Belzutifan (MK-6482) is a HIF-2α inhibitor (hypoxia-inducible factor 2α), which showed favorable antitumor activity and safety as monotherapy, in a phase I trial of patients with metastatic clear cell renal carcinoma (ccRCC)
During the 2021 Genitourinary Cancers Symposium, a preliminary analysis of the phase II trial (NCT03634540), which investigates the combination of belzutifan (MK-6482) and cabozantinib, was presented in patients with advanced clear cell renal carcinoma (ccRCC) previously treated (cohort 2), including immunotherapy and tyrosine kinase inhibitors (TKI). Cohort 1, in turn, involves patients who were exposed to the same intervention strategy, but who had not been treated previously.
In cohort 2, individuals with metastatic ccRCC were recruited, who received no more than two previous systemic treatment regimens. Initially, six participants, from cohort 1 and 2, were treated with belzutifan 120 mg and cabozantinib 60 mg orally once daily for 21 days. A safety review committee conducted an initial efficacy assessment in patients who received ≥ a dose of treatment and who were followed up for ≥ 6 months.
Primary outcomes included objective response rate (ORR) according to the investigator’s analysis by RECISTv1.1. Secondary outcomes were progression-free survival (PFS), overall survival (OS), and response duration (DoR). Safety was assessed in all cohort participants.
Results:
The safety and tolerability of belzutifan 120 mg plus cabozantinib 60 mg were observed in the first six patients. Only one had limiting toxicity (hand-footsyndrome). Therefore, this regimen was determined as the recommended phase II dose.
In total, 53 participants were included in the safety analysis population. The average age was 64 years; 73.6% were male; 54.7% had ECOG 1; 28 (52.8%) received first-line therapies and 24 (45.2%) previous 2nd line therapies. The average time, from registration to cutoff date, was 11.3 months for those with ≥ 6 months of follow-up (n = 41).
The confirmed ORR was 22.0% (9 partial responses) and 90.2% had some tumor reduction. The disease control rate (complete response + partial response + stable disease) was 92.7%.
The median DoR was not reached; all responses were in progress. Median PFS was 16.8months. 6-month PFS rate was 78.3%. 6-month OS rate was 95.0%.
While 98.1% of patients experienced a treatment-related adverse event (TRAE), 92% were grade 1 and 2. Most common TRAEs (≥30%) were anemia (75.5%), fatigue (67.9%), hand-foot syndrome (52.8%), diarrhea (45.3%), hypertension (43.4%), nausea (35.8%) and alt or AST increase (32-34%). The incidence of grade 3 TRAEs greater than 5% was hypertension (22.4%), anemia (11.3%), fatigue (11.3%) and alt increase (5.7%). Two patients had grade 3 hypoxia (3.8%). There were no grade 4 TRAEs or deaths. Interruptions due to TRAEs occurred in six patients (11.3%) for belzutifan and eight (15.1%) for cabozantinib.
The authors conclude that, in this preliminary analysis, belzutifan, in combination with cabozantinib, demonstrated promising antitumor activity in patients previously treated with metastatic ccRCC. Safety was consistent with the individual profiles of each agent.
References:
Choueiri TK, 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). Abstract 272. 2021 Genitourinary Cancers Symposium. DOI:10.1200/JCO.2021.39.6_suppl.272.
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