LBA88 - Belzutifan versus everolimus in participants (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC): Randomized open-label phase III LITESPARK-005 study

Background

Belzutifan is a first-in-class oral HIF-2α inhibitor approved in the US for patients with VHL disease-associated RCC, pNET and CNS hemangioblastoma and has antitumor activity in ccRCC. The phase 3 LITESPARK-005 study (NCT04195750) compares belzutifan vs everolimus in pretreated advanced ccRCC.

Methods

Pts aged ≥18 yrs with KPS ≥70% and advanced ccRCC (1-3 prior systemic regimens including anti–PD-[L]1 mAb and VEGF-TKI) were randomized 1:1 to belzutifan 120 mg QD or everolimus 10 mg QD until progression or unacceptable toxicity. Dual primary endpoints were PFS per RECIST 1.1 by blinded independent central review (BICR) and OS. Secondary endpoints included ORR per RECIST 1.1 by BICR (key), safety and time to deterioration (TTD) per FKSI-DRS. PFS, ORR were formally tested at first interim analysis (IA1).

Results

374 pts were randomized to belzutifan, 372 to everolimus. At IA1 (median follow up [fu] 18.4 mo; range 9.4–31.7), PFS and ORR were superior with belzutifan vs everolimus (Table); OS did not reach statistical significance. At IA2 (median fu 25.7 mo; range 16.8–39.1), PFS, OS and ORR results were consistent with IA1. Complete responses occurred in 13 (3.5%) vs 0 pts with belzutifan vs everolimus. More pts remained progression-free with belzutifan vs everolimus at 12 mo (PFS rate 33.7% vs 17.6%) and 18 mo (22.5% vs 9.0%). 22.6% vs 5.0% of pts had ongoing treatment; 5.9% vs 14.7% of pts discontinued study therapy due to any AE. Grade 3-5 TRAEs occurred in 38.7% vs 39.4% of pts. TTD for FKSI-DRS favored belzutifan (median not reached vs 12.0 mo; HR 0.53; 95% CI 0.41–0.69; nominal P<.0001). Table: LBA88

* denotes statistical significance.

Conclusions

Belzutifan was associated with a statistically significant improvement in PFS and ORR vs everolimus for pts with advanced ccRCC after immune checkpoint and anti-angiogenic therapies. The safety profile of belzutifan was consistent with prior reports with no new safety signals.

Clinical trial identification

MK-6482 LITESPARK-005; (NCT04195750).

Editorial acknowledgement

Writing assistance was provided by Ina Nikolaeva of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Funding

Funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure

L. Albiges: Financial Interests, Institutional, Other, Consulting: Astellas, BMS, EISAI, Ipsen, Janssen, MSD, Novartis, Pfizer, Roche; Non-Financial Interests, Principal Investigator, Clinical trial steering committee: Pfizer, BMS, AVEO, AstraZeneca, MSD; Non-Financial Interests, Principal Investigator: Ipsen; Non-Financial Interests, Other, Clinical trial steering committee: Roche, Exelixis; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Other, Medical Steering Committee: Kidney Cancer Association; Non-Financial Interests, Other, Member of the Renal Cell Carcinoma Guidelines Panel: European Association of Urology (EAU). B.I. Rini: Financial Interests, Personal, Advisory Board: Merck, BMS, AVEO, Alkermes, Pfizer, Eisai, Corvus, EUSA, Debiopharm, Athenex, Surface Oncology, Genentech/Roche, Aravive; Financial Interests, Institutional, Other, Research funding to institution: BMS, Arrowhead, Aravive; Financial Interests, Personal, Stocks/Shares: PTC Therapeutics; Financial Interests, Institutional, Coordinating PI: Merck, Pionyr, Surface Oncology, Daiichi Sankyo, Adela; Financial Interests, Institutional, Steering Committee Member: Pfizer; Financial Interests, Institutional, Local PI: AstraZeneca; Financial Interests, Institutional, Funding: AVeo; Financial Interests, Institutional, Other, Study funding: Janssen. K. Peltola: Financial Interests, Personal, Advisory Board: MSD, Ipsen, Roche, BMS, Pfizer, Lilly, Novartis, Bayer; Financial Interests, Personal, Stocks/Shares: Faron Pharmaceuticals; Financial Interests, Institutional, Local PI, Conduct of sponsored clinical trial: Novartis; Financial Interests, Institutional, Local PI, Sponsored clinical trial: Exelixis; Financial Interests, Institutional, Local PI, Several clinical trials: BMS, MSD, Roche; Financial Interests, Institutional, Local PI, clinical trials: Incyte; Financial Interests, Institutional, Local PI, Conduct of clinical trials: Pfizer; Financial Interests, Institutional, Local PI, Conduct of clinical trial: Bayer. G.A. De Velasco Oria: Financial Interests, Personal, Advisory Board: Pfizer, astellas, BMS, MSD, Ipsen, Bayer, AstraZeneca, EISAI; Financial Interests, Personal, Invited Speaker: Pfizer, astellas, BMS, MSD, Roche, Ipsen, Merck, Novartis, Janssen, Bayer; Financial Interests, Institutional, Research Grant: Roche. M. Burotto: Financial Interests, Personal, Advisory Board: Roche, Merck; Financial Interests, Personal, Invited Speaker: BMS, AstraZeneca. C. Suarez Rodriguez: Financial Interests, Personal, Invited Speaker: Astellas Pharma, Bristol Myers Sqquib (Inst), IPSEN, Pfizer S.L.U, Hoffmann-La Roche LTD, Merck; Financial Interests, Personal, Advisory Board: Bristol Myers Sqquib (Inst), Ipsen, Pfizer S.L.U, Hoffmann-La Roche LTD, Merck Sharp and Dohme, eisai; Financial Interests, Institutional, Funding: Ipsen; Financial Interests, Institutional, Research Grant: pfizer. P. Ghatalia: Financial Interests, Institutional, Funding: BMS. R. Iacovelli: Financial Interests, Personal, Advisory Board: BMS, MSD, Janssen, Astellas, Ipsen, Pfizer, Bayer, Sanofi, EISAI; Financial Interests, Personal, Invited Speaker: RECORDATI; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Local PI: MSD, Seagen; Non-Financial Interests, Member: AIOM. E.T. Lam: Financial Interests, Personal, Other, Consultant: Calithera Biosciencees; Financial Interests, Institutional, Local PI, Clinical Trial Funding: Advaxis, Amgen, Arrowhead Pharmaceuticals, Astellas, Biosplice Therapeutics, Bristol-Myers-Squibb, Calithera Biosciences, Decibel Therapeutics, Exelixis, F. Hoffmann-La Roche Ltd., Forma Therapeutics, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Onquality, Peloton Therapeutics, Pfizer, Phosplatin Therapeutics; Financial Interests, Institutional, Research Grant, Funding for Investigator Initiated Study/Clinical Trial: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.. E. Verzoni: Financial Interests, Personal, Advisory Board: MSD, Janssen, AstraZeneca; Financial Interests, Personal, Invited Speaker: BMS, Astellas, Ipsen, Pfizer; Non-Financial Interests, Principal Investigator: MSD, Ipsen, Astellas, Janssen, Lilly, Pfizer. M. Gumus: Financial Interests, Institutional, Invited Speaker: Pfizer, Gen Pharmaceuticals, Novartis, Bayer; Financial Interests, Institutional, Advisory Board: Amgen, Roche, BMS, Astra-Zeneca; Financial Interests, Institutional, Coordinating PI: Amgen; Financial Interests, Institutional, Local PI: Jounce Therapeutics. W.M. Stadler: Financial Interests, Personal, Speaker, Consultant, Advisor: Astra-Zeneca, Merck, Pfizer, and Treadwell Therapeutics; Financial Interests, Personal, Sponsor/Funding: Astra-Zeneca, Caremark/CVS, EMA Wellness, Fortress Biotech; Financial Interests, Personal, Speaker’s Bureau: Dava Oncology, Global Academy for Medical Education, OncLive, PeerView, Research to P, Vindico; Financial Interests, Institutional, Research Grant: AbbVie, Amgen, Astra-Zeneca, Astellas (Medivation), Bayer, Bristol-Myers-Squibb, Boehringer-Ingelheim, Calithera, Clovis, Corvus, Eisai, Exilixis, Genentech (Roche), Johnson & Johnson (Janssen), Merck, Novartis, Pfizer, Seattle Genetics, X4Pharmaceuticals; Financial Interests, Personal, Stocks or ownership: Fortress Biotech; Financial Interests, Personal, Expert Testimony: Apotex, DRL, Mylan, Sandoz. C.K. Kollmannsberger: Financial Interests, Personal, Advisory Board, ad-hoc advisory board: Pfizer, Ipsen, BMS, Eisai, Merck, Bayer, Astellas; Financial Interests, Personal, Invited Speaker, honoraria for educational presentation: Pfizer; Financial Interests, Personal, Invited Speaker, honoraria for educational lectures: Ipsen; Financial Interests, Personal, Invited Speaker, honoraria for presentations: BMS, Eisai, Merck, Seagen, Bayer, Astellas, Janssen; Financial Interests, Personal, Advisory Board, Ad-hoc advisory board: Seagen, Janssen, AstraZeneca. B. Melichar: Financial Interests, Personal, Advisory Board: Roche, BMS, MSD, Novartis, Merck Serono, E. Lilly, Pfizer, AstraZeneca. B. Venugopal: Financial Interests, Institutional, Principal Investigator: Merck & Co., Inc.; Financial Interests, Personal, Speaker, Consultant, Advisor: Merck & Co., Inc., Eisai, EUSA Pharma, and Ipsen; Financial Interests, Personal, Speaker’s Bureau: Bristol-Myers Squibb Eisai EUSA Pharma, Ipsen, Merck Sharp & Dohme Oncology, and Pfizer/EMD Serono; Financial Interests, Personal, Funding: Ipsen, Bristol-Myers Squibb, and EUSA Pharma. A. Wang, R. Perini, D. Vickery: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks or ownership: Merck & Co., Inc.. T.B. Powles: Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers-Squibb, Exelixis, Incyte, Ipsen, Merck, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, Roche, MSD; Financial Interests, Personal, Other, Travel/Accommodation/Expenses: AstraZeneca, Roche, Pfizer, MSD, Ipsen; Financial Interests, Personal, Other, Sponsorship for Uromigos Podcast: Mashup Ltd; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Bristol Myers-Squibb, Exelixis, Seattle Genetics, Ipsen, Merck, MSD, Pfizer, Merck Serono, Astellas, Johnson & Johnson, Eisai, Novartis. T.K. Choueiri: Financial Interests, Personal, Advisory Board, Advice on GU/RCC drugs: BMS, Pfizer, Merck, Exelixis, AstraZeneca; Financial Interests, Personal, Advisory Board, Advice on Onc drugs: Lilly, EMD Serono, Infinity; Financial Interests, Personal, Advisory Board, Advice on RCC drug: Calithera; Financial Interests, Personal, Invited Speaker, RCC drug: Ipsen; Financial Interests, Personal, Advisory Board, Advice on GU Onc drugs: Surface Oncology; Financial Interests, Personal, Other, Consultant on onc drugs: Analysis Group; Financial Interests, Personal, Invited Speaker, CME, ww2.peerview.com: Peerview; Financial Interests, Personal, Invited Speaker, CME, gotoper.com: PER; Financial Interests, Personal, Invited Speaker, CME, researchtopractice.com: ResearchToPractice; Financial Interests, Personal, Invited Speaker, National Association of Managed Care: NAMC; Financial Interests, Personal, Invited Speaker, ASCO-related event: ASCO-SITC; Financial Interests, Personal, Other, Grant review to Orien Network ($400): ORIEN; Financial Interests, Personal, Advisory Board, Advising oncology strategy: Aptitude Health; Financial Interests, Personal, Invited Speaker, Best of ASCO19 talk: Advent health; Financial Interests, Personal, Invited Speaker, Best of ESMO20 talk ($1000): UAE Society of Onc; Financial Interests, Personal, Invited Speaker, CME, mjhlifesciences.com (OncLive): MJH life sciences; Financial Interests, Personal, Invited Speaker, Grand Rounds: MDACC; Financial Interests, Personal, Invited Speaker, RCC webinar: Cancernet; Financial Interests, Personal, Invited Speaker, CME, Kidney Cancer Association ($1300): France Foundation; Financial Interests, Personal, Invited Speaker, CME, RCC: Springer, WebMed; Financial Interests, Personal, Invited Speaker, CME, ImmunoOncology in RCC: ASiM, CE; Financial Interests, Personal, Invited Speaker, CME, PodCast in RCC ($500.00): Caribou Publishing; Financial Interests, Personal, Invited Speaker, Reimbursement ($432.00): Kidney Cancer Association; Financial Interests, Personal, Other, member of the DSMB for clinical trial: Aravive; Financial Interests, Personal, Advisory Board, GU cancer drug development: alkermes, Gilead; Financial Interests, Personal, Other, Study section reviewer. $200.00 per day for 1 day: National Cancer Institute; Financial Interests, Personal, Other, Cancer Center Grand Rounds: Cleveland Clinic; Financial Interests, Personal, Advisory Board, Advisory Board/month: CURESPONSE; Financial Interests, Personal, Advisory Board: Tempest, Precede Bio (not publicly traded)); Financial Interests, Personal, Stocks/Shares, advisor: Pionyr (not publicly traded), Tempest (publicly traded), Osel (not publicly traded), Precede Bio (not publicly traded)), CURESPONSE (not publicly traded), Inndura; Financial Interests, Personal, Member of Board of Directors, ACCRU; Financial Interests, Personal, Member of Board of Directors, Unpaidhttps://kidneycan.org: KidneyCan; Financial Interests, Personal, Other, External Advisory Board Member: Gustave Roussy; Financial Interests, Personal, Stocks/Shares: Primium; Financial Interests, Personal, Royalties, For writing and updating chapters in GU Oncology: Up-To-Date online textbook; Financial Interests, Institutional, Funding, National Chair: BMS, Merck, Exelixis, AstraZeneca, Takeda, Tracon; Financial Interests, Institutional, Local PI, National Chair: Roche; Financial Interests, Institutional, Funding, National co-chair: Pfizer, EMD-Serono; Financial Interests, Institutional, Funding, Chair of trial: Lilly; Financial Interests, Institutional, Local PI: Surface Oncology, GSK; Financial Interests, Institutional, Funding, SC member: Eisai; Financial Interests, Institutional, Research Grant, for GU oncology translational research: Exelixis; Financial Interests, Institutional, Funding, National co-chair on 3 ongoing trials: ALLIANCE Cooperative Group; Financial Interests, Institutional, Research Grant, for GU oncology translational research through IION program: BMS; Financial Interests, Institutional, Research Grant, For Health outcomes research: Roche; Financial Interests, Institutional, Local PI, leads trials as PI: Nikang; Non-Financial Interests, Leadership Role, Co-Chair of the meeting, 2019- current and BOD member (unpaid): Kidney Cancer Research Summit of KidneyCAN; Non-Financial Interests, Principal Investigator, Trial Global and National PI with GU Cancers, mostly Kidney Cancer: Multiple Academic and Industry entities; Non-Financial Interests, Personal, Other, Track Leader/Session chair/Speaker/Discussant: ASCO; Non-Financial Interests, Personal, Other, Speaker/Discussant/Track Leader: ESMO; Non-Financial Interests, Institutional, Other, Access to genomic database: Foundation Med, Guardant, Invitae; Non-Financial Interests, Personal, Other, Grants reviewers: AACR; Non-Financial Interests, Personal, Other, Reviewer of papers: Various journals (e.g. NEJM, Lancet, JCO); Non-Financial Interests, Personal, Other, Medical writing and editorial assistance support (e.g. ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, Parexel, Oxford PharmaGenesis, pharmagenesis, and others). However, first draft frequently initiated by myself when I am 1st author.: Medical Communication; Non-Financial Interests, Member: ASCO, AACR; Non-Financial Interests, Other, Political vote usually as “independent”, not a member of any political party. I am an issue voter.: General US Politics; Other, Employee at DFCI. I am also the past President of Medical Staff at DFCI 2015-2018: Dana-Farber Cancer Institute (DFCI); Other, Professor at HMS, Harvard Medical School (HMS); Other, The institution filed patents related to biomarkers of immune checkpoint blockers, and circulating tumor DNA. No money made and some patents were abandoned.: Filed patents.