1447O - Phase II study of belzutifan plus cabozantinib as first-line treatment of advanced renal cell carcinoma (RCC): Cohort 1 of LITESPARK-003

Background

HIF-2α is constitutively activated in RCC and is a transcription factor of multiple oncogenic pathways including TGF-α, GLUT1, cyclin D1, CXCR4, and VEGF. VEGF, and its receptor, are key regulators of angiogenesis and are upregulated in RCC. Belzutifan, a first-in-class HIF-2α inhibitor, has shown antitumor activity and favorable safety in heavily pretreated advanced RCC. Cabozantinib, a multikinase inhibitor that targets VEGF, is approved for advanced RCC. We present the first data of the use of belzutifan plus cabozantinib for treatment-naive pts with advanced RCC (cohort 1) enrolled in the ongoing, open-label, phase 2 LITESPARK-003 study (NCT03634540).

Methods

Treatment-naïve pts with advanced clear cell RCC and ECOG PS of 0/1 received belzutifan 120 mg QD PO plus cabozantinib 60 mg QD PO. The primary end point was confirmed ORR (CR + PR) per RECIST v1.1 by investigator review. Secondary end points were DOR, PFS, OS, and safety.

Results

Of 35 pts enrolled in cohort 1, 10 (29%) discontinued treatment; primarily due to progressive disease (n=8; 23%). Median age was 64 years (range, 33-89) and most pts had an ECOG PS of 0 (n=21; 60%), and IMDC favorable risk (n=21; 60%). Median follow-up was 14.0 mo (range, 0.2-33.0). Confirmed ORR was 57% (2 CRs, 18 PRs) and 13 pts (37%) had a best response of SD. Median DOR was 28.6 mo (range, 1.7+ to 28.6); 13 pts remained in response for ≥6 mo. Median PFS was 30.3 mo (95% CI, 9.4 to not reached); the estimated 12-mo PFS rate was 67%. Median OS was not reached; the estimated 12-mo OS rate was 96%. By IMDC risk category, ORR was 62% in 21 pts with favorable risk and 50% in 14 pts with intermediate/poor risk. In all pts, the most common any grade treatment-related AEs were anemia (n=25; 71%) and diarrhea (n=25; 71%). Grade 3 treatment-related AEs occurred in 13 pts (37%), most commonly hypertension (n=4; 11%) and fatigue (n=3; 9%). There were no grade 4 or 5 treatment-related AEs. 1 pt (3%) discontinued cabozantinib due to an AE (abdominal abscess). No pt discontinued belzutifan due to an AE.

Conclusions

Belzutifan plus cabozantinib had manageable safety with promising antitumor activity in treatment-naïve pts with advanced clear cell RCC.

Clinical trial identification

NCT03634540 Release date: August 16, 2018.

Editorial acknowledgement

Medical writing and/or editorial assistance was provided by Robert Steger, PhD and Matt Grzywacz, PhD of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study

Merck & Co., Inc., Rahway, NJ, USA.

Funding

Merck & Co., Inc., Rahway, NJ, USA.

Disclosure

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, Invited Speaker, unpaidhttps://www.accru.org/main/public/index.xhtml: ACCRU; Financial Interests, Personal, Invited Speaker, Unpaidhttps://kidneycan.org: KidneyCan; Financial Interests, Personal, Other, External Advisory Board Member: Gustave Roussy; Financial Interests, Personal, Stocks/Shares: Pionyr (not publicly traded), Tempest (publicly traded), Osel (not publicly traded), Nuscan ((not publicly traded)); 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, Peloton; Financial Interests, Institutional, Invited Speaker: Roche, Surface Oncology, GSK; Financial Interests, Institutional, Funding, National co-chair: Pfizer, EMD-Serono; Financial Interests, Institutional, Funding, Chair of trial: Lilly; Financial Interests, Institutional, Funding, SC member: Eisai; 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 GU oncology translational research: Exelixis; Financial Interests, Institutional, Research Grant, For Health outcomes research: Roche; Financial Interests, Institutional, Invited Speaker, leads trials as PI: Nikang; Non-Financial Interests, Leadership Role, Co-Chair of the meeting, 2019-: 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. Please see https://www.dana-farber.org/ for mission statement (non-profit hospital). I am also the past President of Medical Staff at DFCI 2015-2018: Dana-Farber Cancer Institute (DFCI); Other, Professor at HMS, Please see https://hms.harvard.edu/ for mission statement (non-profit school): Harvard Medical School (HMS); Other, No financial interest. Institutional.Filed patents related to biomarkers of immune checkpoint blockers, and circulating free methylated DNA. No money made and some patents were abandoned: Filed patents. T. Bauer: Financial Interests, Personal and Institutional, Invited Speaker: Pfizer, Lilly, Bayer; Financial Interests, Personal and Institutional, Advisory Board: Pfizer, Lilly, Bayer, AstraZeneca; Financial Interests, Personal and Institutional, Funding: Pfizer; Financial Interests, Personal and Institutional, Principal Investigator: Pfizer, Lilly, Bayer, AstraZeneca, Bristol Myers Squibb; Financial Interests, Personal and Institutional, Speaker’s Bureau: Lilly, Bayer, Bristol Myers Squibb; Financial Interests, Personal and Institutional, Research Grant: Lilly, Bayer, AstraZeneca, Bristol Myers Squibb. J. Merchan: Financial Interests, Personal, Advisory Board: Merck; Other, Institutional, Principal Investigator: Merck, Eisai, Genentech, Rubius Therapeutics, Trishula Therapeutics, Corvus Pharmaceuticals, BioNtech, Vyriad, Seattle Genetics, SillaJen, Exelixis; Other, Institutional, Research Grant: SillaJen. R. Figlin: Financial Interests, Institutional, Funding: Merck; Financial Interests, Institutional, Principal Investigator: Merck. A. Roy: Financial Interests, Institutional, Full or part-time Employment: Merck; Financial Interests, Institutional, Stocks/Shares: Merck. R. Perini: Financial Interests, Institutional, Full or part-time Employment: MSD; Financial Interests, Institutional, Stocks/Shares: MSD. D. Vickery: Financial Interests, Institutional, Full or part-time Employment: MSD. All other authors have declared no conflicts of interest.