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Background: Patients undergoing resection of renal cell carcinoma are at risk of disease relapse. We evaluated the effectiveness of the mammalian target of rapamycin inhibitor everolimus administered after surgery., Methods: In this randomised, double-blind, phase 3 trial, we enrolled adults with histologically confirmed renal cell carcinoma who had undergone a full surgical resection and were at intermediate-high or very high risk of recurrence at 398 academic and community institution centres in the USA. After nephrectomy, patients were randomly assigned (1:1) via a central web-based application using a dynamic balancing algorithm to receive 10 mg oral everolimus daily or placebo for 54 weeks. The primary endpoint was recurrence-free survival. Efficacy analyses included all eligible, randomly assigned patients; safety analysis included all patients who received treatment. This trial is registered with ClinicalTrials.gov, NCT01120249 and is closed to new participants., Findings: Between April 1, 2011, and Sept 15, 2016, a total of 1545 patients were randomly assigned to receive everolimus (n=775) or placebo (n=770), of whom 755 assigned to everolimus and 744 assigned to placebo were eligible for inclusion in the efficacy analysis. With a median follow-up of 76 months (IQR 61-92), recurrence-free survival was longer with everolimus than with placebo (5-year recurrence-free survival 67% [95% CI 63-70] vs 63% [60-67]; stratified log-rank p=0·050; stratified hazard ratio [HR] 0·85, 95% CI 0·72-1·00; p=0·051) but did not meet the prespecified p value for statistical significance of 0·044. Recurrence-free survival was longer with everolimus than with placebo in the very-high-risk group (HR 0·79, 95% CI 0·65-0·97; p=0·022) but not in the intermediate-high-risk group (0·99, 0·73-1·35; p=0·96). Grade 3 or higher adverse events occurred in 343 (46%) of 740 patients who received everolimus and 79 (11%) of 723 who received placebo., Interpretation: Postoperative everolimus did not improve recurrence-free survival compared with placebo among patients with renal cell carcinoma at high risk of recurrence after nephrectomy. These results do not support the adjuvant use of everolimus for renal cell carcinoma after surgery., Funding: US National Institutes of Health, National Cancer Institute, National Clinical Trials Network, Novartis Pharmaceuticals Corporation, and The Hope Foundation., Competing Interests: Declaration of interests CWR reports research funding from Ayala, Bristol Myers Squibb, Daiichi Sankyo, Deciphera, Exelixis, Genentech, Novartis, Karyopharm, Merck, Nektar, Pfizer, Xynomic, Bayer, OSI, PF Argentum IP Holdings, Rain Therapeutics, and Shasqi; consulting fees from Synox, Daiichi-Sankyo, AVEO, Exelixis, AstraZeneca, and Bristol Myers Squibb; and payment for expert testimony from Pfizer, GSK, and Boehringer Ingelheim. EIH reports research funding from Astellas Pharma, Arvinas, AstraZeneca, BioXcel Therapeutics, Bristol Myers Squibb, Calibr, Calithera Biosciences, Caris Life Sciences, Corcept Therapeutics, Corvis Pharmaceuticals, Daiichi Sankyo, Eisai, Exelixis, Five Prime Therapeutics, Fortis Therapeutics, GSK, Gilead Sciences, Harpoon Therapeutics, Roche, Infinity Pharmaceuticals, iTeos Therapeutics, Janssen, Merck Sharp & Dohme, Merck, Mirati Therapeutics, Modra Pharmaceuticals, Oncolys BioPharma, Peloton Therapeutics, Pfizer, Pharmacyclics, POINT Biopharma, and Seattle Genetics; consulting fees from Astellas Pharma; honoraria from Bayer, Sanofi, and Seattle Genetics; support for attending meetings and travel from Astellas Pharma, Caris Life Sciences, Sanofi, and Seattle Genetics; participation on a data safety monitoring board or advisory board for Astellas Pharma, AstraZeneca, Bayer, Sanofi, and Janssen; and leadership or fiduciary role for Zero End of Cancer and Michigan American Cancer Society. MNS reports grants or contracts from Advaxis, Harpoon, Bristol Myers Squibb, Genocea, Bellicum, Xencor, Exelixis, and Seattle Genetics; consulting fees from Janssen, Exelixis, Bristol Myers Squibb, and Xencor; and data safety monitoring board or advisory board participation for AstraZeneca. ASA reports consulting fees from Bristol Myers Squibb, Pfizer, and AstraZeneca; data safety monitoring board or advisory board participation for Eisai; and research grants paid from Merck, Bristol Myers Squibb, V Foundation, AstraZeneca, and NCCN. SKP reports support for attending meetings and travel from Ipsen and CRISPR Therapeutics. IP reports consulting fees from Nouscom, Iovance, Nektar, and Regeneron. JIC reports grants or contracts from Merck, Bristol Myers Squibb, Aveo, Instil Bio, Hookipa, and Castle Biosciences. TKC reports support for research, advisory boards, consultancy, and honoraria from AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GSK, IQVA, Infinity, Ipsen, Janssen, Kanaph, Lilly, Merck, Nikang, Nuscan, Novartis, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, Takeda, Tempest, Up-To-Date, and CME events (Peerview, OncLive, MJH, and others); institutional patents filed on molecular alterations and immunotherapy response and toxicity, and ctDNA; equity interest in Tempest, Pionyr, Osel, Precede Bio, and CureResponse; committee participation in NCCN, NCI GU Steering Committee, ASCO/ESMO, ACCRU, and KidneyCan; and grant funding from Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan Mass Challenge, Hinda and Arthur Marcus Fund, and Loker Pinard Funds for Kidney Cancer Research at DFCI. NA reports research funding from Arnivas, Astellas, AstraZeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Crispr, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, GSK, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon; and consulting fees from Eisai, Seattle Genetics, EMD Serono, Janssen, Exelixis, Bayer, Astellas, AstraZeneca, Immunomedics, Bristol Myers Squibb, Aveo, Genentech, Merck, Lilly, Gilead, and Foundation Medicine. RGU reports a leadership or fiduciary role for Haymarket Media, Genentech, and Merck. NBH reports grants or contracts from DOD KCRC Clinical Consortium Award; consulting fees from Merck, Eisai, Bristol Myers Squibb, Aveo, and Exelixis; participation on a data safety monitoring board or advisory board for Roche; a leadership or fiduciary role for NIH GU Steering Committee; and being ECOG-ACRIN GU co-chair. UNV reports grants or contracts from Merck and Bristol Myers Squibb; consulting fees from Bayer, Exelixis, Merck, Gilead, Bristol Myers Squibb, and Alekermes; honoraria from Sanofi, Bayer, and Exelixis; and a leadership or fiduciary role for Michigan Society of Hematology/Oncology. IMT reports NCI and SWOG funding for SWOG GU Committee Chair. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Everolimus, an oral inhibitor of mammalian target of rapamycin, can augment the efficacy of HER inhibitors in preclinical studies. This study was conducted to determine the safety and pharmacokinetics (PK) of the combination of lapatinib, a Her1 and 2 inhibitor, and everolimus and to describe its anti-tumor activity in the Phase I setting., Methods: In Part I, dose escalation to define the maximum tolerated dose (MTD) was performed. In Part II, PK of both drugs were analyzed to assess drug-drug interaction., Results: Twenty-three evaluable patients with advanced cancers were treated on six different dose levels in Part I of the study. The dose-limiting toxicities were diarrhea, rash, mucositis, and fatigue. The MTD of the combination was 1,250 mg of lapatinib and 5 mg of everolimus once daily. In Part II of the study, 54 patients were treated with the combination at the MTD. The mean everolimus time to maximum concentration was increased by 44 %, and mean clearance was decreased by 25 % when co-administered with lapatinib, though these differences were not statistically significant. There was no significant influence on the PK of lapatinib by everolimus. Two patients achieved a partial response [thymic cancer (45+ months) and breast cancer (unconfirmed PR; 7 months)]; 11 patients attained stable disease of at least 4 months., Conclusions: Lapatinib and everolimus are well tolerated at doses of 1,250 and 5 mg po daily, respectively. Stable disease ≥4 months/PR was achieved in 13 of 78 patients (17 %).