1881O - Safety and efficacy of two doses of belzutifan in patients (pts) with advanced RCC: Results of the randomized phase II LITESPARK-013 study

Background

In the phase 1 LITESPARK-001 study of the HIF-2α inhibitor belzutifan for ccRCC, the MTD was not reached for dosages up to 240 mg per day, and the RP2D was 120 mg QD based on PD, PK, and safety. The phase 2 LITESPARK-013 study (NCT04489771) examined if a higher belzutifan dose could improve efficacy while maintaining an acceptable safety profile.

Methods

Pts with advanced ccRCC, measurable disease per RECIST v1.1, ≤3 prior systemic regimens for advanced ccRCC including an anti–PD-1/L1 agent, and disease progression during or after an anti–PD-1/L1 agent were randomly assigned 1:1 to belzutifan 120 mg or 200 mg QD. Pts were stratified by IMDC risk score (0 vs 1-2 vs 3-6) and number of prior TKI therapies for advanced ccRCC (0 vs 1 vs 2-3). Primary end point was ORR per RECIST v1.1 by blinded independent central review. Secondary end points included DOR, PFS, OS, safety, and PK. Database cutoff was February 10, 2023.

Results

154 pts were enrolled (120 mg: n=76; 200 mg: n=78). Baseline characteristics were well balanced between arms. Median follow-up was 20.1 months (range 14.8-28.4). ORR was 23.7% (18 PR) vs 23.1% (4 CR; 14 PR) for the 120 mg and 200 mg arms, respectively (P=0.5312; −0.5% [95% CI, −14.0 to 12.9] using the Miettinen-Nurminen method stratified by IMDC risk). PFS (median 7.3 vs 9.1 months; HR 0.94 [95% CI 0.63-1.40]) and OS (medians not reached; HR 1.11 [95% CI, 0.65-1.90]) did not differ between arms. Median DOR was not reached for the 120 mg arm (range 2.6+ to 16.1+) and was 16.1 mo (2.1+ to 23.5+) for the 200 mg arm; 64.7% and 51.3% of pts had ongoing responses ≥15 mo, respectively. 142 pts had a treatment-related AE (TRAE; 70 [92.1%] with 120 mg; 72 [92.3%] with 200 mg]. 2 pts (2.6%) in the 120 mg arm and 7 (9.0%) in the 200 mg arm discontinued treatment due to a TRAE. Treatment-related anemia (81.6% with 120 mg and 83.3% with 200 mg) and hypoxia (23.7% with 120 mg and 26.9% with 200 mg) was similar between arms.

Conclusions

The efficacy of belzutifan was similar between the RP2D of 120-mg dose and the 200-mg dose and was consistent with prior reports of antitumor activity in ccRCC. Safety at both doses was consistent with the known safety profile of belzutifan. These results further support 120 mg QD as the preferred dose for belzutifan.

Clinical trial identification

NCT04489771.

Editorial acknowledgement

Medical writing and/or editorial assistance was provided by Shane Walton and Robert Steger of ApotheCom (Yardley, PA). Funding for this assistance was provided by 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

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

Disclosure

N. Agarwal: Financial Interests, Personal, Advisory Role: Astellas, AstraZeneca, Aveo, Bayer, BMS, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, Seattle Genetics; Financial Interests, Institutional, Research Funding: Arnivas, Astellas, AstraZeneca, Bavarian Nordic, Bayer, BMS, Calithera, Celldex, Clovis, Crispr, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, GSK, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neole. J. Brugarolas: Financial Interests, Personal and Institutional, Licencing Fees or royalty for IP: UT Southwestern Medical Center. P. Ghatalia: Non-Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Funding: Oryzon, Merck. S. George: Financial Interests, Institutional, Research Grant: Pfizer, Merck, Agensys, Novartis, BMS, Bayer, Eisai, Seattle Genetics/Astellas, Calithera Biosciences, Corvus Pharmaceuticals, Surface Oncology, Exelixis, Aravive, Aveo, Gilead Sciences; Financial Interests, Personal, Advisory Board: BMS, Bayer, Pfizer, Exelixis, Corvus Pharmaceuticals, Sanofi, EMD Serono, Seattle Genetics/Astellas, Eisai, Merck, Aveo, QED Therapeutics; Financial Interests, Institutional, Sponsor/Funding: Pfizer, Merck, Agensys, Novartis, BMS, Bayer, Eisai, Seattle Genetics/Astellas, Calithera Biosciences, Corvus Pharmaceuticals, Surface Oncology, Exelixis, Aravive, Aveo, Gilead Sciences. J.B.A.G. Haanen: Financial Interests, Institutional, Research Grant: Amgen, BioNTech, BMS, MSD, Neogene Tx, Novartis; Financial Interests, Personal and Institutional, Advisory Board: Achilles Tx, CureVac, Imcyse, Instil Bio, Iovance Bio, Ipsen, Merck, Molecular Partners, PokeAcell, Pfizer, Sanofi, Scenic, T-Knife, TRV. H.P. Gurney: Financial Interests, Personal, Advisory Board: BMS AstraZeneca Astella Merck Serono MSD Ipsen Pfizer. R. Ravilla: Financial Interests, Personal, Speaker’s Bureau: Janssen, Exelixis, BMS; Financial Interests, Personal, Advisory Board: Seagen/Astellas. A.A.M. Van der Veldt: Financial Interests, Institutional, Advisory Board: BMS, MSD, Pfizer, Merck, Roche, Novartis, Sanofi, Ipsen, Eisai, Pierre Fabre. B. Beuselinck: Financial Interests, Institutional, Advisory Board: MSD, BMS, Ipsen; Financial Interests, Institutional, Expert Testimony: MSD; Financial Interests, Institutional, Speaker’s Bureau: BMS, Pfizer, Ipsen; Financial Interests, Institutional, Research Grant: BMS. M. Tuthill: Non-Financial Interests, Personal, Advisory Board: Vaccitech UK Limited; Financial Interests, Personal, Advisory Board: Merck & Co., Inc., Novartis, AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Merck & Co., Inc., AstraZeneca; Financial Interests, Personal, Principal Investigator: Merck & Co., Inc., Novartis; Financial Interests, Personal, Research Grant: AstraZeneca. D. Vaena: Financial Interests, Personal, Advisory Board: Seattle Genetics, Bayer, Eisai, BMS, EMD Serono, Exelixis, Janssen; Non-Financial Interests, Institutional, Principal Investigator: Compugen, OBI Pharma, Merck, Atreca, NGM Bio, BMS, Genentech. F. Zagouri: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Eli Lilly, Merck, Novartis, MSD, Pfizer, Genesis Pharma, Roche; Financial Interests, Personal, Invited Speaker: AstraZeneca, Daiichi Sankyo, Eli Lilly, Merck, Novartis, MSD, Pfizer, Genesis Pharma, Roche. Y. Liu: Financial Interests, Personal, Full or part-time Employment: Merck; Financial Interests, Personal, Stocks/Shares: Merck; Financial Interests, Personal, Sponsor/Funding: Merck. R. Perini: Financial Interests, Personal, Full or part-time Employment: Merck Sharpe and Dohme; Financial Interests, Personal, Stocks/Shares: Merck Sharpe and Dohme. J.R. Merchan: Financial Interests, Personal and Institutional, Advisory Board: Merck; Financial Interests, Institutional, Principal Investigator: Merck, Sillajen, Eisai, Exelixis, Imugene, Seattle Genetics, Peloton Therapeutics, Genentech, Rubius Therapeutics, Replimune; Financial Interests, Institutional, Research Grant: Sillajen. M.B. Atkins: Financial Interests, Personal and Institutional, Advisory Board: Merck, BMS; Financial Interests, Personal and Institutional, Research Grant: Merck, BMS; Financial Interests, Personal, Advisory Board: Exelixis, Eisai, Genentech-Roche. All other authors have declared no conflicts of interest.