High Disease Control Rate Achieved With Belzutifan and Cabozantinib in ccRCC

Toni K. Choueiri, MD

The addition of the oral hypoxia-inducible factor 2α (HIF-2α) inhibitor belzutifan (MK-6482) to cabozantinib (Cabometyx) led to disease control in a majority of patients with previously treated advanced clear cell renal cell carcinoma (ccRCC), according to preliminary results from a phase 2 trial (NCT03634540) presented at the 2021 Genitourinary Cancers Symposium.¹

Lead author Toni K. Choueiri, MD, presented early findings from a cohort of 52 patients treated in the ongoing study. He cautioned that the results looked favorable but were very preliminary.

“These preliminary, interim results for the combination of belzutifan and cabozantinib showed promising activity in previously treated metastatic clear cell RCC,” said Choueiri, director of the Lank Center for Genitourinary (GU) Oncology at Dana-Farber Cancer Institute (DFCI)/Brigham and Women’s Hospital and the Jerome and Nancy Kohlberg Chair and Professor of Medicine at Harvard Medical School. “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 inhibitor, among other kinases, cabozantinib could be an effective treatment for patients with metastatic clear cell RCC.”

Investigators analyzed 41 patients for efficacy. The confirmed objective response rate (ORR) was 22% (9/41); all responses were partial responses. Investigators also observed another 5 (12%) unconfirmed partial responses. Twenty-eight (68%) patients had stable disease as best responses. The median duration of response was not reached, and all confirmed responses were still ongoing as of data cutoff of October 15, 2020. The median time from enrollment to data cutoff was 8.9 months.

Investigators are still enrolling a cohort of untreated patients into the study.

Eligible patients were assigned to 120 mg belzutifan plus 60 mg cabozantinib orally once daily for 21 days. This efficacy analysis includes patients who received at least 1 dose of treatment and had an opportunity for at least 6 months of follow-up.

The progression-free survival (PFS) rate was 78% at 6 months and 65% at 12 months. Choueiri noted that 95% of patients were alive at 6 months.

“The median should not be considered real given only 1 patient was at risk at month 17, [but] the median PFS here was 16.8 months,” he said.

David A. Braun, MD, PhD, a physician and investigator with Dana-Farber, urged caution. He delivered a discussant on Choueiri’s presentation. “The median follow up was only about 11 months and the minimum follow up only 5.6 months. This is interesting and potentially exciting, but we really need to have further follow-up.

“When we look at the PFS curve, which looks impressive, it’s a median of 16.8 months. But, again, there are very few patients that are out that far. It’s definitely preliminary.”

Nearly all (98%) of patients experienced any-grade treatment-related adverse events (TRAEs). Grade 3 TRAEs were fairly common (60%), but there was no incidence of grade 4/5 TRAEs.

Six (12%) patients discontinued belzutifan due to treatment-emergent AEs and 8 (15%) discontinued cabozantinib. Seven (13%) patients experienced serious TRAEs.

In July 2020, the FDA granted breakthrough therapy designation to belzutifan for the treatment of patients with von Hippel-Lindau (VHL) disease-associated RCC with nonmetastatic RCC tumors smaller than 3 cm in size unless immediate surgery is required. The agency also granted orphan drug designation to belzutifan for VHL disease.² Both designations were based on data from a phase 2 trial evaluating patients with VHL-associated clear cell RCC that was presented at the 2020 American Society of Clinical Oncology Annual Meeting.

Results showed that the agent induced a confirmed ORR of 27.9% (95% CI, 17.1-40.8); all responses were partial response. Notably, most of the patients on the trial (86.9%) experienced a reduction in the size of their target lesions.³

Previous data from a phase 1/2 trial (NCT02974738) showed encouraging single-agent activity with belzutifan in patients with heavily pretreated clear cell RCC, a benefit that was observed across all International Metastatic RCC Database risk groups analyzed.⁴

In 55 patients enrolled to the dose escalation/expansion cohort of the trial, the ORR was 24% with the agent, while the disease control rate was 80%. The ORR was comprised of 13 confirmed PRs. Moreover, the median progression-free survival (PFS) reported with belzutifan in the overall patient population studied was 11.0 months. At 1 year, 49% of patients remained progression free.

_References

_{Choueiri TK, Bauer TM, McDermott DF, et al. Phase 2 study of the oral hypoxia-inducible factor 2α (HIF-2α) inhibitor MK-6482 in combination with cabozantinib in patients with advanced clear cell renal cell carcinoma (ccRCC). J Clin Oncol. 2021;39(suppl 6; abstr 272). doi: 10.1200/JCO.2021.39.6_suppl.272}

_{FDA grants breakthrough therapy designation to Merck’s novel HIF-2α inhibitor MK-6482 for treatment of certain patients with Von Hippel-Lindau disease-associated renal cell carcinoma. News release. Merck. July 29, 2020. Accessed February 13, 2021. bit.ly/3qkNRGK}

_{Jonasch E, Donskov F, Iliopoulos O, et al. Phase II study of the oral HIF-2α MK-6482 for Von Hippel-Lindau disease–associated renal cell carcinoma. J Clin Oncol. 2020;38(suppl 15):5003. doi:10.1200/JCO.2020.38.15_suppl.5003}

_{Choueiri TK, Plimack ER, Bauer TM, et al. Phase I/II study of the oral HIF-2 α inhibitor MK-6482 in patients with advanced clear cell renal cell carcinoma (RCC). J Clin Oncol. 2020;38(suppl 6):611. doi:10.1200/JCO.2020.38.6_suppl.611}