Search

Belzutifan (Welireg, Merck & Co., Inc., Rahway, NJ, USA) is an oral, potent hypoxia-inducible factor-2α inhibitor, recently approved in the United States for the treatment of von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC) and other VHL disease-associated neoplasms. Safety and efficacy were investigated in two clinical studies: a Phase 1 dose escalation/expansion study in solid tumors and RCC and a Phase 2 study in VHL-RCC. A population pharmacokinetic model was used to estimate belzutifan exposures to facilitate exposure-response (E-R) analyses for efficacy and safety endpoints. Relationships between exposure and efficacy (overall response rate, disease control rate, progression-free survival, best overall tumor size response, and other endpoints), safety outcomes (Grade ≥3 anemia, Grade ≥3 hypoxia, and time to first dose reduction/dose interruption), and pharmacodynamic biomarkers (erythropoietin [EPO] and hemoglobin [Hgb]) were evaluated using various regression techniques and time-to-event analyses. Efficacy E-R was generally flat with non-significant positive trends with exposure. The safety E-R analyses demonstrated a lack of relationship for Grade ≥3 hypoxia and a positive relationship for Grade ≥3 anemia, with incidences also significantly dependent on baseline Hgb. Exposure-dependent reductions in EPO and Hgb were observed. Based on the cumulative benefit-risk assessment in VHL disease-associated neoplasms using E-R, no a priori dose adjustment is recommended for any subpopulation. These analyses supported the benefit-risk profile of belzutifan 120 mg once daily dosing in patients with VHL-RCC for labeling and the overall development program., (© 2024 Merck Sharp & Dohme LLC. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Background: Belzutifan, a hypoxia-inducible factor 2α inhibitor, showed clinical activity in clear-cell renal-cell carcinoma in early-phase studies., Methods: In a phase 3, multicenter, open-label, active-controlled trial, we enrolled participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies and randomly assigned them, in a 1:1 ratio, to receive 120 mg of belzutifan or 10 mg of everolimus orally once daily until disease progression or unacceptable toxic effects occurred. The dual primary end points were progression-free survival and overall survival. The key secondary end point was the occurrence of an objective response (a confirmed complete or partial response)., Results: A total of 374 participants were assigned to belzutifan, and 372 to everolimus. At the first interim analysis (median follow-up, 18.4 months), the median progression-free survival was 5.6 months in both groups; at 18 months, 24.0% of the participants in the belzutifan group and 8.3% in the everolimus group were alive and free of progression (two-sided P = 0.002, which met the prespecified significance criterion). A confirmed objective response occurred in 21.9% of the participants (95% confidence interval [CI], 17.8 to 26.5) in the belzutifan group and in 3.5% (95% CI, 1.9 to 5.9) in the everolimus group (P<0.001, which met the prespecified significance criterion). At the second interim analysis (median follow-up, 25.7 months), the median overall survival was 21.4 months in the belzutifan group and 18.1 months in the everolimus group; at 18 months, 55.2% and 50.6% of the participants, respectively, were alive (hazard ratio for death, 0.88; 95% CI, 0.73 to 1.07; two-sided P = 0.20, which did not meet the prespecified significance criterion). Grade 3 or higher adverse events of any cause occurred in 61.8% of the participants in the belzutifan group (grade 5 in 3.5%) and in 62.5% in the everolimus group (grade 5 in 5.3%). Adverse events led to discontinuation of treatment in 5.9% and 14.7% of the participants, respectively., Conclusions: Belzutifan showed a significant benefit over everolimus with respect to progression-free survival and objective response in participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies. Belzutifan was associated with no new safety signals. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; LITESPARK-005 ClinicalTrials.gov number, NCT04195750.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: The safety profile of adjuvant pembrolizumab was evaluated in a pooled analysis of 4 phase 3 clinical trials., Methods: Patients had completely resected stage IIIA, IIIB, or IIIC melanoma per American Joint Committee on Cancer, 7th edition, criteria (AJCC-7; KEYNOTE-054); stage IIB or IIC melanoma per AJCC-8 (KEYNOTE-716); stage IB, II, or IIIA non-small cell lung cancer per AJCC-7 (PEARLS/KEYNOTE-091); or postnephrectomy/metastasectomy clear cell renal cell carcinoma at increased risk of recurrence (KEYNOTE-564). Patients received adjuvant pembrolizumab 200 mg (2 mg/kg up to 200 mg for pediatric patients) or placebo every 3 weeks for approximately 1 year. Adverse events (AEs) were summarized for patients who received ≥ 1 dose of treatment., Results: Data were pooled from 4125 patients treated with pembrolizumab (n = 2060) or placebo (n = 2065). Median (range) duration of treatment was 11.1 months (0.0-18.9) with pembrolizumab and 11.2 months (0.0-18.1) with placebo. Treatment-related AEs occurred in 78.6 % (1620/2060) of patients in the pembrolizumab group (grade 3-5, 16.3 % [336/2060]) and 58.7 % (1212/2065) in the placebo group (grade 3-5, 3.5 % [72/2065]). Immune-mediated AEs (e.g. adrenal insufficiency, hypophysitis, and thyroiditis) occurred in 36.2 % (746/2060) of patients in the pembrolizumab group (grade 3-5, 8.6 % [177/2060]) and 8.4 % (174/2065) in the placebo group (grade 3-5, 1.1 % [23/2065]). Of patients with ≥ 1 immune-mediated AE or infusion reaction, systemic corticosteroids were required for 35.2 % (268/761) and 20.2 % (39/193) of patients in the pembrolizumab and placebo groups, respectively., Conclusions: Adjuvant pembrolizumab demonstrated a manageable safety profile that was comparable to prior reports in advanced disease., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jason J. Luke reports grants or contracts from AbbVie, Astellas, AstraZeneca, Bristol Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, MSD, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimmune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, and Xencor; consulting fees from 7 Hills, Bright Peak, Exo, Fstar, Inzen, RefleXion, Xilio, Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, Saros, STipe, Tempest, AbbVie, Alnylam, Atomwise, Bayer, Bristol Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Eisai, EMD Serono, Endeavor, Flame, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, KSQ, Janssen, Ikena, Inzen, Immatics, Immunocore, Incyte, Instil, IO Biotech, Macrogenics, MSD, Mersana, Nektar, Novartis, Partner, Pfizer, Pioneering Medicines, PsiOxus, Regeneron, Ribon, Roivant, Servier, STINGthera, Synlogic, and Synthekine; patents planned, issued, or pending for Serial #15/612,657 (Cancer Immunotherapy) and PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof) (both provisional); participation in a Data Safety Monitoring Board or Advisory Board for AbbVie, Immutep, and Evaxion; a leadership or fiduciary role at the Society for Immunotherapy of Cancer; and stock or stock options in Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, Saros, STipe, and Tempest. Georgina V. Long reports consulting fees and participating on a Data Safety Monitoring Board or Advisory Board for Agenus Inc, Amgen Inc, Array Biopharma, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA Inc, MSD, Novartis Pharma AG, OncoSec Medical Australia, Pierre Fabre, Provectus Australia, Qbiotics Group Limited, and Regeneron Pharmaceuticals; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bristol Myers Squibb and Pierre Fabre. Caroline Robert reports support for medical writing for the present manuscript from MSD; consulting fees from BMS, Roche, MSD, Sanofi, Pierre Fabre, Sunpharma, Pfizer, and Regeneron; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS, Pierre Fabre, and Sanofi; participation on a Data Safety Monitoring Board or Advisory Board from Ultimovacs and Regeneron; and stock or stock options in Ribonexus. Matteo S. Carlino reports consulting fees from Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre Fabre, Qbiotics, Regeneron, Roche, SMD, and Sanofi; and honoraria for lectures from BMS, MSD, Novartis, Pierre Fabre, and Sanofi. Toni K. Choueiri reports support from Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infiniti, Ipsen, Kanaph, Lilly, MSD, Nikang, Novartis, Nuscan, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, Takeda, Tempest, Up-To-Date, and CME events (Peerview, PER, MJH Life Sciences, Research to Practice, France Foundation, Springer, WebMed, ASiM Ce, Caribou Publishing, and others); grants or contracts from AstraZeneca, Aveo, Arcus, Bayer, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Lilly, MSD, Nikang, Novartis, Pfizer, Roche, Sanofi/Aventis, and Takeda; consulting fees from AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVIA, Infiniti, Ipsen, Kanaph, Lilly, MSD, Nikang, Novartis, Nuscan, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, Takeda, Tempest, Up-To-Date, and CME events (Peerview, PER, MJH Life Sciences, Research to Practice, France Foundation, Springer, WebMed, ASiM Ce, Caribou Publishing); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVIA, Infiniti., Ipsen, Kanaph, Lilly, MSD, Nikang, Novartis, Pfizer, Roche, Sanofi/Aventis, Takeda, Tempest, Up-To-Date, CME events (Peerview, PER, MJH Life Sciences, Research to Practice, France Foundation, Springer, WebMed, ASiM Ce, Caribou Publishing); a patent planned, issued, or pending related to ctDNA and biomarkers of response to immune checkpoint inhibitors; participation in a Data Safety Monitoring Board or Advisory Board for Aravive; a leadership or fiduciary role with KidneyCan, ASCO, ESMO, NCCN, GU, and NCI; stock or stock options in Pionyr, Tempest, Precede Bio, Osel, Curesponse, Immdura, and Primium; and other financial or non-financial interests including support from 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 DFC. Naomi B. Haas reports participation on a data safety monitoring board or advisory board for MSD, Eisai, and Exelixis. Mary O’Brien reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca and MSD; support for attending ESMO from AstraZeneca; and participation on an IDMC. Luis Paz-Ares reports grants or contracts from MSD, AstraZeneca, BMS, Pfizer, and PharmaMar; consulting fees from Lilly, MSD, Roche, PharmaMar, AstraZeneca, Novartis, Amgen, Pfizer, Sanofi, Bayer, BMS, Mirati, GSK, Janssen, Takeda, and Regeneron; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Lilly, MSD, Roche, PharmaMar, AstraZeneca, Novartis, Amgen, Pfizer, Sanofi, Bayer, BMS, Mirati, GSK, Janssen, Takeda, and Regeneron; support for attending meetings and/or travel from Lilly, MSD, Roche, PharmaMar, AstraZeneca, Novartis, Amgen, Pfizer, Sanofi, Bayer, BMS, Mirati, GSK, Janssen, Takeda, and Regeneron; participation on a data safety monitoring board or advisory board for Altum Sequencing and Stab Therapeutics; and stock or stock options in Altum Sequencing and Stab Therapeutics. Solange Peters reports support for the present manuscript from MSD; grants or contracts from Amgen, Arcus, AstraZeneca, BeiGene, Bristol Myers Squibb, GSK, iTeos, MSD, Mirati, Pharma Mar, Promontory Therapeutics, Roche/Genentech, and Seattle Genetics; consulting fees from AbbVie, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, BerGenBio, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GSK, Hutchmed, Illumina, Incyte, Ipsen, iTeos, Janssen, MSD, Merrimack, Mirati, Nykode Therapeutics, Novartis, Novocure, Pharma Mar, Promontory Therapeutics, Pfizer, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics, and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Foundation Medicine, GSK, Illumina, Ipsen, MSD, Mirati, Novartis, Pfizer, Roche/Genentech, Sanofi, and Takeda; support for attending meetings and/or travel from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pfizer, Roche/Genentech, and Takeda; participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, BerGenBio, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GSK, Hutchmed, Illumina, Incyte, Ipsen, iTeos, Janssen, MSD, Merrimack, Mirati, Nykode Therapeutics, Novartis, Novocure, Pharma Mar, Promontory Therapeutics, Pfizer, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics, and Takeda; and a leadership or fiduciary role with Galenica SA. Thomas Powles reports support for the present manuscript from Astellas and Open Health; grants or contracts from AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Ipsen, MSD, Novartis, Pfizer, Seattle Genetics, Astellas, Johnson & Johnson, and Eisai; consulting fees from AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Ipsen, MSD, Novartis, Pfizer, Seattle Genetics, Astellas, Johnson & Johnson, Eisai, and Mashup Ltd; and support for attending meetings and/or travel from Roche, Pfizer, MSD, AstraZeneca, and Ipsen. Melanie A. Leiby, Jianxin Lin, Clemens Krepler, Rodolfo F. Perini, M. Catherine Pietanza, Todd Gruber, and Nageatte Ibrahim report employment at Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and stock ownership in Merck & Co., Inc., Rahway, NJ, USA. Ayman Samkari and Yujie Zhao reports employment at Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Alexander M. M. Eggermont reports support for the present manuscript from Merck & Co; consulting fees from Alcetra, Agenus, BioInvent, Brenus, CatalYm, Ellipses, Epics, GSK, IO Biotech, IQVIA, ISA Pharmaceuticals, Merck & Co., Inc., MSD, Oncimmune, Pierre Fabre, Sairopa, Scorpion, Sellas, Skyline, TigaTX, and Trained Immunity TTC; payment or honoraria for lectures from IO Biotech, BMS, Merck & Co., Inc./MSD; participation on a Data Safety Monitoring Board for BioNTech, Boehringer Ingelheim, and Pfizer; and stock or stock options in IO Biotech, Sairopa, and SkylineDX., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Adjuvant pembrolizumab therapy after surgery for renal-cell carcinoma was approved on the basis of a significant improvement in disease-free survival in the KEYNOTE-564 trial. Whether the results regarding overall survival from the third prespecified interim analysis of the trial would also favor pembrolizumab was uncertain., Methods: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 1:1 ratio) participants with clear-cell renal-cell carcinoma who had an increased risk of recurrence after surgery to receive pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks for up to 17 cycles (approximately 1 year) or until recurrence, the occurrence of unacceptable toxic effects, or withdrawal of consent. A significant improvement in disease-free survival according to investigator assessment (the primary end point) was shown previously. Overall survival was the key secondary end point. Safety was a secondary end point., Results: A total of 496 participants were assigned to receive pembrolizumab and 498 to receive placebo. As of September 15, 2023, the median follow-up was 57.2 months. The disease-free survival benefit was consistent with that in previous analyses (hazard ratio for recurrence or death, 0.72; 95% confidence interval [CI], 0.59 to 0.87). A significant improvement in overall survival was observed with pembrolizumab as compared with placebo (hazard ratio for death, 0.62; 95% CI, 0.44 to 0.87; P = 0.005). The estimated overall survival at 48 months was 91.2% in the pembrolizumab group, as compared with 86.0% in the placebo group; the benefit was consistent across key subgroups. Pembrolizumab was associated with a higher incidence of serious adverse events of any cause (20.7%, vs. 11.5% with placebo) and of grade 3 or 4 adverse events related to pembrolizumab or placebo (18.6% vs. 1.2%). No deaths were attributed to pembrolizumab therapy., Conclusions: Adjuvant pembrolizumab was associated with a significant and clinically meaningful improvement in overall survival, as compared with placebo, among participants with clear-cell renal-cell carcinoma at increased risk for recurrence after surgery. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: In patients with renal cell carcinoma (RCC) enrolled in the phase III KEYNOTE-564 trial (NCT03142334), disease-free survival (DFS) following nephrectomy was prolonged with use of adjuvant pembrolizumab therapy versus placebo. Patient-reported outcomes (PROs) provide an important measure of health-related quality of life (HRQoL) and can complement efficacy and safety results., Patients and Methods: In KEYNOTE-564, 994 patients were randomly assigned to receive pembrolizumab 200 mg (n = 496) or placebo (n = 498) intravenously every 3 weeks for ≤17 cycles. Patients who received ≥1 dose of treatment and completed ≥1 HRQoL assessment were included in this analysis. HRQoL end points were assessed using the EORTC QLQ-C30, FKSI-DRS, and EQ VAS. Prespecified and exploratory PRO end points were mean change from baseline in EORTC QLQ-C30 GHS/QoL score, EORTC QLQ-C30 physical function subscale score, and FKSI-DRS score., Results: No clinically meaningful difference in least squares mean scores for pembrolizumab versus placebo were observed at week 52 for EORTC QLQ-C30 GHS/QoL (-2.5; 95% CI -5.2 to 0.1), EORTC QLQ-C30 physical functioning (-0.87; 95% CI -2.7 to 1.0), and FKSI-DRS (-0.7; 95% CI -1.2 to -0.1). Most PRO scores remained stable or improved for the EORTC QLQ-C30 GHS/QoL (pembrolizumab, 54.3%; placebo, 67.5%), EORTC QLQ-C30 physical functioning (pembrolizumab, 64.7%; placebo, 68.8%), and FKSI-DRS (pembrolizumab, 58.2%; placebo, 66.3%)., Conclusions: Adjuvant treatment with pembrolizumab did not result in deterioration of HRQoL. These findings together with the safety and efficacy findings support adjuvant pembrolizumab treatment following nephrectomy., Trial Registration: Clinicaltrials.gov Identifier: NCT03142334., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Accumulation of the HIF-2α transcription factor is an oncogenic event implicated in the tumorigenesis of clear cell renal cell carcinoma (ccRCC). In the phase I LITESPARK-001 study, the first-in-class HIF-2α inhibitor belzutifan demonstrated antitumor activity and an acceptable safety profile for pretreated patients with advanced ccRCC. Updated data with additional follow-up of > 40 months are presented., Methods: LITESPARK-001 is an ongoing open-label study with a 3 + 3 dose-escalation design followed by an expansion phase. Patients with ccRCC enrolled at 7 sites received belzutifan 120 mg orally once daily until disease progression, unacceptable toxicity, or patient withdrawal. The data cutoff date was July 15, 2021. The primary end point was identifying the maximum tolerated dose and/or the recommended phase II dose. Secondary end points included objective response rate (ORR) and duration of response (DOR) per RECIST v1.1 by investigator assessment and safety., Results: Median follow-up was 41.2 months (range, 38.2-47.7). Patients received a median of 3 (range, 1-9) prior systemic therapies. Of 55 patients, 14 (25 %) achieved an objective response. Median DOR was not reached (range, 3.1 + to 38.0 + months). Adverse events (AEs) attributed to study treatment by investigator assessment were reported in 53 patients (96 %). 22 patients (40 %) had grade 3 treatment-related AEs; the most common were anemia (n = 13; 24 %) and hypoxia (n = 7; 13 %). No grade 4 or 5 treatment-related AEs occurred., Conclusion: After a median follow-up of 41.2 months, belzutifan monotherapy demonstrated durable antitumor activity in patients with advanced ccRCC and acceptable safety., Clinicaltrials: gov. NCT02974738., Competing Interests: Declaration of Competing Interest E. Jonasch has received research support from MSD, NiKang, Novartis, Arrowhead, Corvus, ProFoundBio, Telix, Aveo; consulting fees from Aveo, Esai, Exelixis, Ipsen, MSD, and NiKang; and honoraria from DAVA; has participated on advisory boards for Novartis; and has a leadership role with NCCN. T. M. Bauer has received research support from MSD, consulting fees from Pfizer, Bayer, Eli Lilly and Company, AstraZeneca, and BluePrint; and honoraria from Pfizer, Bayer, and Eli Lilly.K. P. Papadopoulos has received research support from 3D Medicines, Abbvie, ADC Therapeutics, Amgen, Anheart Therapeutics, Bayer, Daiichi Sankyo, F-Star, Incyte, Jounce, LillyLoxo, MSD, Mersana, Mirati, Pfizer, Regeneron, RevolutionMedicines, Syros Pharma, Tempest Therapeutics, Treadwell Therapeutics, CytomX, AstraZeneca, Kezar, Monte Rosa, and Storm; has received travel support from Jounce; and participated on advisory boards for Basilla, Bicycle, and Turning Point Therapuetics. E. R. Plimack has received research support from MSD, BMS, Seagen, and Genentech; has participated in advisory boards for Astellas, AstraZeneca, Aveo, BMS, Calithera, EMD Serono, Exelixis, IMV, Janssen, MEI, MSD, Pfizer, Regeneron, Seagen, Signatera; and was a member of an external data monitoring committee for AstraZeneca and Infinity Pharma. J. R. Merchan has received research grants from MSD, Sillagen, Seattle Genetics, Genentech, EISAI, Exelixis, Imugene, Rubius Therapeutics, Trishula Therapeutics, Corvus, Peloton Therapeutics, and Vyriad; receives royalties from UpToDate; and has participated on an advisory board for MSD. D. F. McDermott has received research support from BMS, MSD, Genentech, Pfizer, Exelixis, X4 Pharma, and Alkermes, Inc; and has honoraria from BMS, Pfizer, MSD, Eisai Inc., Xilio, Aveo, Genentech, Cullinan, and Exelixis. M. Dror Michaelson has participated on advisory boards for MSD, Eisai, Exelixis, and Janssen. L. J. Appleman has received research support from MSD. A. Roy, R. F. Perini, and Y. Liu are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and has stock ownership in Merck & Co., Inc., Rahway, NJ, USA. T. K. Choueiri reports institutional and personal support, paid and unpaid support for research, participating in advisory boards, consultancy, and honoraria from Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, IQVIA, Infinity, Ipsen, Jansen, Kanaph, Lilly, MSD, Nikang, Nuscan, Novartis, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, UpToDate, and CME events (Peerview, OncLive, MJH, and others), outside the submitted work; institutional patents filed on molecular mutations, immunotherapy response and toxicity, and circulating tumor DNA; equity in Tempest, Pionyr, Osel, Precede Bio, and CureResponse; being part of committees in the National Comprehensive Cancer Network, GU Steering Committee, American Society of Clinical Oncology, European Society for Medical Oncology, Academic and Community Cancer Research United, and KidneyCAN; having mentored several non-US citizens on research projects partly funded by non-US sources; additional independent funding from drug companies or royalties for having received research around the subject matter paid to institution; and 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, and Loker Pinard Funds for Kidney Cancer Research at DFCI., (Copyright © 2023. Published by Elsevier Ltd.)

Combination treatment with immunotherapy agents and/or vascular endothelial growth factor tyrosine kinase inhibitors are a standard of care for patients with advanced clear cell renal cell carcinoma (ccRCC). Novel therapeutic combinations that include the hypoxia-inducible factor 2α inhibitor belzutifan and the cytotoxic T-lymphocyte-associated protein 4 inhibitor quavonlimab are being investigated for their potential to further improve patient outcomes. This protocol describes the rationale and design of the randomized, phase III LITESPARK-012 study, which will evaluate the efficacy and safety of pembrolizumab plus lenvatinib with or without belzutifan or quavonlimab as first-line treatment for advanced ccRCC. Results from this study may support triplet combination therapies as a potential new standard of care for advanced ccRCC. Clinical trial registry: NCT04736706 (ClinicalTrials.gov).

Background: Immune-Oncology (IO) therapies have changed first-line (1L) treatment paradigm for metastatic renal cell carcinoma (mRCC) in last few years with robust clinical trial data. We examined clinical outcomes among clear cell mRCC (mccRCC) patients who received pembrolizumab + axitinib (pembro-axi) or ipilimumab + nivolumab (ipi-nivo) in the US community oncology setting., Methods: This retrospective cohort study utilized data from electronic health records and chart review within The US Oncology Network to identify adult patients with mccRCC initiating 1L pembro-axi or ipi-nivo from January 01, 2019 to December 31, 2020 and followed through March 31, 2021. Physician-recorded response (real-world overall response rate [rwORR] and real-world disease control rate [rwDCR]) was assessed descriptively. Real-world progression-free survival (rwPFS), real-world time to next treatment (rwTTNT) and time on treatment (rwToT) were estimated using Kaplan-Meier analysis. Association of 1L systemic treatment with time-to-event outcomes was examined using multivariable cox proportional hazards models., Results: Study included 331 mccRCC patients (pembro-axi:44%, ipi-nivo:56%). Median age was 65 years, 75.5% were male, and 82.5% had intermediate/poor (I/P) IMDC risk score. RwORR and rwDCR were 71.0% and 80.0% for pembro-axi and 45.2% and 58.6% for ipi-nivo. In multivariable analysis, pembro-axi was associated with longer rwToT (aHR, 0.53 [95% CI, 0.40, 0.71]), rwTTNT (aHR, 0.60 [95% CI, 0.42, 0.87]), and rwPFS (aHR, 0.70 [95% CI, 0.49, 0.99]) compared to ipi-nivo (P < 0.01)., Conclusions: Our study provides insight into newer mccRCC treatment tolerability and effectiveness in the real-world US community setting. Our real-world results were comparable to data from clinical trials, which is encouraging for mccRCC patients., Competing Interests: Declaration of Competing Interest Neil J. Shah has a consulting/advisory role from Merck & Co., Inc., Rahway, NJ, USA and research funding from Aravive. Sneha Sura and Junxin She are employee of Ontada. Reshma Shinde, Puneet Singhal and Rodolfo Perini are employees of Merck & Co., Inc., Rahway, NJ, USA and own stock in Merck & Co., Inc., Rahway, NJ, USA. Robert J. Motzer has a consulting/advisory role from Novartis, Eisai, Exelixis, Merck, Genentech/Roche, Incyte, Lilly, Pfizer, AstraZeneca, EMD Serono, and Calithera Biosciences and travel, accommodations, and expenses from Bristol-Myers Squibb, and research funding from Pfizer, Bristol-Myers Squibb, Eisai, Novartis, Genentech/Roche, Exelixis and Merck., (Copyright © 2023 Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, The Author(s). Published by Elsevier Inc. All rights reserved.)

Belzutifan (Welireg, Merck & Co., Inc., Rahway, NJ, USA) is an oral, potent inhibitor of hypoxia-inducible factor 2α, approved for the treatment of certain patients with von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors. It is primarily metabolized by the polymorphic uridine 5'-diphospho-glucuronosyltransferase (UGT) 2B17 and cytochrome (CYP) 2C19. A population pharmacokinetic (PK) model was built, using NONMEM version 7.3, based on demographics/PK data from three clinical pharmacology (food effect, formulation bridging, and genotype/race effect) and two clinical studies (phase I dose escalation/expansion in patients with RCC and other solid tumors; phase II in patients with VHL). Median (range) age for the combined studies was 55 years (19-84) and body weight was 73.6 kg (42.1-165.8). Belzutifan plasma PK was well-characterized by a linear two-compartment model with first-order absorption and elimination. For patients with VHL, the predicted geometric mean (% coefficient of variation) apparent clearance was 7.3 L/h (51%), apparent total volume of distribution was 130 L (35%), and half-life was 12.39 h (42%). There were no clinically relevant differences in belzutifan PK based on the individual covariates of age, sex, ethnicity, race, body weight, mild/moderate renal impairment, or mild hepatic impairment. In this model, dual UGT2B17 and CYP2C19 poor metabolizers (PMs) were estimated to have a 3.2-fold higher area under the plasma concentration-time curve compared to UGT2B17 extensive metabolizer and CYP2C19 non-PM patients. This population PK analysis enabled an integrated assessment of PK characteristics with covariate effects in the overall population and subpopulations for belzutifan labeling., (© 2023 Merck Sharp & Dohme LLC. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

In the CLEAR trial, lenvatinib plus pembrolizumab met study endpoints of superiority vs sunitinib in the first-line treatment of patients with advanced renal cell carcinoma. We report the efficacy and safety results of the East Asian subset (ie, patients in Japan and the Republic of Korea) from the CLEAR trial. Of 1069 patients randomly assigned to receive either lenvatinib plus pembrolizumab, lenvatinib plus everolimus or sunitinib, 213 (20.0%) were from East Asia. Baseline characteristics of patients in the East Asian subset were generally comparable with those of the global trial population. In the East Asian subset, progression-free survival was considerably longer with lenvatinib plus pembrolizumab vs sunitinib (median 22.1 vs 11.1 months; HR 0.38; 95% CI: 0.23-0.62). The HR for overall survival comparing lenvatinib plus pembrolizumab vs sunitinib was 0.71; 95% CI: 0.30-1.71. The objective response rate was higher with lenvatinib plus pembrolizumab vs sunitinib (65.3% vs 49.2%; odds ratio 2.14; 95% CI: 1.07-4.28). Dose reductions due to treatment-emergent adverse events (TEAEs) commonly associated with tyrosine kinase inhibitors occurred more frequently than in the global population. Hand-foot syndrome was the most frequent any-grade TEAE with lenvatinib plus pembrolizumab (66.7%) and sunitinib (57.8%), a higher incidence compared to the global population (28.7% and 37.4%, respectively). The most common grade 3 to 5 TEAEs were hypertension with lenvatinib plus pembrolizumab (20%) and decreased platelet count with sunitinib (21.9%). Efficacy and safety for patients in the East Asian subset were generally similar to those of the global population, except as noted., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Immunotherapy-based combinations including pembrolizumab plus lenvatinib are the standard of care for patients with first-line clear-cell renal cell carcinoma, but these combinations are not well characterised in non-clear-cell renal cell carcinoma. We aimed to assess the activity and safety of pembrolizumab plus lenvatinib as a first-line treatment for patients with advanced non-clear-cell renal cell carcinoma., Methods: KEYNOTE-B61 is a single-arm, phase 2 trial being conducted at 48 sites (hospitals and cancer centres) in 14 countries (Australia, Canada, France, Hungary, Ireland, Italy, Poland, South Korea, Russia, Spain, Türkiye, Ukraine, the UK, and the USA). Adult patients (aged ≥18 years) with previously untreated stage IV non-clear-cell renal cell carcinoma and a Karnofsky performance status of 70% or higher were eligible for enrolment. All enrolled patients received pembrolizumab 400 mg intravenously every 6 weeks for up to 18 cycles (2 years) plus lenvatinib 20 mg orally once daily or until disease progression, unacceptable toxicity, or withdrawal; lenvatinib could be continued beyond 2 years. The primary endpoint was the proportion of patients with a confirmed objective response as per adjusted Response Evaluation Criteria in Solid Tumours (version 1.1) assessed by independent central review. Activity and safety were analysed in all patients who received at least one dose of study treatment (the as-treated population). This trial is registered with ClinicalTrials.gov (NCT04704219) and is no longer recruiting participants but is ongoing., Findings: Between Feb 23, 2021, and Jan 21, 2022, 215 patients were screened; 158 were enrolled and received treatment. Median age at baseline was 60 years (IQR 52-69), 112 (71%) of 158 patients were male, 46 (29%) were female, 128 (81%) were White, 12 (8%) were Asian, three (2%) were Black or African American, and 15 (9%) were missing data on race. As of data cutoff (Nov 7, 2022), median study follow-up was 14·9 months (IQR 11·1-17·4). 78 of 158 patients had a confirmed objective response (49%; 95% CI 41-57), including nine (6%) patients with a confirmed complete response and 69 (44%) with a confirmed partial response. Grade 3-4 treatment-related adverse events occurred in 81 (51%) of 158 patients, the most common of which were hypertension (37 [23%] of 158), proteinuria (seven [4%]), and stomatitis (six [4%]). Serious treatment-related adverse events occurred in 31 (20%) of 158 patients. Eight (5%) patients died due to adverse events, none of which was considered related to the treatment by the investigators (one each of cardiac failure, peritonitis, pneumonia, sepsis, cerebrovascular accident, suicide, pneumothorax, and pulmonary embolism)., Interpretation: Pembrolizumab plus lenvatinib has durable antitumour activity in patients with previously untreated advanced non-clear-cell renal cell carcinoma, with a safety profile consistent with that of previous studies. Results from KEYNOTE-B61 support the use of pembrolizumab plus lenvatinib as a first-line treatment option for these patients., Funding: Merck Sharp & Dohme (a subsidiary of Merck & Co, NJ, USA), and Eisai., Competing Interests: Declaration of interests LA reports consulting fees (paid to their institution) from Astellas, Bristol Myers Squibb, Ipsen, Janssen, Merck, MSD, Pfizer, Eisai, and Roche; and travel expenses from Bristol Myers Squibb, MSD, and Ipsen. HG has received honoraria from Pfizer and MSD; and participated on advisory boards for Pfizer, Merck Serono, MSD, Ipsen, Bristol Myers Squibb, and Astellas. CS has received research support from Ipsen; honoraria from Bristol Myers Squibb, Pfizer, Roche, Astellas, Ipsen, Sanofi, Bayer, and MSD; and travel support from Bristol Myers Squibb, Pfizer, Roche, Astellas, Ipsen, Sanofi, Bayer, and MSD. MAC has received honoraria from Bristol Myers Squibb, Roche, MSD, Ipsen, EUSA, AstraZeneca, Merck, Pfizer, Astellas, Janssen, and Bayer; and travel support from Astellas, Janssen, Bayer, Roche, MSD, Merck, and Pfizer. DP has received honoraria from Bayer and Merck/Pfizer; travel support from Merck/Pfizer and Janssen, and participated in advisory boards for Merck/Pfizer, Bristol Myers Squibb, and MSD. PB has received research support from MSD, Bristol Myers Squibb, Ipsen, Pfizer, Merck, AstraZeneca, and Janssen; consulting fees from Bristol Myers Squibb, Ipsen, MSD, Merck, Pfizer, Janssen-Cilag, Astellas, Amgen, Gilead, Eisai, and AstraZeneca; honoraria from Bristol Myers Squibb, Ipsen, MSD, Merck, Pfizer, Janssen-Cilag, Astellas, Bayer, Novartis, Eisai, and AstraZeneca; travel support from Bristol Myers Squibb, Ipsen, MSD, Merck, Pfizer, Janssen-Cilag, and Astellas; and participated on a data safety monitoring board or advisory board for Orion. JLL has received research support (paid to their institution) from Pfizer, Ipsen, Bristol Myers Squibb, MSD, Merck, Roche, Genentech, AstraZeneca, Amgen, SeaGen, and GI Innovation; participated on a data safety monitoring board or advisory board for Pfizer Korea, Astellas Korea, Bristol Myers Squibb, Merck, MSD, AstraZeneca, Amgen, and GI Innovation; and has stocks in Amgen, Johnson and Johnson, and Merck. VS has received research support from Merck Sharp & Dohme (a subsidiary of Merck & Co, Rahway, NJ, USA); honoraria from Pfizer Export BV, Stada-Ukraine, Kyiv Vitamin Plant, Astellas Pharma, PrJSC Pharmaceutical firm Darnytsia, and Pharma Personal Group Bionorica. TF has received research support from MSD; and travel support from Bayer and MSD. PW has received consulting fees and honoraria from Astellas Pharma and MSD, Bayer, Janssen Cilag, Ipsen, Pfizer, and Merck; travel support from Pfizer; and has participated on advisory boards for Astellas Pharma, MSD, Bayer, Janssen Cilag, Ipsen, Pfizer, and Merck. EG has received honoraria from Eli Lilly, Roche, Pfizer, Novartis, Janssen Oncology, Astellas Pharma, Amgen, AstraZeneca, Bristol Myers Squibb, Gilead Sciences, Sandoz-Novartis, Abdi Ibrahim, MSD Oncology, and Genekor; travel support from Roche, Pfizer, Novartis, Janssen Oncology, Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Sciences, and Abdi Ibrahim; participated on advisory boards for Eli Lilly, Roche, Pfizer, Novartis, AstraZeneca, Bristol Myers Squibb, Gilead Sciences, Sandoz-Novartis, and MSD Oncology; and owns stock in ImmunoGen and MacroGenics. CG has received consulting fees from Cadex Genomics and BCAL Diagnostics, participated on a data safety monitoring board or advisory board for Alloplex Biotherapeutics, and was a member of a scientific advisory committee for Brain Cancer Biobanking Australia, Cooperative Trials Group for Neuro-Oncology, Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Mark Hughes Foundation, and International Kidney Cancer Coalition. RFP, MS, and XP are employees of Merck & Co (Rahway, NJ, USA). C-HL has received research support (paid to institution) from Merck, Eisai, AstraZeneca, Bristol Myers Squibb, Calithera Biosciences, and Exelixis; consulting fees from Aveo, Bristol Myers Squibb, Exelixis, Eisai, Merck, Pfizer, EMD Serono, and Cardinal; honoraria from AiCME, IDEOlogy Health, Intellisphere, MJH Life Sciences, Medscape, and Research to Practice; and is on the medical steering committee for the Kidney Cancer Association. PT, LL, and VA declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Lenvatinib plus pembrolizumab showed significantly improved progression-free and overall survival outcomes compared with sunitinib in patients with advanced renal cell carcinoma in the CLEAR study (NCT02811861). Here, we used CLEAR data to characterize common adverse reactions (ARs; adverse-event preferred terms grouped in accordance with regulatory authority review) associated with lenvatinib plus pembrolizumab and review management strategies for select ARs., Materials and Methods: Safety data from the 352 patients who received lenvatinib plus pembrolizumab in the CLEAR study were analyzed. Key ARs were chosen based on frequency of occurrence (≥30%). Time to first onset and management strategies for key ARs were detailed., Results: The most frequent ARs were fatigue (63.1%), diarrhea (61.9%), musculoskeletal pain (58.0%), hypothyroidism (56.8%), and hypertension (56.3%); grade ≥3 severity ARs that occurred in ≥5% of patients were hypertension (28.7%), diarrhea (9.9%), fatigue (9.4%), weight decreased (8.0%), and proteinuria (7.7%). Median times to first onset of all key ARs were within approximately 5 months (approximately 20 weeks) of starting treatment. Strategies for effectively managing ARs included baseline monitoring, drug-dose modifications, and/or concomitant medications., Conclusion: The safety profile of lenvatinib plus pembrolizumab was consistent with the known profile of each monotherapy; ARs were considered manageable with strategies including monitoring, dose modifications, and supportive medications. Proactive and prompt identification and management of ARs are important for patient safety and to support continued treatment., Clinicaltrials.gov Id: NCT02811861., (© The Author(s) 2023. Published by Oxford University Press.)

Background: In the primary analysis of the CLEAR study, lenvatinib plus pembrolizumab significantly improved progression-free survival and overall survival versus sunitinib in patients with advanced renal cell carcinoma (data cutoff Aug 28, 2020). We aimed to assess overall survival based on 7 months of additional follow-up., Methods: This is a protocol-prespecified updated overall survival analysis (data cutoff March 31, 2021) of the open-label, phase 3, randomised CLEAR trial. Patients with clear-cell advanced renal cell carcinoma who had not received any systemic anticancer therapy for renal cell carcinoma, including anti-vascular endothelial growth factor therapy, or any systemic investigational anticancer drug, were eligible for inclusion from 200 sites (hospitals and cancer centres) across 20 countries. Patients were randomly assigned (1:1:1) to receive lenvatinib (20 mg per day orally in 21-day cycles) plus pembrolizumab (200 mg intravenously every 21 days; lenvatinib plus pembrolizumab group), lenvatinib (18 mg per day orally) plus everolimus (5 mg per day orally; lenvatinib plus everolimus group [not reported in this updated analysis]) in 21-day cycles, or sunitinib (50 mg per day orally, 4 weeks on and 2 weeks off; sunitinib group). Eligible patients were at least 18 years old with a Karnofsky performance status of 70 or higher. A computer-generated randomisation scheme was used, and stratification factors were geographical region and Memorial Sloan Kettering Cancer Center prognostic groups. The primary endpoint was progression-free survival assessed by independent imaging review according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). In this Article, extended follow-up analyses for progression-free survival and protocol-specified updated overall survival data are reported for the intention-to-treat population. No safety analyses were done at this follow-up. This study is closed to new participants and is registered with ClinicalTrials.gov, NCT02811861., Findings: Between Oct 13, 2016, and July 24, 2019, 1417 patients were screened for inclusion in the CLEAR trial, of whom 1069 (75%; 273 [26%] female, 796 [74%] male; median age 62 years [IQR 55-69]) were randomly assigned: 355 (33%) patients (255 [72%] male and 100 [28%] female) to the lenvatinib plus pembrolizumab group, 357 (33%) patients (275 [77%] male and 82 [23%] female) to the sunitinib group, and 357 (33%) patients to the lenvatinib plus everolimus group (not reported in this updated analysis). Median follow-up for progression-free survival was 27·8 months (IQR 20·3-33·8) in the lenvatinib plus pembrolizumab group and 19·4 months (5·5-32·5) in the sunitinib group. Median progression-free survival was 23·3 months (95% CI 20·8-27·7) in the lenvatinib plus pembrolizumab group and 9·2 months (6·0-11·0) in the sunitinib group (stratified hazard ratio [HR] 0·42 [95% CI 0·34-0·52]). Median overall survival follow-up was 33·7 months (IQR 27·4-36·9) in the lenvatinib plus pembrolizumab group and 33·4 months (26·7-36·8) in the sunitinib group. Overall survival was improved with lenvatinib plus pembrolizumab (median not reached [95% CI 41·5-not estimable]) versus sunitinib (median not reached [38·4-not estimable]; HR 0·72 [95% CI 0·55-0·93])., Interpretation: Efficacy benefits of lenvatinib plus pembrolizumab over sunitinib were durable and clinically meaningful with extended follow-up. These results support the use of lenvatinib plus pembrolizumab as a first-line therapy for patients with advanced renal cell carcinoma., Funding: Eisai and Merck Sharp & Dohme., Competing Interests: Declaration of interests TKC reports research funding, paid to their institution, from AstraZeneca, Aveo, Bayer, Bristol-Myers Squibb, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Lilly, Merck, Nikang, Novartis, Pfizer, Roche, Sanofi/Aventis, and Takeda; consulting fees from AstraZeneca, Aravive, Aveo, Bayer, Bristol-Myers Squibb, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infiniti, Ipsen, Kanaph, Lilly, Merck, Nikang, Novartis, Nuscan, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, Takeda, Tempest, Up-To-Date, and CME events; payment or honoraria for lectures, presentations, manuscript writing, or educational events from AstraZeneca, Aravive, Aveo, Bayer, Bristol-Myers Squibb, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infiniti, Ipsen, Kanaph, Lilly, Merck, Nikang, Novartis, Pfizer, Roche, Sanofi/Aventis, Takeda, Tempest, Up-To-Date, and CME events; support for attending meetings or travel from Eisai, Merck, Exelixis, and Pfizer; patents planned, issued, or pending related to ctDNA and biomarkers of response to immune checkpoint inhibitors (no royalties as of April 12, 2022); participated on a data safety monitoring board or advisory board for Aravive; a leadership or fiduciary role in other board, society, committee, or advocacy group, for KidneyCan (unpaid), committees for American Society of Clinical Oncology, European Society for Medical Oncology, National Comprehensive Cancer Network®, and Genitourinary Steering Committee of the National Cancer Institute; stock or stock options from Pionyr, Tempest, Precede Bio, and Osel; and salary and research support from Dana-Farber and Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School, and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at Dana-Farber Cancer Institute. ME reports research funding from Kissei, Sanofi, Astellas, ONO, Takeda, and Bayer; and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from MSD, ONO, Chugai, Novartis, Pfizer, Bristol Myers Squibb, Takeda, Janssen, and Merck. RM reports research funding, paid to their institution from Bristol Myers Squibb, Eisai, Exelixis, Genentech/Roche, Merck, Pfizer, and Aveo Pharmaceuticals and consulting fees from AstraZeneca, Aveo Pharmaceuticals, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly, Merck, Novartis, Pfizer, and Takeda. UDG reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis oncology, Eisai, Janssen, MSD, Pfizer, Ipsen, and Roche and support for attending meetings or travel from Janssen, Bristol-Myers Squibb, and Ipsen. TB reports research support, paid to their institution from AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Merck, and Novartis; consulting fees from Bristol Myers Squibb, Astellas, Janssen, and Sanofi/Aventis; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Bristol-Myers Squibb, Servier, and Pfizer; and receipt of equipment, materials, drugs, medical writing, gifts, or other services, paid to their institution from Bristol-Myers Squibb, AstraZeneca, Roche, and Servier. NSB reports consulting fees from Bristol-Myers Squibb, Ipsen, Eisai, Janssen, Pfizer, Roche, Merck, EMD Serono, AstraZeneca, and Bayer; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events (personal) from Bristol-Myers Squibb, Ipsen, and Merck; and support for attending meetings or travel from Eisai and Janssen. MJM-V reports consulting fees from Astellas Pharma, Bristol-Myers Squibb, EUSA Pharma, Ipsen, Eisai, Janssen-Cilag, Novartis, Pfizer, Roche, and Sanofi; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Astellas Pharma, Bristol-Myers Squibb, Ipsen, EUSA Pharma, Janssen-Cilag, Pfizer, and Roche; and support for attending meetings or travel from Astellas Pharma, Bristol-Myers Squibb, Ipsen, Janssen-Cilag, Pfizer, and Roche. BM reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Roche, Pfizer, Bristol-Myers Squibb, Astellas, Novartis, Bayer, MSD, Merck Serono, Sanofi, Servier, AstraZeneca, Amgen, Janssen, Eisai, E Lilly, and Pierre Farbre; support for attending meetings or travel from Bristol-Myers Squibb and Merck Serono; and participation on a data safety monitoring board or advisory board for Roche, Pfizer, Bristol-Myers Squibb, Astellas, Novartis, Bayer, MSD, Merck Serono, Sanofi, Servier, AstraZeneca, Amgen, Janssen, Eisai, E Lilly, and Pierre Farbre. TH reports grants or contracts, paid to their institution, from Bristol-Myers Squibb, Eisai, Exelixis, Johnson & Johnson, and Pfizer; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Astellas Pharma, Bristol-Myers Squibb, Eisai, Exelixis, Johnson & Johnson, and Pfizer; and participation on a data safety monitoring board or advisory board for Astellas Pharma, Bayer/Onyx, Bristol Myers Squibb, Exelixis, Johnson & Johnson, Novartis, and Pfizer. BMcG reports grants or contracts, paid to their institution from Exelixis, SeaGen, Pfizer, Bristol Myers Squibb and consulting fees from Astellas, Bristol-Myers Squibb, Calithera, Eisai, Exelixis, Pfizer, and SeaGen. TP reports research funding from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; consulting fees from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; support for attending meetings or travel Astra Zeneca, Ipsen, MSD, Pfizer, and Roche. VG reports grants or contracts, paid to their institution, from AstraZeneca, Bristol-Myers Squibb, MSD, Pfizer, Ipsen; consulting fees from Bristol-Myers Squibb, Pfizer, Roche, MSD, Oncorena, PCI Biotech, Nanobiotix, Merck Serono, EUSA Pharm, Debiopharm, Eisai, and Apogepha; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Eisai, Ipsen, Janssen-Cilag, Merck Serono, MSD, Novartis, Pfizer, Roche, AstraZeneca, and Astellas; support for attending meetings or travel from Pfizer and Merck; participation on a data safety monitoring board or advisory board for Bristol-Myers Squibb, Ipsen, Eisai, PharmaMar, and PharmaMar; leadership or fiduciary role in other board, society, committee, or advocacy group from National Working Group AIO (Working Group on Internal Oncology in the German Cancer Society), German Cancer Society; and stock or stock options in AstraZeneca, Bristol-Myers Squibb, MSD, and SeaGen. BA reports grants or contracts from Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Ipsen, Janssen, Merck, MSD, Pfizer, and Roche; consulting fees from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck, MSD, Pfizer, and Roche; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events: Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck, MSD, Pfizer, Roche; payment for expert testimony from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck, MSD, Pfizer, and Roche; and support for attending meetings or travel from Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Ipsen, Janssen, Merck, MSD, Pfizer, and Roche. SYR reports grants or contracts from Amgen, Merck, Bristol-Myers Squibb, MSD, Lilly, Daiichi Sankyo, Beigene, Eisai, and AstraZeneca; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Amgen, Lilly, Bristol-Myers Squibb, MSD, and Eisai; and participation on a data safety monitoring board or advisory board from Amgen, MSD, Bristol-Myers Squibb, Merck, Indivumed, Beigene, Eisai, and Daiichi Sankyo. AK reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Merck, Bristol-Myers Squibb, Ipsen, Eisai, Janssen, AbbVie; leadership or fiduciary role in for Kidney Cancer Canada; and stock in Verity Pharma. TAG reports grants or contracts from Pfizer, Roche, and Ipsen; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Lilly, Pfizer, Roche, Bristol-Myers Squibb, MSD, Eisai, Bayer, Janssen, Sanofi, and Astellas. JCG reports consulting fees for an advisory board meeting from Merck Sharp & Dohme (Australia), Bristol-Myers Squibb, and GlaxoSmithKline; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Janssen–Cilag, Ipsen, Merck Sharp and Dohme (Australia), and AstraZeneca (Australia); and support for attending meetings or travel AstraZeneca (Australia), GlaxoSmithKline, and MSD. MS reports grants or contracts from Pfizer, GlaxoSmithKline, AVEO, Bristol Myers Squibb, Novartis, Bayer, Roche/Genentech, Immatics, Wilex, Ipsen, Exelixis, and Eisai; consulting fees from Pfizer, GlaxoSmithKline, Novartis, Bayer, Roche, Aveo, EUSA Pharm, Astellas, Ipsen, Exelixis, Pelloton, Eisai, Bristol-Myers Squibb, MSD, Apogepha, and Oncorena; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Pfizer, GlaxoSmithKline, AVEO, Novartis, Bayer, EUSA Pharma, Astellas, Ipsen, Exelixis, Pelloton, Eisai, Bristol-Myers Squibb, MSD, and Apogepha; and support for attending meetings or travel from Pfizer, EUSAPharm, Ipsen, Eisai, Bristol-Myers Squibb, MSD, and Apogepha. JRM reports grants or contracts, paid to their institution from Corvus Pharmaceuticals, Eisai, Genentech/Roche, Lilly, Merck, Novartis, Peloton Therapeutics, Pfizer, Replimune, Seattle Genetics/Astellas, Sillajen, Tizona Therapeutics, Tocagen, and Vyriad, and consulting fees from Exelixis. RX, KM, and JMcK are employees of Eisai. RFP is an employee of and holds stock in Merck, Rahway, NJ, USA. CGP reports consulting fees from Angelini Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Ipsen, and MSD; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Angelini Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, General Electric, Ipsen, and MSD; and participation on a data safety monitoring board or advisory board for Bristol-Myers Squibb, Eisai, MSD, the European Society of Medical Oncology, and the Italian Association for Medical Oncology. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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.)

Background: Results from the phase 3 CLEAR study showed that lenvatinib plus pembrolizumab improved progression-free survival and overall survival compared with sunitinib in patients with advanced renal cell carcinoma. We aimed to assess the health-related quality-of-life (HRQOL) outcomes from the CLEAR study., Methods: This open-label, randomised, phase 3 study was done across 200 hospitals and cancer centres in 20 countries. Patients were required to be 18 years or older, with advanced clear-cell renal cell carcinoma, and a Karnofsky performance status of 70% or higher. Patients who had received previous systemic anticancer therapy for renal cell carcinoma were not eligible. Patients were randomly assigned (1:1:1) to lenvatinib (oral 20 mg per day) plus pembrolizumab (intravenous 200 mg every 21 days), lenvatinib (oral 18 mg per day) plus everolimus (oral 5 mg per day) in 21-day cycles, or sunitinib (oral 50 mg per day, 4 weeks on followed by 2 weeks off). Patients were assigned to treatments with a computer-generated randomisation scheme and were stratified by geographical region and Memorial Sloan Kettering Cancer Center prognostic groups. The primary endpoint, previously reported, was progression-free survival, and HRQOL was a secondary endpoint. Most HRQOL analyses were done in patients who underwent randomisation, received at least one dose of study treatment, and had any HRQOL data. Completion and compliance analyses were done in the full analysis set. Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease-Related Symptoms (FKSI-DRS), European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), and the EQ-5D-3 Level (EQ-5D-3L) preference questionnaire were administered at baseline and on day 1 of each subsequent 21-day cycle. This study is registered with ClinicalTrials.gov, NCT02811861, and is closed to new participants., Findings: Between Oct 13, 2016, and July 24, 2019, 355 patients were randomly assigned to the lenvatinib plus pembrolizumab group, 357 to the lenvatinib plus everolimus group, and 357 to the sunitinib group. Median follow-up for HRQOL analyses was 12·9 months (IQR 5·6-22·3). Because of the promising efficacy and safety results of lenvatinib plus pembrolizumab in the first-line setting, we focus the HRQOL results in this report on that combination versus sunitinib. Mean change from baseline in the lenvatinib plus pembrolizumab group compared with the sunitinib group was -1·75 (SE 0·59) versus -2·19 (0·66) for FKSI-DRS, -5·93 (0·86) versus -6·73 (0·94) for EORTC QLQ-C30 global health status/quality of life (GHS/QOL), and -4·96 (0·85) versus -6·64 (0·94) for the EQ-5D visual analogue scale (VAS). Median time to first deterioration in the lenvatinib plus pembrolizumab group compared with the sunitinib group was 9·14 weeks (95% CI 6·43-12·14) versus 12·14 weeks (9·14-15·29; HR 1·13 [95% CI 0·94-1·35], log-rank p=0·20) for FKSI-DRS, 12·00 weeks (7·29-15·14) versus 9·14 weeks (6·29-12·14; 0·88 [0·74-1·05], log-rank p=0·17) for EORTC QLQ-C30 GHS/QOL, and 9·43 weeks (6·43-12·29) versus 9·14 weeks (6·29-12·00; 0·83 [0·70-0·99], log-rank p=0·041) for the EQ-5D VAS. Median time to definitive deterioration in the lenvatinib plus pembrolizumab group compared with the sunitinib group was 134·14 weeks (95% CI 120·00-not estimable) versus 117·43 weeks (90·14-131·29; HR 0·70 [95% CI 0·53-0·92], log-rank p=0·0081) for FKSI-DRS, 114·29 weeks (102·14-153·29) versus 75·14 weeks (57·29-105·14; 0·60 [0·47-0·77], log-rank p<0·0001) for EORTC QLQ-C30 GHS/QOL, and 124·86 weeks (94·71-134·57) versus 74·86 weeks (54·14-96·00; 0·67 [0·53-0·85], log-rank p=0·0012) for the EQ-5D VAS. No outcomes on any of the instruments significantly favoured sunitinib over lenvatinib plus pembrolizumab. Most HRQOL comparisons of lenvatinib plus everolimus versus sunitinib were similar or favoured sunitinib., Interpretation: These HRQOL results demonstrate that patients given lenvatinib plus pembrolizumab treatment had similar or favourable scores compared with patients given sunitinib, particularly with respect to time to definitive deterioration. These results support the efficacy and safety profile of lenvatinib plus pembrolizumab as first-line therapy for patients with advanced renal cell carcinoma., Funding: Eisai (Nutley, NJ, USA) and Merck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA)., Competing Interests: Declaration of interests RM reports research funding (institutional) from Bristol Myers Squibb, Eisai, Exelixis, Genentech/Roche, Merck, and Pfizer; and consulting fees from AstraZeneca, Aveo Pharmaceuticals, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly, Merck, Novartis, and Pfizer. CP reports consulting fees and honoraria from Angelini Farma, AstraZeneca, Bristol Myers Squibb, Eisai, EUSA Pharma, General Electric, Ipsen, Janssen, Merck, Merck Sharp & Dohme (MSD), Novartis, and Pfizer; expert testimony for EUSA Pharma and Pfizer; protocol steering committee membership for Bristol Myers Squibb, Eisai, EUSA Pharma, and MSD; and travel support from Roche. BA reports support for the present manuscript from Eisai; grants or contracts from Amgen, AstraZeneca, Astellas, Bayer, Bristol Myers Squibb, Ferring, Ipsen, Janssen, Merck, MSD, Pfizer, Sanofi, and Roche; consulting fees and honoraria from Amgen, AstraZeneca, Astellas, Bayer, Bristol Myers Squibb, Ferring, Ipsen, Janssen, Merck, MSD, Pfizer, Sanofi, and Roche; expert testimony for Amgen, AstraZeneca, Astellas, Bayer, Bristol Myers Squibb, Ferring, Ipsen, Janssen, Merck, MSD, Pfizer, Sanofi, and Roche; travel support from AstraZeneca, Astellas, Bayer, Bristol Myers Squibb, Ferring, Ipsen, Janssen, Merck, MSD, Pfizer, Sanofi, and Roche; and participation on a data safety monitoring board or advisory board for Astellas, Ipsen, and Janssen. SYR reports grants or contracts and honoraria from, and participation on a data safety monitoring board or advisory board for, Eisai. TKC reports support for the present manuscript from Eisai and Merck; research funding (institutional) from AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Lilly, Merck, Nikang, Novartis, Pfizer, Roche, Sanofi/Aventis, and Takeda; patents filed, royalties, or other intellectual properties (no income as of current date) related to biomarkers of immune checkpoint blockers and circulating tumour DNA; consulting fees, honoraria, or advisory roles for Alexion, Analysis Group, Aravive, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Cerulean, Corvus, Eisai, EMD Serono, Exelixis, Foundation Medicine, Genentech, GlaxoSmithKline, Heron Therapeutics, Infinity Pharma, Ipsen, Janssen Oncology, IQVIA, Lilly, Merck, NCCN, NiKang, Novartis, Nuscan, Peloton, Pfizer, Prometheus Labs, Roche, Sanofi/Aventis, Surface Oncology, Tempest, Up-to-Date, Continuing Medical Education-related events (eg, OncLive, PVI, and MJH Life Sciences), US National Cancer Institute Genitourinary Steering Committee, American Society of Clinical Oncology, European Society for Medical Oncology, and National Comprehensive Cancer Network; travel in relation to meetings, lectures, and advisory boards; stock ownership in Pionyr and Tempest. MJM-V reports consulting fees from Astellas Pharma, Bristol Myers Squibb, EUSA Pharma, Ipsen, EISAI, Janssen-Cilag, Novartis, Pfizer, Roche, and Sanofi; honoraria from Astellas Pharma, Bristol Myers Squibb, Ipsen, EUSA Pharma, Janssen-Cilag, Pfizer, and Roche; and support for attending meetings or travel from Astellas Pharma, Bristol Myers Squibb, Ipsen, Janssen-Cilag, Pfizer, and Roche. AK reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Merck, Bristol Myers Squibb, Ipsen, Eisai, Janssen, and AbbVie; leadership or fiduciary roles in other board, society, committee, or advocacy groups, paid or unpaid; being vice chair of Kidney Cancer Canada; and stock or stock options from Verity Pharma. JCG reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca, MSD Australia (Merck), Ipsen, and Bristol Myers Squibb; participation on a data safety monitoring board or advisory board for Bristol Myers Squibb and Janssen (Johnson & Johnson); and stock or stock options from ICON Cancer Care, Australia. ME reports research funding from Kissei, Sanofi, Astellas, ONO, Takeda, and Bayer; and honoraria for lectures from MSD, ONO, Chugai, Novartis, Pfizer, Bristol Myers Squibb, Takeda, Janssen, and Merck. LB and JW are employees of RTI Health Solutions, which was contracted by Eisai, to perform statistical analyses reported in this manuscript. JJP and CSH are full-time employees of Eisai. TLS is a paid employee of and shareholder in Merck & Co. RFP is an employee and a stock owner of Merck & Co. KM is an employee of Eisai. DC reports consulting fees (personal) from Eisai, Bristol Myers Squibb, Pfizer, Merck, Novartis, Ipsen, and Evidera, and is president of FACIT.org. S-HH declares no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Patients with von Hippel-Lindau (VHL) disease have a high incidence of renal cell carcinoma owing to VHL gene inactivation and constitutive activation of the transcription factor hypoxia-inducible factor 2α (HIF-2α)., Methods: In this phase 2, open-label, single-group trial, we investigated the efficacy and safety of the HIF-2α inhibitor belzutifan (MK-6482, previously called PT2977), administered orally at a dose of 120 mg daily, in patients with renal cell carcinoma associated with VHL disease. The primary end point was objective response (complete or partial response) as measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1, by an independent central radiology review committee. We also assessed responses to belzutifan in patients with non-renal cell carcinoma neoplasms and the safety of belzutifan., Results: After a median follow-up of 21.8 months (range, 20.2 to 30.1), the percentage of patients with renal cell carcinoma who had an objective response was 49% (95% confidence interval, 36 to 62). Responses were also observed in patients with pancreatic lesions (47 of 61 patients [77%]) and central nervous system hemangioblastomas (15 of 50 patients [30%]). Among the 16 eyes that could be evaluated in 12 patients with retinal hemangioblastomas at baseline, all (100%) were graded as showing improvement. The most common adverse events were anemia (in 90% of the patients) and fatigue (in 66%). Seven patients discontinued treatment: four patients voluntarily discontinued, one discontinued owing to a treatment-related adverse event (grade 1 dizziness), one discontinued because of disease progression as assessed by the investigator, and one patient died (of acute toxic effects of fentanyl)., Conclusions: Belzutifan was associated with predominantly grade 1 and 2 adverse events and showed activity in patients with renal cell carcinomas and non-renal cell carcinoma neoplasms associated with VHL disease. (Funded by Merck Sharp and Dohme and others; MK-6482-004 ClinicalTrials.gov number, NCT03401788.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: Patients with renal-cell carcinoma who undergo nephrectomy have no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence., Methods: In a double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with clear-cell renal-cell carcinoma who were at high risk for recurrence after nephrectomy, with or without metastasectomy, to receive either adjuvant pembrolizumab (at a dose of 200 mg) or placebo intravenously once every 3 weeks for up to 17 cycles (approximately 1 year). The primary end point was disease-free survival according to the investigator's assessment. Overall survival was a key secondary end point. Safety was a secondary end point., Results: A total of 496 patients were randomly assigned to receive pembrolizumab, and 498 to receive placebo. At the prespecified interim analysis, the median time from randomization to the data-cutoff date was 24.1 months. Pembrolizumab therapy was associated with significantly longer disease-free survival than placebo (disease-free survival at 24 months, 77.3% vs. 68.1%; hazard ratio for recurrence or death, 0.68; 95% confidence interval [CI], 0.53 to 0.87; P = 0.002 [two-sided]). The estimated percentage of patients who remained alive at 24 months was 96.6% in the pembrolizumab group and 93.5% in the placebo group (hazard ratio for death, 0.54; 95% CI, 0.30 to 0.96). Grade 3 or higher adverse events of any cause occurred in 32.4% of the patients who received pembrolizumab and in 17.7% of those who received placebo. No deaths related to pembrolizumab therapy occurred., Conclusions: Pembrolizumab treatment led to a significant improvement in disease-free survival as compared with placebo after surgery among patients with kidney cancer who were at high risk for recurrence. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: Despite advances in the first-line treatment of metastatic renal cell carcinoma (RCC), there is an unmet need for options to address disease progression during or after treatment with immune checkpoint inhibitors (ICIs). Pembrolizumab and lenvatinib are active as monotherapies in RCC; thus, we aimed to evaluate the combination of lenvatinib plus pembrolizumab in these patients., Methods: We report results of the metastatic RCC cohort from an open-label phase 1b/2 study of lenvatinib plus pembrolizumab in patients aged at least 18 years with selected solid tumours and an Eastern Cooperative Oncology Group performance status of 0-1. Oral lenvatinib at 20 mg was given once daily along with intravenous pembrolizumab at 200 mg once every 3 weeks. Patients remained on study drug treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent. Efficacy was analysed in patients with clear cell metastatic RCC receiving study drug by previous therapy grouping: treatment naive, previously treated ICI naive (previously treated with at least one line of therapy but not with an anti-PD-1 or anti-PD-L1 ICI), and ICI pretreated (ie, anti-PD-1 or anti-PD-L1) patients. Safety was analysed in all enrolled and treated patients. The primary endpoint was the objective response rate at week 24 per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) by investigator assessment. This trial is registered with ClinicalTrials.gov (NCT02501096) and with the EU Clinical Trials Register (EudraCT2017-000300-26), and is closed to new participants., Findings: Between July 21, 2015, and Oct 16, 2019, 145 patients were enrolled in the study. Two patients had non-clear cell RCC and were excluded from the efficacy analysis (one in the treatment-naive group and one in the ICI-pretreated group); thus, the population evaluated for efficacy comprised 143 patients (n=22 in the treatment-naive group, n=17 in the previously treated ICI-naive group, and n=104 in the ICI-pretreated group). All 145 enrolled patients were included in the safety analysis. The median follow-up was 19·8 months (IQR 14·3-28·4). The number of patients with an objective response at week 24 by irRECIST was 16 (72·7%, 95% CI 49·8-89·3) of 22 treatment-naive patients, seven (41·2%, 18·4-67·1) of 17 previously treated ICI-naive patients, and 58 (55·8%, 45·7-65·5) of 104 ICI-pretreated patients. Of 145 patients, 82 (57%) had grade 3 treatment-related adverse events and ten (7%) had grade 4 treatment-related adverse events. The most common grade 3 treatment-related adverse event was hypertension (30 [21%] of 145 patients). Treatment-related serious adverse events occurred in 36 (25%) patients, and there were three treatment-related deaths (upper gastrointestinal haemorrhage, sudden death, and pneumonia)., Interpretation: Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC., Funding: Eisai and Merck Sharp & Dohme., Competing Interests: Declaration of interests C-HL received support for this Article from Eisai and Merck; grants or contracts to their institution from Eisai and Merck; consulting fees from Eisai and Merck; for attending meetings and travel from Eisai; and fees for participation in a scientific advisory committee for Merck; consulting fees from Amgen, Bristol Myers Squibb, Exelixis, Pfizer, and EMD Serono; honoraria from AiCME, Intellisphere, and Research to Practice; research funds to the institute from Bristol Myers Squibb, Calithera, Eisai, Eli Lilly, Exelixis, Merck, and Pfizer. AYS participated on an advisory board for Eisai, Exelixis, Pfizer, and Roche; and received research funding from Bristol Myers Squibb, Eisai, and EMD Serono. DR received support for this Article from Eisai. AR received grants or contracts to their institution from Eisai and Merck; consulting fees to their institution from Eli Lilly; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bayer, Cardinal Health, Eli Lilly, and Sanofi; and research funding to their institution from Clovis Oncology, Eli Lilly, Pfizer/Astellas, and Seattle Genetics/Astellas. MHT received clinical research funding for the present work to their institution from Eisai; and honoraria for participation in advisory boards and speakers' bureaus from Eisai. JJH received grants or contracts from Merck; consulting fees from BostonGene and Eisai; support for attending meetings or travel, or both from Elsevier; and stock or stock options from BostonGene. AP received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Ipsen, and Pfizer; and support for attending meetings or travel, or both, from Bristol Myers Squibb and Pfizer. RGS received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Janssen, and Roche; support for attending meetings or travel, or both, from MSD-Merck and Pfizer; and participation on a data safety monitoring board or advisory board from Bristol Myers Squibb. ALC received consulting fees from Amgen; and payment for expert testimony from the Department of Justice. NJV received support for this Article, including provision of study patients, payments to institution, medical writing, and manuscript writing charges from Eisai and Merck; consulting fees from Eisai and Merck; and payment for legal testimony from Merck. MAB received grants or contracts to their institution from Advanced Accelerator Applications, a Novartis Company, AstraZeneca, Bayer, Bristol Myers Squibb, Genentech/Roche, Genome & Company, Incyte, Nektar, Peloton Therapeutics, Pfizer, Seattle Genetics, Tricon Pharmaceuticals, and Xencor; honoraria for participation in a data safety monitoring board or advisory board for AstraZeneca, Bayer, Bristol Myers Squibb, Calithera Biosciences, Eisai, Exelixis, Genomic Health, Janssen, Nektar, Pfizer, and Sanofi. ØKT received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from Astellas and Bristol Myers Squibb; and fees for participation on a data safety monitoring board or advisory board for Bayer. RFS received grants or contracts to their institution from AbbVie, Aduro, Bayer, Bristol Myers Squibb, CytomX, Eisai, Eli Lilly, Genentech/Roche, Immunocore, Merck, Mirati, Moderna, Novartis, and QED therapeutics; consulting fees from Aduro, Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, Janssen, Mirati, Pfizer, Puma, and Seattle Genetics; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astellas, Bristol Myers Squibb, Eisai, Exelixis, Pfizer, and Seattle Genetics; support for attending meetings or travel, or both, from AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Mirati; and patents pending, PCT/US2020/031357 on neoantigens in cancer. DH received support for this Article to their institution from Eisai; consulting fees from Astellas, AstraZeneca, Bayer, Eisai, Ipsen, Janssen-Cilag, and Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Advanced Accelerator Applications, a Novartis Company, Astellas, Bayer, Bristol Myers Squibb, Ipsen, Janssen-Cilag, Novartis, and Sanofi; and participation on an advisory board for Astellas, AstraZeneca, Bayer, Eisai, Ipsen, Janssen-Cilag, and Roche; SJ has stock or stock options in Merck. EVS and RFP are employed by, and have stock or stock options in, Merck. JW and PK are employed by Eisai. CEO and ADS are employed by Eisai Europe. RJM received support for the present Article from Eisai and Merck; grants or contracts from Bristol Myers Squibb, Genentech, Novartis, Pfizer, and Roche; consulting fees from AstraZeneca, Aveo Pharmaceuticals, EMD Serono, Exelixis, Genentech, Incyte, Eli Lilly, Novartis, Pfizer, and Roche; and support for attending meetings or travel, or both, from Bristol Myers Squibb. CDS, DRS, SGR, MG, DR, and JC declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear., Methods: In this phase 3 trial, we randomly assigned (in a 1:1:1 ratio) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously once every 3 weeks), lenvatinib (18 mg orally once daily) plus everolimus (5 mg orally once daily), or sunitinib (50 mg orally once daily, alternating 4 weeks receiving treatment and 2 weeks without treatment). The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated., Results: A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels., Conclusions: Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.)., (Copyright © 2021 Massachusetts Medical Society.)

Purpose: Pembrolizumab, a programmed death 1 inhibitor, demonstrated promising single-agent activity in untreated patients with various cancer types. The phase II KEYNOTE-427 study evaluated efficacy and safety of single-agent pembrolizumab in treatment-naive patients with advanced clear cell renal cell carcinoma (ccRCC; cohort A) and advanced non-ccRCC (cohort B). Results of cohort A are reported., Methods: In this open-label, single-arm phase II study, patients with advanced ccRCC received pembrolizumab 200 mg every 3 weeks for ≤ 24 months. The primary end point was objective response rate by RECIST, version 1.1., Results: In the total population (N = 110), median time from enrollment to data cutoff was 35.9 (range, 29.5-40.3) months. Objective response rate was 36.4% with four (3.6%) complete responses and 36 (32.7%) partial responses; disease control rate was 58.2% (95% CI, 48.4 to 67.5). Most patients (68.2%) had a decrease in target lesions, including 30.9% with a reduction ≥ 60%. Median duration of response was 18.9 (range, 2.3-37.6+) months; 64.1% of responders had a response ≥ 12 months (Kaplan-Meier). Median progression-free survival was 7.1 months (95% CI, 5.6 to 11.0). Median overall survival was not reached; 12-month and 24-month overall survival rates were 88.2% and 70.8%, respectively. Durable responses were observed across all International Metastatic RCC Database Consortium categories. Grade 3-5 treatment-related adverse events were reported in 30.0% of patients, of which colitis and diarrhea were most frequent., Conclusion: Single-agent pembrolizumab showed promising antitumor activity as a first-line treatment in patients with advanced ccRCC, with durable responses across International Metastatic RCC Database Consortium categories. Safety and tolerability profile of pembrolizumab monotherapy was comparable to what has been previously described in other tumor types.

Purpose: Programmed death 1 (PD-1) pathway inhibitors have not been prospectively evaluated in patients with non-clear cell renal cell carcinoma (nccRCC). The phase II KEYNOTE-427 study (cohort B) was conducted to assess the efficacy and safety of single-agent pembrolizumab, a PD-1 inhibitor, in advanced nccRCC., Methods: Patients with histologically confirmed, measurable (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) nccRCC and no prior systemic therapy received pembrolizumab 200 mg intravenously once every 3 weeks for ≤ 24 months. The primary end point was objective response rate (ORR) per RECIST v1.1., Results: Among enrolled patients (N = 165), 71.5% had confirmed papillary, 12.7% had chromophobe, and 15.8% had unclassified RCC histology. Most patients (67.9%) had intermediate or poor International Metastatic RCC Database Consortium risk status and tumors with programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 1 (61.8%). The median time from enrollment to database cutoff was 31.5 months (range, 22.7-38.8). In all patients, the ORR was 26.7%. The median duration of response was 29.0 months; 59.7% of responses lasted ≥ 12 months. The ORR by CPS ≥ 1 and CPS < 1 status was 35.3% and 12.1%, respectively. The ORR by histology was 28.8% for papillary, 9.5% for chromophobe, and 30.8% for unclassified. Overall, the median progression-free survival was 4.2 months (95% CI, 2.9 to 5.6); the 24-month rate was 18.6%. The median overall survival was 28.9 months (95% CI, 24.3 months to not reached); the 24-month rate was 58.4%. Overall, 69.7% of patients reported treatment-related adverse events, most commonly pruritus (20.0%) and hypothyroidism (14.5%). Two deaths were treatment related (pneumonitis and cardiac arrest)., Conclusion: First-line pembrolizumab monotherapy showed promising antitumor activity in nccRCC. The safety profile was similar to that observed in other tumor types.

Objective: Pembrolizumab/axitinib significantly prolonged overall survival (OS) and progression-free survival (PFS), and increased objective response rate versus sunitinib in the phase III trial KEYNOTE-426 among previously untreated patients with advanced renal cell carcinoma (RCC). This study assessed the cost-effectiveness of pembrolizumab/axitinib versus other first-line treatments of advanced RCC from a US public healthcare payer perspective., Methods: A partitioned survival model with three states (progression-free, progressed, death) evaluated lifetime costs and quality-adjusted life-years (QALYs) for pembrolizumab/axitinib and other first-line regimens: sunitinib, pazopanib and avelumab/axitinib in the overall population; and sunitinib, cabozantinib and nivolumab/ipilimumab in the subgroup with intermediate/poor prognostic risk. Costs of treatments, adverse events and medical resources were estimated. OS, PFS and treatment duration were extrapolated using parametric models fitted to KEYNOTE-426 data and hazard ratios from network meta-analyses. Utilities were derived through mixed-effects regressions of KEYNOTE-426 EuroQol-5 Dimensions-3 Levels data., Results: In the overall population, pembrolizumab/axitinib was associated with incremental cost-effectiveness ratios (ICERs) of $95,725/QALY versus sunitinib and $128,210/QALY versus pazopanib, and was dominant (lower cost, higher effectiveness) versus avelumab/axitinib, with incremental QALY gains of 2.73, 2.40 and 1.80 versus these therapies, respectively. In the intermediate/poor-risk subgroup, base-case ICERs for pembrolizumab/axitinib were $101,030/QALY versus sunitinib, $6989/QALY versus cabozantinib, and $130,934/QALY versus nivolumab/ipilimumab, with incremental QALY gains of 2.62, 1.78 and 1.06 versus these therapies., Conclusions: In this economic evaluation, pembrolizumab/axitinib was associated with higher life expectancy and QALYs and, based on typical willingness-to-pay thresholds of $150,000-$180,000/QALY, was found cost-effective versus other first-line treatments for advanced RCC in the US.

Background: The combination of pembrolizumab and axitinib showed antitumor activity in a phase 1b trial involving patients with previously untreated advanced renal-cell carcinoma. Whether pembrolizumab plus axitinib would result in better outcomes than sunitinib in such patients was unclear., Methods: In an open-label, phase 3 trial, we randomly assigned 861 patients with previously untreated advanced clear-cell renal-cell carcinoma to receive pembrolizumab (200 mg) intravenously once every 3 weeks plus axitinib (5 mg) orally twice daily (432 patients) or sunitinib (50 mg) orally once daily for the first 4 weeks of each 6-week cycle (429 patients). The primary end points were overall survival and progression-free survival in the intention-to-treat population. The key secondary end point was the objective response rate. All reported results are from the protocol-specified first interim analysis., Results: After a median follow-up of 12.8 months, the estimated percentage of patients who were alive at 12 months was 89.9% in the pembrolizumab-axitinib group and 78.3% in the sunitinib group (hazard ratio for death, 0.53; 95% confidence interval [CI], 0.38 to 0.74; P<0.0001). Median progression-free survival was 15.1 months in the pembrolizumab-axitinib group and 11.1 months in the sunitinib group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.57 to 0.84; P<0.001). The objective response rate was 59.3% (95% CI, 54.5 to 63.9) in the pembrolizumab-axitinib group and 35.7% (95% CI, 31.1 to 40.4) in the sunitinib group (P<0.001). The benefit of pembrolizumab plus axitinib was observed across the International Metastatic Renal Cell Carcinoma Database Consortium risk groups (i.e., favorable, intermediate, and poor risk) and regardless of programmed death ligand 1 expression. Grade 3 or higher adverse events of any cause occurred in 75.8% of patients in the pembrolizumab-axitinib group and in 70.6% in the sunitinib group., Conclusions: Among patients with previously untreated advanced renal-cell carcinoma, treatment with pembrolizumab plus axitinib resulted in significantly longer overall survival and progression-free survival, as well as a higher objective response rate, than treatment with sunitinib. (Funded by Merck Sharp & Dohme; KEYNOTE-426 ClinicalTrials.gov number, NCT02853331.)., (Copyright © 2019 Massachusetts Medical Society.)

Purpose: Pembrolizumab monotherapy, ipilimumab monotherapy, and pegylated interferon alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC. Experimental Design: The phase Ib KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) included independent pembrolizumab plus reduced-dose ipilimumab and pembrolizumab plus PEG-IFN cohorts. Pembrolizumab 2 mg/kg every 3 weeks (Q3W) plus 4 doses of ipilimumab 1 mg/kg Q3W was tolerable if ≤6 of 18 patients experienced a dose-limiting toxicity (DLT). The target DLT rate for pembrolizumab 2 mg/kg Q3W plus PEG-IFN was 30%, with a maximum of 14 patients per dose level. Response was assessed per RECIST v1.1 by central review. Results: The ipilimumab cohort enrolled 22 patients, including 19 evaluable for DLTs. Six patients experienced ≥1 DLT. Grade 3 to 4 treatment-related adverse events occurred in 13 (59%) patients. Responses occurred in 5 of 12 (42%) patients with melanoma and 3 of 10 (30%) patients with RCC. In the PEG-IFN cohort, DLTs occurred in 2 of 14 (14%) patients treated at dose level 1 (PEG-IFN 1 μg/kg/week) and 2 of 3 (67%) patients treated at dose level 2 (PEG-IFN 2 μg/kg/week). Grade 3 to 4 treatment-related adverse events occurred in 10 of 17 (59%) patients. Responses occurred in 1 of 5 (20%) patients with melanoma and 2 of 12 (17%) patients with RCC. Conclusions: Pembrolizumab 2 mg/kg Q3W plus ipilimumab 1 mg/kg Q3W was tolerable and provided promising antitumor activity in patients with advanced melanoma or RCC. The maximum tolerated dose of pembrolizumab plus PEG-IFN had limited antitumor activity in this population. Clin Cancer Res; 24(8); 1805-15. ©2018 AACR ., (©2018 American Association for Cancer Research.)