Separate studies presented at the 2021 Genitourinary Cancers Symposium provide supportive evidence for belzutifan (formerly MK-6482) as an active treatment for metastatic clear cell renal cell carcinoma (RCC). One study showed single-agent activity for this novel approach in an early-phase trial, and another showed activity in combination with cabozantinib.^1,2

Belzutifan offers a novel approach to treating RCC, taking a different path than commonly used vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors, such as sunitinib and its cousins, or checkpoint inhibitors, which are used in various combinations to treat metastatic clear cell RCC. About 90% of patients with RCC lack the von Hippel-Lindau tumor-suppressor gene, leading to the clustering of hypoxia-inducing factor (HIF) proteins in the tumor cell and creating a false signal for a shortage of oxygen, which then activates the formation of blood vessels and fuels tumor growth. Belzutifan is a highly selective small molecule that inhibits the function of the HIF-2α transcription factor. As a result, hypoxic signaling in cancer cells is impaired, blocking the transcription of several genes involved in cancer cell growth, proliferation, and abnormal blood vessel formation.

Dose-Expansion Cohort of Phase II Trial

Belzutifan achieved promising activity as monotherapy in the dose-expansion cohort of patients with RCC,  an extension of a phase I/II trial in heavily pretreated patients with metastatic clear cell RCC, and the drug was well tolerated with a favorable toxicity profile, said lead author Todd Michael Bauer, MD, of Tennessee Oncology.¹ The median duration of response was not reached in 71% of patients at the time of the 2021 Genitourinary Cancers Symposium.

“This study validates the growing preclinical and clinical evidence for HIF-2α inhibition as a promising approach to RCC.”

— Todd Michael Bauer, MD

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“This study validates the growing preclinical and clinical evidence for HIF-2α inhibition as a promising approach to RCC,” Dr. Bauer said.

A total of 55 patients with metastatic RCC were included in the expansion cohort; 44 came off treatment (60% due to disease progression), and 11 are continuing on treatment in the study. Treatment with belzutifan was continued until toxicity or disease progression. Dr. Bauer presented efficacy data on 41 patients evaluable for response, with a median follow-up of 27.7 months.

Data are still preliminary, but the rate of disease control was 83% in patients treated at 160 mg and 43% in those who received 200 mg. “These numbers of patients are small and difficult to tease apart,” he noted. “An important point is that increases in pharmacokinetic concentration are dose-related.”

The rest of his talk focused on all 55 patients in the RCC cohort. Median age was 62. Patients were predominantly male, and all but one had an Eastern Cooperative Oncology Group performance status of 0 or 1. Most patients were at intermediate or poor risk, most had received prior therapies (63% had three or more prior lines of therapy), 91% were treated with prior VEGF tyrosine kinase inhibitors, and 80% were given prior immunotherapy checkpoint inhibitors. A total of 39 patients (71%) had received both therapies.

All patients experienced an adverse event of any grade; 96% experienced a treatment-related adverse event. Grade 3 treatment-related adverse events were reported in 40%, and there were no grade 4 and 5 treatment-related adverse events. Dr. Bauer said, “Only two patients had to discontinue therapy due to a treatment-related adverse event—hypoxia.”

The objective response rate was 25% overall: 31% in favorable-risk patients and 24% in intermediate-risk patients. Disease control rates were 92% and 76%, respectively, for the two risk categories.

“A waterfall plot shows a great deal of disease stability. About 64% had a reduction in target lesion size. On the flip side, a number of patients without tumor shrinkage had prolonged stable disease. With this drug, we don’t see a quick response, but we do see prolonged late responses. Nineteen patients [35%] were on the drug beyond 12 months,” Dr. Bauer told the audience. “Of the responders, 10 of 14 [71%] had a response lasting more than 6 months.”

He continued: “I use this information when I counsel patients, letting them know that we don’t see quick drops in tumor volume, but we may see small tumor shrinkage with each successive scan, and we see great clinical benefit. Belzutifan can work very well over a prolonged period.” 

For all risk categories, median progression-free survival was 14.5 months. No median was reached in favorable-risk patients. For intermediate- and poor-risk patients, median progression-free survival was 11 months.

A phase III trial of belzutifan monotherapy in previously treated patients is ongoing.

Combination With Cabozantinib

Belzutifan in combination with cabozantinib achieved 88% tumor shrinkage in target lesions and a disease control rate of 90% for patients with previously treated advanced clear cell RCC, according to preliminary results from cohort 2 in an ongoing phase II study presented at the 2021 Genitourinary Cancers Symposium.²

Lead author Toni K. Choueiri, MD, Director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute/Brigham and Women’s Hospital and the Jerome and Nancy Kohlberg Chair and Professor of Medicine at Harvard Medical School, Boston, presented early findings from 52 patients enrolled in the phase II trial evaluating belzutifan plus cabozantinib. Although preliminary, the data were encouraging.

“These very preliminary, interim results for the combination of belzutifan and cabozantinib showed promising activity in previously treated metastatic clear cell RCC.”

— Toni K. Choueiri, MD

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“These very preliminary, interim results for the combination of belzutifan and cabozantinib showed promising activity in previously treated metastatic clear cell RCC. We believe that targeting the underlying pathology of clear cell RCC, targeting the transcription factor HIF-2α with belzutifan, and targeting downstream with the VEGF receptor tyrosine kinase inhibitor cabozantinib could be an effective treatment for patients with metastatic clear cell RCC,” Dr. Choueiri told listeners. Cabozantinib also targets c-MET, VEGFR2, AXL, and RET.

A total of 41 patients were in ongoing treatment and evaluable for efficacy at the time of the presentation, and the confirmed objective response rate was 22% (9/41); all responses were partial responses. Another 5 patients (12%) had unconfirmed partial responses, and 28 patients (68%) had stable disease as best responses. The disease control rate was 90%. 

“They are very, very interim response rates,” Dr. Choueiri cautioned. The median duration of response was not reached, and all confirmed responses were still ongoing as of the data cutoff on October 15, 2020. The median time from enrollment to data cutoff was 8.9 months.

The median age of patients was 63. To be enrolled in cohort 2, these previously treated patients had to have one or more measurable lesions and a good performance status. Cohort 1, comprising untreated patients, is also included in the phase II study, and patient accrual to that cohort is ongoing.

Eligible patients were assigned to 120 mg of belzutifan plus 60 mg of cabozantinib orally once daily for 21 days. This efficacy analysis includes patients who have received at least one dose of treatment and have had at least 6 months of follow-up.

The progression-free survival rate was 78% at 6 months and 65% at 12 months. Median progression-free survival was 16.8 months. Dr. Choueiri pointed out that the median progression-free survival was “not reliable” at this early time point. “A total of 95% of patients were alive at 6 months,” he said.

Nearly all patients (98%) experienced any-grade treatment-related adverse events. Grade 3 treatment-related adverse events were fairly common (60%), but no grade 4 or 5 treatment-related adverse events were reported.

Six patients (12%) discontinued belzutifan due to treatment-emergent adverse events, and eight (15%) discontinued cabozantinib. Seven patients (13%) experienced serious treatment-related adverse events, but no deaths were reported due to such events.

“Hypoxia is an on-target adverse event of belzutifan, but this occurred in only two patients,” he said. “The side effects of belzutifan are manageable. The vast majority were grade 1 or 2. The safety [of the combination] is consistent with the individual profile of each agent.”

In July 2020, the U.S. Food and Drug Administration granted Breakthrough Therapy designation to ­belzutifan for the treatment of patients with von Hippel-Lindau disease–­associated RCC with nonmetastatic tumors smaller than 3 cm, unless immediate surgery is required. The agency also granted Orphan Drug designation to belzutifan for von Hippel-Lindau disease. 

DISCLOSURE: Dr. Bauer has been employed by Tennessee Oncology; has served as a consultant or advisor to AstraZeneca, Bayer, Blueprint Medicines, Exelixis, Foundation Medicine, Guardant Health, Loxo, and Pfizer; has served in an institutional consulting or advisory role for Ignyta, Moderna Therapeutics, and Pfizer; has participated in a speakers’bureau for Bayer, Bristol Myers Squibb, and Lilly; has received institutional research funding from AbbVie, Aileron Therapeutics, Amgen, ARMO BioSciences, Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Clovis Oncology, Daiichi Sankyo, Deciphera, Five Prime Therapeutics, Foundation Medicine, Genentech/Roche, GlaxoSmithKline, Ignyta, Immunocore, Immunogen, Incyte, Jacobio, Janssen, Karyopharm Therapeutics, Kolltan Pharmaceuticals, Leap Therapeutics, Lilly, Loxo, MabVax, MedImmune, MedPacto, Merck, Merrimack, Millennium, Mirati Therapeutics, Moderna Therapeutics, Novartis, Onyx, Peleton, Pfizer, Phosplatin Therapeutics, Principia Biopharma, Roche, Sanofi, Stemline Therapeutics, Takeda, and Top Alliance BioScience; and has been reimbursed for travel, accommodations, or other expenses by Astellas Pharma, AstraZeneca, Celgene, Clovis Oncology, EMD Serono, Genentech, Lilly, Merck, Novartis, Pfizer, Pharmacyclics, and Sysmex. Dr. Choueiri has been employed by Dana-Farber Cancer Hospital; has served in a leadership role for ASCO, Dana-Farber Cancer Hospital, KidneyCAN, and the National Comprehensive Cancer Network (NCCN); holds stock or other ownership interests in Pionyr and Tempest; has received honoraria from Alexion Pharmaceuticals, Allegiant, Analysis Group, ASCO, AstraZeneca, Bayer, Bristol Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eisai, EMD Serono, Exelixis, Foundation Medicine, Genentech/Roche, GlaxoSmithKline, Harborside Press, Heron, Ipsen, IQvia, Janssen Oncology, Kidney Cancer Journal, The Lancet Oncology, Lilly, Lpath, Merck, Michael J. Hennessy Associates, Navinata Healthcare, NCCN, The New England Journal of Medicine, (NEJM), Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus, Sanofi/Aventis, and UpToDate; has served as a consultant or advisor to Alexion Pharmaceuticals, Allegiant, Analysis Group, ASCO, AstraZeneca, Bayer, Bristol Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eisai, EMD Serono, the European Society for Medical Oncology (ESMO), Exelixis, Foundation Medicine, GlaxoSmithKline, Harborside Press, Heron, Ipsen, Kidney Cancer Journal, The Lancet Oncology, Lilly, Lpath, Merck, Michael J. Hennessy Associates, Navinata Healthcare, NCCN, NEJM, Novartis, Peloton Therapeutics, Pfizer, Platform Q, Prometheus Laboratories, Roche/Genentech, Sanofi/Aventis, and UpToDate; has received institutional research funding from Agensys, Analysis Group, AstraZeneca, Bayer, Bristol Myers Squibb, Calithera Biosciences, Celldex, Cerulean Pharma, Congressionally Directed Medical Research Programs (DOD), Corvus Pharmaceuticals, Eisai, Exelixis, Foundation Medicine, Gateway for Cancer Research, GlaxoSmithKline, Ipsen, Merck, the National Cancer Institute, Novartis, Peloton Therapeutics, Pfizer, Prometheus, Roche, Roche/Genentech, Seattle Genetics/Astellas, Takeda, and Tracon Pharma; holds patents for “Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy” and “PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response”; has been reimbursed for travel, accommodations, or other expenses by Alexion Pharmaceuticals, Allegiant, Analysis Group, AstraZeneca, Bayer, Bristol Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eisai, EMD Serono, ESMO, Exelixis, Foundation Medicine, GlaxoSmithKline, Harborside Press, Heron, Ipsen, Kidney Cancer Journal, The Lancet Oncology, Lilly, Lpath, Merck, Michael J. Hennessy Associates, Navinata Healthcare, NCCN, NEJM, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus, Roche/Genentech, Sanofi/Aventis, and UpToDate; and has held other relationships with “communications companies funded by pharmaceutical companies such as ClinicalThinking, Health Interactions, Envision Pharma Group, Fishawack Group of Companies, Parexel.”

REFERENCES

1. Bauer TM, Chouieri T, P Papadopoulos K, et al: The oral HIF-2 α inhibitor MK-6482 in patients with advanced clear cell renal cell carcinoma: Updated follow-up of a phase I/II study. 2021 Genitourinary Cancers Symposium. Abstract 273. Presented February 13, 2021.

2. Choueiri TK, Bauer TM, McDermott DF, et al: Phase 2 study of the oral hypoxia-inducible factor 2 alfa inhibitor MK-6482 in combination with cabozantinib in patients with advanced clear cell renal cell carcinoma. 2021 Genitourinary Cancers Symposium. Abstract 272. Presented February 13, 2021.