was 34.6% and 75.0% in the PD-L1 = 0% and > 20% categories, respectively ( P = .050). Ninety-seven patients with PD or prolonged stable disease were potentially eligible for part B, and 35 were enrolled. The ORR for part B was 11.4%. Grade ≥ 3 treatment-related adverse events occurred in 35% of patients on nivolumab and 43% of those on salvage nivolumab/ipilimumab., Conclusion: Nivolumab monotherapy is active in treatment-naive ccRCC. Although efficacy appears to be less than that of nivolumab/ipilimumab in patients with intermediate-risk/poor-risk disease, favorable-risk patients had notable benefit. Efficacy correlated with tumor PD-L1 status. Salvage nivolumab/ipilimumab was frequently not feasible and of limited benefit.

Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX + CD8 + T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration., Competing Interests: Declaration of interests B.I. has received honoraria from consulting with Merck, Janssen Pharmaceuticals, Astra Zeneca, and Volastra Therapeutics. M.A.D. has been a consultant to Roche/Genentech, Array, Pfizer (New York, NY, United States of America), Novartis, BMS, GSK, Sanofi-Aventis (Bridgewater, NJ, United States of America), Vaccinex, Apexigen, EISAI, and ABM Therapeutics and he has been the PI of research grants to MD Anderson by Roche/Genentech (South San Francisco, CA, United States of America), GSK, Sanofi-Aventis, Merck, Myriad, and Oncothyreon. A.R. has received honoraria from consulting with CStone, Merck, and Vedanta, is or has been a member of the scientific advisory board and holds stock in Advaxis, Appia, Apricity, Arcus, Compugen, CytomX, Highlight, ImaginAb, ImmPact, ImmuneSensor, Inspirna, Isoplexis, Kite-Gilead, Lutris, MapKure, Merus, PACT, Pluto, RAPT, Synthekine, and Tango, has received research funding from Agilent (Santa Clara, CA, United States of America) and from Bristol-Myers Squibb through Stand Up to Cancer (SU2C), and patent royalties from Arsenal Bio. T.E. has acted as a consultant for Almiral Hermal, Bristol-Myers Squibb, MSD, Novartis, Pierre Fabre, and Sanofi. E.Z.M. is a consultant for Curio Bioscience. The other authors do not declare competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Immune-related adverse events (irAEs) often require treatment with high-dose systemic steroids (SS) and other immunosuppressive agents (ISAs). NCCN Guidelines recommend prophylactic antibiotics for Pneumocystis jirovecii pneumonia (PJP) for patients receiving prolonged SS/ISAs. However, there is a paucity of evidence regarding the incidence of opportunistic infections (OIs) and non-OIs and the role of prophylactic antibiotics in patients on SS/ISAs for irAEs., Methods: A retrospective analysis was conducted of patients treated using immune checkpoint inhibitor (ICI) therapy at 5 MedStar Health hospitals from January 2011 to April 2018. OIs were defined per the Infectious Diseases Society of America guidelines for the prevention and treatment of OIs in patients with HIV. The study cohort included patients who received ≥20 mg daily of a prednisone equivalent for ≥4 weeks to manage irAEs., Results: The study cohort identified 112 (15%) of 758 total patients treated using ICIs. Baseline characteristics included the following: median age was 64 years, 74% (n=82) of patients were White, 89% (n=100) had an ECOG performance status ≤1, 61% (n=68) had melanoma, 19% (n=21) had non-small cell lung cancer, 45% (n=50) were treated using an anti-PD-(L)1 ICI, and 33% (n=37) were treated using an anti-PD-1/anti-CTLA-4 combination. The median starting SS dose was 100 mg of a prednisone equivalent, and 25% of patients required additional ISAs, with infliximab (n=15) and mycophenolate mofetil (n=9) being the most common. We found that 20% (n=22) of patients developed any infection, including 7% (n=8) with OIs (oral candidiasis [n=4], nondisseminated varicella zoster infection [n=2], PJP [n=1], and Listeria monocytogenes endophthalmitis [n=1]) and 13% (n=14) with non-OIs (most common: Clostridium difficile and pneumonia [n=5 each]). PJP prophylaxis with sulfamethoxazole/trimethoprim was given to 13% (n=14) patients, of whom 43% (n=6) developed OIs/non-OIs., Conclusions: Our study highlights the fundamental issues for patients on ICI therapy who require SS/ISAs for irAEs: the degree of immunosuppression and the relative risk of OI. We noted a low incidence of OIs overall and breakthrough infections despite PJP prophylaxis. We question whether PJP prophylaxis is efficacious or necessary. Prospective trials are required to answer these questions.

Purpose: Both immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor receptor (VEGFR) inhibitors are approved for advanced renal cell carcinoma treatment and can cause cardiovascular events (CVs); thus, combination therapy could lead to major adverse CV events (MACE). Cardiac serum biomarker assessment and imaging, including left ventricular ejection fraction (LVEF) monitoring, can be used to evaluate MACE., Methods: To our knowledge, the JAVELIN Renal 101 trial, assessing avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma, is the first randomized study of ICI plus VEGFR inhibitor treatment to include prospective serial cardiac monitoring of LVEF and serum cardiac biomarkers., Results: MACE (defined as grade ≥ 3 CV AEs) occurred in 31 patients (7.1%) in the combination arm and 17 patients (3.9%) in the sunitinib arm. Patients in the combination arm who had high baseline troponin T values were at higher risk of MACE versus patients with low values (MACE in 6/35 v 7/135, respectively; relative risk, 3.31; 95% CI, 1.19 to 9.22). This association was not observed in patients treated with sunitinib. Other CV baseline risk factors and serum cardiac biomarkers were not significantly predictive for MACE, although a trend toward an association with dyslipidemia was seen in the combination arm. No clinical value of on-treatment routine monitoring of LVEF in relation to MACE was observed. Although LVEF decline was significantly more frequent in the combination arm, most patients recovered, and decline was not associated with other significant cardiac events or symptoms., Conclusion: Patients with high baseline troponin T levels receiving ICI and VEGFR combinations may need to be monitored more closely for MACE. Routine monitoring of LVEF in asymptomatic patients is not recommended., Competing Interests: Brian I. RiniLeadership: MJH Life SciencesStock and Other Ownership Interests: PTC TherapeuticsConsulting or Advisory Role: Pfizer, Merck & Co (Kenilworth, NJ), Synthorx, Bristol Myers Squibb, AVEO, Surface Oncology, 3D Medicines, Corvus Pharmaceuticals, Aravive, Arrowhead Pharmaceuticals, Shionogi, Eisai, GlaxoSmithKlineResearch Funding: Pfizer (Inst), Roche/Genentech (Inst), Bristol Myers Squibb (Inst), Merck & Co (Kenilworth, NJ) (Inst), AstraZeneca/MedImmune (Inst), Incyte (Inst), Arrowhead Pharmaceuticals (Inst), Taris (Inst), Seattle Genetics (Inst), Immunomedics (Inst), Surface Oncology (Inst), Dragonfly Therapeutics (Inst), Aravive (Inst), Exelixis (Inst)Travel, Accommodations, Expenses: Pfizer, Bristol Myers Squibb, Merck & Co (Kenilworth, NJ) Javid J. MoslehiConsulting or Advisory Role: Aerovate Therapeutics, AstraZeneca, Audentes Pharmaceuticals, Boehringer, Bristol Myers Squibb, Cytokinetics, Deciphera, GlaxoSmithKline, Kurome Therapeutics, Mallinckrodt Pharmaceuticals, Myokardia, Myovant, Novartis, Pfizer, Pharmacyclics, ProteinCure, Takeda, Silverback Therapeutics, Star Therapeutics Marc BonacaResearch Funding: ARCA BioPahrma (Inst), AstraZeneca/MedImmune (Inst), Bayer (Inst), Better Therapeutics (Inst), CellResearch (Inst), EverlyWell (Inst), Janssen (Inst), Novo Nordisk (Inst), Osiris Medical (Inst), Amgen (Inst), HDL Therapeutics (Inst) Manuela SchmidingerHonoraria: Pfizer, Bristol Myers Squibb, Ipsen, Roche/Genentech, Merck & Co (Kenilworth, NJ), EISAI, EUSA Pharma, ALKERMESConsulting or Advisory Role: Pfizer, Bristol Myers Squibb, Roche, Ipsen, Merck & Co (Kenilworth, NJ), EUSA Pharma, EisaiTravel, Accommodations, Expenses: Bristol Myers Squibb, Roche, Ipsen Laurence AlbigesConsulting or Advisory Role: Bristol Myers Squibb (Inst), Ipsen (Inst), Roche (Inst), Novartis (Inst), Pfizer (Inst), Astellas Pharma (Inst), Merck & Co (Kenilworth, NJ) (Inst), AstraZeneca (Inst), Janssen (Inst), Eisai (Inst), Corvus Pharmaceuticals (Inst), Bellerophon Theraeutics (Inst)Research Funding: Bristol Myers Squibb (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Merck & Co (Kenilworth, NJ) Toni K. ChoueiriEmployment: Dana Farber Cancer HospitalLeadership: Dana Farber Cancer Hospital, NCCN, KidneyCan, ASCOStock and Other Ownership Interests: Pionyr, Tempest TherapeuticsHonoraria: NCCN, UpToDate, Michael J. Hennessy Associates, ASCO, Harborside Press, Analysis Group, AstraZeneca, Alexion Pharmaceuticals, Sanofi/Aventis, Bayer, Bristol Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck & Co (Kenilworth, NJ), Novartis, Peloton Therapeutics, Pfizer, Corvus Pharmaceuticals, Ipsen, Foundation Medicine, Eisai, PlatformQ Health, Clinical Care Options, Navinata Health, Kidney Cancer Association, Exelixis, Prometheus, Lpath, The New England Journal of Medicine, Lancet Oncology, Cerulean Pharma, alligent, the healthcare business of Merck KGaA (Darmstadt, Germany), HERON, Lilly, Janssen Oncology, IQvia, Aveo, NCI Genitourinary Cancers Steering CommitteeConsulting or Advisory Role: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck & Co (Kenilworth, NJ), Bristol Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus, alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis, Peloton Therapeutics, UpToDate, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney Cancer Association, Clinical Care Options, PlatformQ Health, Navinata Health, Harborside Press, ASCO, The New England Journal of Medicine, Lancet Oncology, the healthcare business of Merck KGaA (Darmstadt, Germany), HERON, Lilly, ESMO, NiKang Therapeutics, Kanaph Therapeutics, Infinity Pharmaceuticals, AraviveResearch Funding: Pfizer (Inst), Novartis (Inst), Merck & Co (Kenilworth, NJ) (Inst), Exelixis (Inst), TRACON Pharma (Inst), GlaxoSmithKline (Inst), Bristol Myers Squibb (Inst), AstraZeneca (Inst), Peloton Therapeutics (Inst), Roche/Genentech (Inst), Celldex (Inst), Agensys (Inst), Eisai (Inst), Takeda (Inst), Prometheus (Inst), Ipsen (Inst), Corvus Pharmaceuticals (Inst), Cerulean Pharma (Inst), Seattle Genetics/Astellas (Inst), Bayer (Inst), Foundation Medicine (Inst), Roche (Inst), Calithera Biosciences (Inst), Analysis Group (Inst), NCI (Inst), Gateway for Cancer Research (Inst), Congressionally Directed Medical Research Programs (DOD) (Inst)Patents, Royalties, Other Intellectual Property: International Patent Application No. PCT/US2018/058430, titled Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy (Inst), International Patent Application No. PCT/US2018/12209, titled PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response (Inst)Travel, Accommodations, Expenses: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck & Co (Kenilworth, NJ), Bristol Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus, alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis, UpToDate, Peloton Therapeutics, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney Cancer Association, Clinical Care Options, PlatformQ Health, Harborside Press, Navinata Health, The New England Journal of Medicine, Lancet Oncology, the healthcare business of Merck KGaA (Darmstadt, Germany), HERON, Lilly, ESMOOther Relationship: Medical writing and editorial assistance support may have been funded by communications companies funded by pharmaceutical companies such as ClinicalThinking, Health Interactions, Envision Pharma Group, Fishawack Group of Companies, Parexel Robert J. MotzerConsulting or Advisory Role: Novartis, Eisai, Exelixis, Merck & Co (Kenilworth, NJ), Genentech/Roche, Incyte, Lilly, Pfizer, AstraZeneca, the healthcare business of Merck KGaA (Darmstadt, Germany), Calithera Biosciences, AveoResearch Funding: Pfizer (Inst), Bristol Myers Squibb (Inst), Eisai (Inst), Novartis (Inst), Genentech/Roche (Inst), Exelixis (Inst), Merck & Co (Kenilworth, NJ) (Inst), Aveo (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb Michael B. AtkinsStock and Other Ownership Interests: Werewolf Pharma, PyxisConsulting or Advisory Role: Genentech, Novartis, Bristol Myers Squibb, Merck & Co (Kenilworth, NJ), Exelixis, Eisai, Agenus, Arrowhead Pharmaceuticals, Werewolf Pharma, Surface Oncology, Iovance Biotherapeutics, Pyxis, Pneuma Respiratory, Leads Biolabs, Fathom Biotechnology, Aveo, Cota Healthcare, Neoleukin Therapeutics, Adagene, Idera, Ellipses Pharma, AstraZeneca, PACT Pharma, Seattle Genetics, Pfizer, Scholar Rock, Asher Biotherapeutics, Calithera Biosciences, Takeda, Sanofi, Simcha TherapeuticsResearch Funding: Bristol Myers Squibb (Inst) John HaanenStock and Other Ownership Interests: Neogene TherapeuticsConsulting or Advisory Role: Merck & Co (Kenilworth, NJ) (Inst), Pfizer (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Roche/Genentech (Inst), Ipsen (Inst), Achilles Therapeutics (Inst), Immunocore (Inst), Sanofi (Inst), Third Rock Ventures (Inst), Neogene Therapeutics, Molecular Partners (Inst), bioNTech (Inst), T-Knife (Inst), PokeAcel (Inst), Instil Bio (Inst), Iovance Biotherapeutics (Inst)Research Funding: Merck & Co (Kenilworth, NJ) (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Neon Therapeutics (Inst), Amgen (Inst), BioNTech (Inst), Asher Biotherapeutics (Inst) Mariangela MarianiStock and Other Ownership Interests: Pfizer Jing WangEmployment: PfizerStock and Other Ownership Interests: Pfizer Subramanian HariharanEmployment: PfizerStock and Other Ownership Interests: Pfizer James LarkinHonoraria: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Roche/Genentech, Incyte, iOnctura, the healthcare business of Merck KGaA (Darmstadt, Germany), Eisai, Dynavax Technologies, Cancer Research UK, touchIME, touchEXPERTSConsulting or Advisory Role: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Boston Biomedical, Incyte, iOnctura, Iovance Biotherapeutics, Immunocore, YKT Corporation, Apple Tree PartnersResearch Funding: Pfizer (Inst), Novartis (Inst), Merck & Co (Kenilworth, NJ) (Inst), Bristol Myers Squibb (Inst), Achilles Therapeutics (Inst), Roche (Inst), Nektar (Inst), Covance (Inst), Immunocore (Inst), AVEO (Inst), Pharmacyclics (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Pfizer, Novartis, Roche/Genentech, AstraZeneca, Incyte, GlaxoSmithKline, Pierre Fabre, the healthcare business of Merck KGaA (Darmstadt, Germany), iOnctura, British Uro-Oncology Group (BUG), ESMO, National Cancer Research Institute (NCRI), EUSA Pharma, Syneos Health, Kidney Cancer Association, Bioevents, MedConcept, RV MaisNo other potential conflicts of interest were reported.

Aim: To assess overall survival (OS) in patients with advanced BRAF -mutant melanoma by first-line (1L) targeted therapy (TT) or checkpoint inhibitor (CPI) use, second-line (2L) TT or CPI use, and treatment sequence. Patients & methods: Advanced BRAF -mutant melanoma patients treated with 1L CPI or TT were selected from a real-world, electronic health record-derived database. Results: CPI was associated with improved survival after adjustment for potential confounders (hazard ratio, 0.75 [95% CI, 0.66-0.87]). Median OS was similar between 2L therapies and among likely treatment sequences. Conclusion: This real-world study demonstrated a survival benefit with 1L CPI versus TT. Analyses of 2L and treatment sequences were unable to detect or rule out clinically relevant differences in OS.

Introduction: Many patients with renal cell carcinoma (RCC) who undergo surgery with curative intent have a high risk of disease recurrence and until recently no palatable adjuvant systemic therapy options. Blocking the programmed death ligand (PD-1) immune checkpoint pathway with pembrolizumab has robust clinical efficacy in patients with metastatic RCC. Results from the KEYNOTE 564 trial demonstrate that adjuvant pembrolizumab significantly improves disease- free survival after nephrectomy or metastasectomy., Areas Covered: We provide an overview of efforts to develop an adjuvant therapy in patients with high-risk RCC. This includes a critical review of efficacy, toxicity, and clinical implications from a large phase III trial leading to the FDA and EMA approvals of adjuvant pembrolizumab., Expert Opinion: Pembrolizumab offers an effective and well-tolerated adjuvant therapy for patients with surgically resected RCC at high-risk of disease recurrence. Future research will focus on optimal patient selection and biomarkers that predict benefit and/or toxicity from therapy.

Background: Pembrolizumab plus axitinib improved efficacy over sunitinib in treatment-naive advanced renal cell carcinoma in the KEYNOTE-426 (NCT02853331) study. However, a relatively high incidence of grade 3/4 aminotransferase elevations was observed., Objective: To further characterize treatment-emergent aminotransferase elevations in patients treated with pembrolizumab-axitinib., Design, Setting, and Participants: Patients enrolled in KEYNOTE-426 were included in this study., Outcome Measurements and Statistical Analysis: Three Standardized MedDRA Queries for potential hepatic disorders were used to identify patients for the hepatic event analysis subpopulation (HEAS). Alanine aminotransferase events were characterized for time to onset, time to recovery, corticosteroid use, and rechallenge with study treatment(s)., Results and Limitations: The HEAS comprised 189/429 (44%) pembrolizumab-axitinib patients and 128/425 (30%) sunitinib patients. Grade 3/4 hepatic adverse events were more common in the combination arm: 22% (94/429) versus 7% (29/425); 3% (13/429) discontinued the combination due to hepatic adverse events. In the pembrolizumab-axitinib arm, 125/426 patients (29%) had alanine aminotransferase (ALT) ≥3× upper limit of normal (ULN), with median time to onset of 84 d (range, 7-840 d). Among patients with ALT ≥3× ULN, 120/125 (96%) recovered to <3× ULN following study treatment interruption/discontinuation, with a median time to recovery of 15 d (3-176 d): 68/120 (57%) received corticosteroids. One hundred patients were rechallenged with one or both study treatment(s): 45/100 (45%) had ALT ≥3× ULN recurrence, and all 45 recovered to ALT <3× ULN following study treatment interruption/discontinuation. No fatal hepatic events occurred., Conclusions: A higher incidence of grade 3/4 aminotransferase elevations occurs with pembrolizumab-axitinib. These events should be carefully evaluated and managed with prompt study treatment interruption or discontinuation, with or without corticosteroid treatment. The decision to rechallenge with one or both drugs should be based on severity of event and thorough causality assessment., Patient Summary: Renal cell carcinoma patients receiving pembrolizumab-axitinib are at a higher risk of liver enzyme elevations, which could be reversed with appropriate management., (Copyright © 2021. Published by Elsevier B.V.)

Invasive melanoma is the deadliest type of skin cancer, with 101,110 expected cases to be diagnosed in 2021. Recurrent BRAF and NRAS mutations are well documented in melanoma. Biologic implications of gene fusions and the efficacy of therapeutically targeting them remains unknown. Retrospective review of patient samples that underwent next-generation sequencing of the exons of 592 cancer-relevant genes and whole transcriptome sequencing for the detection of gene fusion events and gene expression profiling. Expression of PDL1 and ERK1/2 was assessed by immunohistochemistry (IHC). There were 33 (2.6%) cases with oncogenic fusions (14 novel), involving BRAF , RAF1 , PRKCA , TERT , AXL , and FGFR3 . MAPK pathway-associated genes were over-expressed in BRAF and RAF1 fusion-positive tumors in absence of other driver alterations. Increased expression in tumors with PRKCA and TERT fusions was concurrent with MAPK pathway alterations. For a subset of samples with available tissue, increased phosphorylation of ERK1/2 was observed in BRAF , RAF1 , and PRKCA fusion-positive tumors. Oncogenic gene fusions are associated with transcriptional activation of the MAPK pathway, suggesting they could be therapeutic targets with available inhibitors. Additional analyses to fully characterize the oncogenic effects of these fusions may support biomarker driven clinical trials.

The second Kidney Cancer Research Summit was held virtually in October 2020. The meeting gathered worldwide experts in the field of kidney cancer, including basic, translational, and clinical scientists as well as patient advocates. Novel studies were presented, addressing areas of unmet need related to different topics. These include novel metabolic targets, promising immunotherapeutic regimens, predictive genomic and transcriptomic biomarkers, and variant histologies of renal cell carcinoma (RCC). With the development of pioneering technologies, and an unprecedented commitment to kidney cancer research, the field has tremendously evolved. This perspective aims to summarize the different sessions of the conference, outline major advances in the understanding of RCC and discuss current challenges faced by the field., (©2021 American Association for Cancer Research.)

Background: Patients with cancer and health care workers (HCW) are at higher risk for SARS-CoV-2 infection. There are limited data regarding the rate of symptomatic versus asymptomatic infection and subsequent seropositivity in both populations., Methods: We performed a prospective study of patients and HCW across two institutions during the first wave of the pandemic to analyze the prevalence of SARS-CoV-2 antibodies, the extent of associated symptoms, and durability of serologic response., Results: In 1,953 persons (733 patients and 1,220 HCW), overall seropositivity rates for 3.1% patients (95% CI 2.0-4.7) and 3.7% HCW (95% CI 2.7-4.9, p =0.520), were similar. Each institutions' seropositivity rates were numerically higher in HCW than patients. Non-Hispanic Whites and Asians had lower antibody rates (2.8%, 95% CI 2.0-3.8 and 3.3%, 95% CI 1.2-7.0) compared to Hispanics (6.9%, 95% CI 3.4-12.4) and non-Hispanic Blacks (5.9%, 95% CI 3.3-9.7), p < 0.001. Among persons with a positive SARS-CoV-2 antibody, 87% of patients and 56% of HCW did not recall having had a fever. Among HCW, administrative and technical personnel were most likely to be seropositive. The rate of persistent seropositivity at 3 months was similar between patients and HCW and was not influenced by the reporting of fever, cancer type, or therapy., Conclusion: These data suggest that patients are not at higher risk for febrile SARS-CoV-2 infections or more transient immunity than HCWs. Furthermore, racial differences and lack of association with the extent of HCW contact with COVID-19 patients suggest that community rather than hospital virus exposure was a source of many infections., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2022 Catherine Lai et al.)