Belzutifan/Cabozantinib Displays Encouraging Antitumor Activity in Advanced ccRCC

David McDermott, MD

Belzutifan (Welireg) in combination with cabozantinib (Cabometyx) has demonstrated promising activity in patients with advanced, clear cell renal cell carcinoma (ccRCC), according to results from cohort 2 of a phase 2 study (NCT03634540).¹

The confirmed objective response rate (ORR) shown with belzutifan plus cabozantinib was 30.8% (95% CI, 18.7%-45.1%). The ORR included 1 complete response (2%), 15 partial responses (29%), 32 cases of stable disease (62%), and progressive disease in 3 patients (6%). Response data were not available for 1 patient (2%).

"Earlier work credentialed HIF2α transcription factor as a driver in ccRCC and VHL disease and investigators have sought to bring HIF2α inhibitors to the clinic," David McDermott," MD told Targeted Oncology^TM.

Preclinical research hinted that belzutifan, a first-in-class HIF-2α inhibitor, might block HIF-2αdriven VEGF gene expression, considering that HIF activates VEGF expression in tumors cell, hypoxic stromal cells, and immune cells. In a phase 1 study (NCT02974738), belzutifan demonstrated antitumor activity in patients with heavily pretreated ccRCC. The ORR observed was 25% out of 55 patients treated.

"Over the last several years, studies of a first-in-class inhibitor belzutifanestablished proof of concept that HIF2α can be drugged. Single agent belzutifan was well tolerated and clinically active in a subset of heavily pre-treated patients.² Building on this work, a pivotal belzutifan trial was launched in ccRCC patients who have failed standard therapy and results are eagerly awaited (NCT04195750)," added McDermott, professor, Medicine, Harvard Medical School, staff physician, Hematology/Oncology, Beth Israel Deaconess Medical Center, and director, Biologic Therapy and Cutaneous Oncology Programs, Hematology/Oncology, Beth Israel Deaconess Medical Center.

In the phase 2 study, investigators aimed to determine the antitumor activity and safety of belzutifan and the VEGFR inhibitor cabozantinib in patients with advanced ccRCC who were either treatment-naïve (cohort 1) or previously treated with immunotherapy (cohort 2).

The primary end point of the study was ORR, and the secondary end points were duration of response (DOR), progression-free survival (PFS), time to response (TTR), overall survival (OS), the number of patients with adverse events (AEs), and the number of patients who discontinue treatment due to AEs. The study also investigated plasma concentration and plasma metabolite concentration of belzutifan, and plasma concentration of cabozantinib.³

Image Credit: © Saiful52 [stock.adobe.com]

Overall, 117 patients were screened for the study and 29 were excluded based on the enrollment criteria. All patients were required to have locally advanced or metastatic ccRCC, at least 1 measurable lesion, an ECOG performance status of 0 or 1, and adequate organ function. For inclusion in cohort 2, patients must also have been previously treated with immunotherapy and no more than 2 prior treatments for advanced or metastatic ccRCC. Ultimately, 88 patients were enrolled in the study, 32 of whom were included in cohort 1, and 52 of whom were included in cohort 2.¹

Cohort 2 had a median age of 63.0 (57.5-68.5) years and patients were predominantly male (73%). In terms of race and ethnicity, most patients identified as not Hispanic or Latino (94%), and 92% of the population identified as White. Asian and Black patients made up 8% of the population (4% each).

ECOG performance status at baseline was 0 in 44% of patients and 1 in 56%. Most patients included in cohort 2 had intermediate-risk disease (71%), but patients with favorable-risk disease made up 21% of the population, and 8% of patients were poor risk. Fifty-six percent of patients received 1 prior line of therapy, and 44% received 2 prior lines. In terms of the type of prior anticancer therapy, 54% of patients had immunotherapy alone, and 46% had immunotherapy and anti-VEGF therapy or anti-VEGFR therapy. Eighty-one percent of patients had previously undergone nephrectomy.

Results for the second end points were encouraging, according to the study investigators. The median DOR observed with belzutifan plus cabozantinib was 18.6 months (95% CI, 8.3-22.8). with 34 PFS events, the combination showed a median PFS of 13.8 months (95% CI, 9.2-19.4). The estimated PFS rate at 12 months was 56.2% (95% CI, 40.5-69.2). Belzutifan plus cabozantinib also showed a median OS of 24.1 months (95% CI, 20.0-37.4) based on 26 events. The estimated 12-month OS was 76.5% (95% CI, 62.3-85.9).

Toni K. Choueiri, MD

"This is the first evidence that combining a VEGF TKI and HIF2 inhibitor is safe and can result in activity. The results are relevant because such combination is moving to a phase 3 and perhaps one day will become a standard of care," said Toni K. Choueiri, MD, director, Lank Center for Genitourinary Oncology, and medical director, International Strategic Initiative at Dana-Farber Cancer Insititute, and Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School.

For safety, all 52 patients in cohort 2 experienced AEs of any cause, and these AEs were grade 3 to grade 5 in 73% of patients. Any-grade treatment-related AEs (TRAEs) occurred in 98% of patients in cohort 2, and grade 3 TRAEs were observed in 63%. No grade 4 TRAEs were observed, but 1 patient (2%) experienced a grade 5 TRAE.

The most frequent grade 3/4 TRAEs were anemia (15%), fatigue (12%), and hypertension (27%). Serious TRAEs occurred in 29% of patients in cohort 2. The events included acute kidney injury, which occurred in 4% of patients, as well as anemia, asthenia, cardiac failure, decreased ejection fraction, hypoxia, intestinal perforation, mental status changes, myocardial infarction, perineal rash, respiratory failure, seizure, transient ischemic attack, and wound infection, which each occurred in 2% of patients.

Twenty-seven percent of patients required dose reductions due to belzutifan-related AEs. Dose interruptions occurred in 58% of patients. Finally, AEs led to treatment discontinuation of belzutifan in 19% of patients and discontinuation of cabozantinib in 21%.

"Investigators are now attempting to confirm the value of this approach in a randomized trial of belzutifan+lenvatinib versus cabozantinib [NCT04586231] that is enrolling," said McDermott.

"Many things are on the horizon for belzutifan. The combination of belzutifan and cabozantinib is for refractory disease, but it's also used in a triplet combination with the addition of an IO agent like pembrolizumab. This is a 1L study that is recruiting patients at this time," said Choueiri.

_REFERENCES:

_{1. Choueiri TK, McDermott DF, Merchan J, et al. Belzutifan plus cabozantinib for patients with advanced clear cell renal cell carcinoma previously treated with immunotherapy: an open-label, single-arm, phase 2 study. Published online March 31, 2023. doi:10.1016/S1470-2045(23)00097-9}

_{2. Choueiri TK, Bauer TB, Papadopolous KP, et al. Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. Nat Med. 2021;27(5):802-805. doi: 10.1038/s41591-021-01324-7.}

_{3. A trial of belzutifan (PT2977, MK-6482) in combination with cabozantinib in patients with clear cell renal cell carcinoma (ccRCC) (MK-6482-003). ClinicalTrials.gov. Updated January 12, 2023. Accessed May 5, 2023. https://bit.ly/3VCWDR5}