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Background: Emerging agents blocking the programmed cell death 1 (PD-1) pathway show activity in metastatic clear cell renal cell carcinoma (mRCC). The aim of this study was to evaluate the efficacy and safety of vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-tyrosine kinase inhibitor (TKI) therapy after PD-1 inhibition. Patients and methods: Patients with mRCC treated with anti-PD-1 antibody (aPD-1) monotherapy or in combination (with VEGFR-TKI or ipilimumab) that subsequently received VEGFR-TKI were retrospectively reviewed. The efficacy end points were objective response rate (ORR) and progression-free survival (PFS) stratified by the type of prior PD-1 regimen. Safety by the type and PD-1 exposure was also evaluated. Results: Seventy patients were included. Forty-nine patients received prior therapy with immune checkpoint inhibitors (CPIs) alone and 21 had combination therapy of aPD-1 and VEGFR-TKI. Overall, ORR to VEGFR-TKI after PD-1 inhibition was 28% (19/68) and the median PFS was 6.4 months (mo) (4.3-9.5). ORR to VEGFR-TKI after aPD-1 in combination with VEGFR-TKI was lower than that in patients treated with VEGFR-TKI after CPI alone (ORR 10% versus 36%, P = 0.039). In the multivariable analysis, patients treated with prior CPI alone were more likely to achieve an objective response than those treated with aPD-1 in combination with VEGFR-TKI (OR = 5.38; 95% CI 1.12-26.0, P = 0.03). There was a trend toward numerically longer median PFS in the VEGFR-TKI after the CPI alone group, 8.4 mo (3.2-12.4) compared with 5.5 mo (2.9-8.3) for those who had VEGFR-TKI after aPD-1 in combination with VEGFR-TKI (P = 0.15). The most common adverse events (AEs) were asthenia, hypertension, and diarrhea. Conclusions: The efficacy and safety of VEGFR-TKIs after PD-1 inhibition were demonstrated in this retrospective study. The response rate was lower and the median progression-free survival was shorter in those patients who received prior PD-1 in combination with VEGFR-TKI. PD-1 exposure does not seem to significantly influence the safety of subsequent VEGFR-TKI treatment. [ABSTRACT FROM AUTHOR]

Background: 'Stable disease (SD)' as per RECIST is a common but ambiguous outcome in patients receiving immune checkpoint inhibitors (ICIs). This study aimed to characterize SD and identify the subset of patients with SD who are benefiting from treatment. Understanding SD would facilitate drug development and improve precision in correlative research., Patients and Methods: A systematic review was carried out to characterize SD in ICI trials. SD and objective response were compared to proliferation index using The Cancer Genome Atlas gene expression data. To identify a subgroup of SD with outcomes mirroring responders, we examined a discovery cohort of non-small-cell lung cancer (NSCLC). Serial cutpoints of two variables, % best overall response and progression-free survival (PFS), were tested to define a subgroup of patients with SD with similar survival as responders. Results were then tested in external validation cohorts., Results: Among trials of ICIs (59 studies, 14 280 patients), SD ranged from 16% to 42% in different tumor types and was associated with disease-specific proliferation index (ρ = -0.75, P = 0.03), a proxy of tumor kinetics, rather than relative response to ICIs. In a discovery cohort of NSCLC [1220 patients, 313 (26%) with SD to ICIs], PFS ranged widely in SD (0.2-49 months, median 4.9 months). The subset with PFS >6 months and no tumor growth mirrored partial response (PR) minor (overall survival hazard ratio 1.0) and was proposed as the definition of SD responder. This definition was confirmed in two validation cohorts from trials of NSCLC treated with durvalumab and found to apply in tumor types treated with immunotherapy in which depth and duration of benefit were correlated., Conclusions: RECIST-defined SD to immunotherapy is common, heterogeneous, and may largely reflect tumor growth rate rather than ICI response. In patients with NSCLC and SD to ICIs, PFS >6 months and no tumor growth may be considered 'SD responders'. This definition may improve the efficiency of and insight derivable from clinical and translational research., Competing Interests: Disclosure JL has received honoraria from Targeted Oncology and Physicians’ Education Resource. SW and QZ are former employees of AstraZeneca. MKC receives institutional research funding from Bristol-Myers Squibb; and has received personal fees from Merck, InCyte, Moderna, ImmunoCore, and AstraZeneca. ANS reports advisory board positions with Bristol-Myers Squibb, Immunocore, Novartis, and Castle Biosciences; and institutional research support from BMS, Immunocore, Xcovery, Polaris, Novartis, Pfizer, Checkmate Pharmaceuticals, and Foghorn Therapeutics. MAP reports consulting fees from Bristol-Myers Squibb, Merck, Array BioPharma, Novartis, Incyte, NewLink Genetics, Pfizer, and Aduro; honoraria from BMS and Merck; and institutional research support from Rgenix, Infinity, BMS, Merck, Array BioPharma, Novartis, and AstraZeneca. MHV reports receiving commercial research support from Bristol-Myers Squibb, Pfizer, and Genentech/Roche; honoraria from Novartis and Bristol-Myers Squibb; travel/accommodation from Astra Zeneca, Eisai, Novartis, and Takeda; and consultant/advisory board member for Aveo, Calithera Biosciences, Corvus Pharmaceuticals, Exelixis, Eisai, Merck, Onquality Pharmaceuticals, Novartis, and Pfizer. MSG has been a compensated consultant for Ultimate Opinions in Medicine LLC and MORE Health, Inc. AG and RR are employees of AstraZeneca. RR has a patent pending related to tumor mutation burden. MGK receives personal fees from AstraZeneca, Pfizer, Regeneron, and Daiichi-Sankyo; received honoraria for participation in educational programs from WebMD, OncLive, Physicians Education Resources, Prime Oncology, Intellisphere, Creative Educational Concepts, Peerview, i3 Health, Paradigm Medical Communications, AXIS, Carvive Systems, AstraZeneca, and Research to Practice; and received travel support from AstraZeneca, Pfizer, Regeneron, and Genentech; is an employee of Memorial Sloan Kettering. Memorial Sloan Kettering has received research funding from The National Cancer Institute (USA), The Lung Cancer Research Foundation, Genentech/Roche, and PUMA Biotechnology for research conducted by MGK. MSK has licensed testing for EGFR T790M to MolecularMD. MDH, as of November 2021, is an employee of AstraZeneca; has received personal fees from Achilles, Adagene, Adicet, Arcus, Blueprint Medicines, Bristol-Myers Squibb, DaVolterra, Eli Lilly, Genentech/Roche, Genzyme/Sanofi, Janssen, Immunai, Instil Bio, Mana Therapeutics, Merck, Mirati, Natera, Pact Pharma, Shattuck Labs, and Regeneron; has options from Factorial, Shattuck Labs, Immunai, and Arcus; and has a patent filed by Memorial Sloan Kettering related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from PGDx. All other authors have declared no conflicts of interest., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: Immunoglobulin E (IgE) blockade with omalizumab has demonstrated clinical benefit in pruritus-associated dermatoses (e.g. atopic dermatitis, bullous pemphigoid, urticaria). In oncology, pruritus-associated cutaneous adverse events (paCAEs) are frequent with immune checkpoint inhibitors (CPIs) and targeted anti-human epidermal growth factor receptor 2 (HER2) therapies. Thus, we sought to evaluate the efficacy and safety of IgE blockade with omalizumab in cancer patients with refractory paCAEs related to CPIs and anti-HER2 agents., Patients and Methods: Patients included in this multicenter retrospective analysis received monthly subcutaneous injections of omalizumab for CPI or anti-HER2 therapy-related grade 2/3 pruritus that was refractory to topical corticosteroids plus at least one additional systemic intervention. To assess clinical response to omalizumab, we used the Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was defined as reduction in the severity of paCAEs to grade 1/0., Results: A total of 34 patients (50% female, median age 67.5 years) received omalizumab for cancer therapy-related paCAEs (71% CPIs; 29% anti-HER2). All had solid tumors (29% breast, 29% genitourinary, 15% lung, 26% other), and most (n = 18, 64%) presented with an urticarial phenotype. In total 28 of 34 (82%) patients responded to omalizumab. The proportion of patients receiving oral corticosteroids as supportive treatment for management of paCAEs decreased with IgE blockade, from 50% to 9% (P < 0.001). Ten of 32 (31%) patients had interruption of oncologic therapy due to skin toxicity; four of six (67%) were successfully rechallenged following omalizumab. There were no reports of anaphylaxis or hypersensitivity reactions related to omalizumab., Conclusions: IgE blockade with omalizumab demonstrated clinical efficacy and was well tolerated in cancer patients with pruritus related to CPIs and anti-HER2 therapies., Competing Interests: Disclosure AM has an advisory board role in AstraZeneca, receives research funding from Incyte, and is supported by a Dermatology Foundation Career Development Award. EQ receives royalties from UpToDate. SAF receives research funding from AstraZeneca and Genentech/Roche, has a consulting/advisory relationship with Merck, and has ownership interests in Urogen, Allogene Therapeutics, Neogene Therapeutics, Kronos Bio, InconOVir and Vida Ventures. MHV reports receiving commercial research support from Pfizer and honoraria from Pfizer, Exelixis, Eisai, Calithera Biosciences, and Corvus Pharmaceuticals. AD discloses honoraria/advisory board participation for Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millennium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, and MORE Health; associated research funding paid to the institution from Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho, and PharmaMar; research for Foundation Medicine; royalties from Wolters Kluwer; expenses from Merck and Puma; and CME honoraria from Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, and Research to Practice. MDH receives research funding from Bristol Myers Squibb; is a paid consultant to Merck, Bristol Myers Squibb, AstraZeneca, Genentech/Roche, Nektar, Syndax, Mirati, Blueprint, Achilles Therapeutics, PACT Pharma, Immunai, and Shattuck Labs; receives travel support/honoraria from AstraZeneca, Eli Lilly, Merck, and BMS; and a patent has been filed by MSK related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from PGDx. EAC reports consultancy fees from Pfizer, Novartis, Bristol Myers Squibb, COTA, Genentech-Roche, and Heron Therapeutics. DYML has been a consultant for Genentech and Novartis. MEL has a consultant role with Johnson and Johnson, Novocure, QED, Bicara, Janssen, Novartis, F. Hoffmann-La Roche AG, EMD Serono, Astrazeneca, Innovaderm, Deciphera, DFB, Azitra, Kintara, RBC/La Roche Posay, Trifecta, Varsona, Genentech, Loxo, Seattle Genetics, Lutris, OnQuality, Azitra, Roche, NCODA, Apricity, Oncoderm Labs, Hoth Therapeutics. Dr. Lacouture also receives research funding from Lutris, Paxman, Novocure, J&J, US Biotest, OQL, Novartis and AZ. All other authors have declared no conflicts of interest., (Copyright © 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) are being increasingly utilised in the front-line (1L) setting of metastatic clear-cell renal cell carcinoma (mccRCC). Limited data exist on responses and survival on second-line (2L) vascular endothelial growth factor-receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy after 1L ICI therapy., Patients and Methods: This is a retrospective study of mccRCC patients treated with 2L VEGFR-TKI after progressive disease (PD) with 1L ICI. Patients were treated at MD Anderson Cancer Center or Memorial Sloan Kettering Cancer Center between December 2015 and February 2018. Objective response was assessed by blinded radiologists' review using Response Evaluation Criteria in Solid Tumours v1.1. Descriptive statistics and Kaplan-Meier method were used., Results: Seventy patients were included in the analysis. Median age at mccRCC diagnosis was 59 years; 8 patients (11%) had international metastatic database consortium favourable-risk disease, 48 (69%) had intermediate-risk disease and 14 (20%) had poor-risk disease. As 1L therapy, 12 patients (17%) received anti-programmed death ligand-1 (PD-(L)1) monotherapy with nivolumab or atezolizumab, 33 (47%) received nivolumab plus ipilimumab and 25 (36%) received combination anti-PD-(L)1 plus bevacizumab. 2L TKI therapies included pazopanib, sunitinib, axitinib and cabozantinib. On 2L TKI therapy, one patient (1.5%) achieved a complete response, 27 patients (39.7%) a partial response and 36 patients (52.9%) stable disease. Median progression-free survival (mPFS) was 13.2 months (95% confidence interval: 10.1, NA). Forty-five percent of subjects required a dose reduction, and twenty-seven percent of patients discontinued treatment because of toxicity., Conclusions: In this retrospective study of patients with mccRCC receiving 2L TKI monotherapy after 1L ICI, we observed 2L antitumour activity and tolerance comparable to historical data for 1L TKI., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Mutations in VHL , PBRM1 , SETD2 , BAP1 , and KDM5C are common in clear cell renal cell carcinoma (ccRCC), and presence of certain mutations has been associated with outcomes in patients with non-metastatic disease. Limited information is available regarding the correlation between genomic alterations and outcomes in patients with metastatic disease, including response to VEGF-targeted therapy. Objective: To explore correlations between mutational profiles and cancer-specific outcomes, including response to standard VEGF-targeted agents, in patients with metastatic cc RCC. Methods: A retrospective review of 105 patients with metastatic ccRCC who had received systemic therapy and had targeted next-generation sequencing of tumors was conducted. Genomic alterations were correlated to outcomes, including overall survival and time to treatment failure to VEGF-targeted therapy. Results: The most frequent mutations were detected in VHL (83%), PBRM1 (51%), SETD2 (35%), BAP1 (24%), KDM5C (16%), and TERT (14%). Time to treatment failure with VEGF-targeted therapy differed significantly by PBRM1 mutation status ( p  = 0.01, median 12.0 months for MT versus 6.9 months for WT) and BAP1 mutation status ( p  = 0.01, median 6.4 months for MT versus 11.0 months for WT). Shorter overall survival was associated with TERT mutations ( p  = 0.03, median 29.6 months for MT versus 52.6 months for WT) or BAP1 mutations ( p  = 0.02, median 28.7 months for MT versus not reached for WT). Conclusions: Genomic alterations in ccRCC tumors have prognostic implications in patients with metastatic disease. BAP1 and TERT promoter mutations may be present in higher frequency than previously thought, and based on this data, deserve further study for their association with poor prognosis.