HIF-2α is constitutively activated in RCC and is a transcription factor of multiple oncogenic pathways including TGF-α, GLUT1, cyclin D1, CXCR4, and VEGF. VEGF, and its receptor, are key regulators of angiogenesis and are upregulated in RCC. Belzutifan, a first-in-class HIF-2α inhibitor, has shown antitumor activity and favorable safety in heavily pretreated advanced RCC. Cabozantinib, a multikinase inhibitor that targets VEGF, is approved for advanced RCC. We present the first data of the use of belzutifan plus cabozantinib for treatment-naive pts with advanced RCC (cohort 1) enrolled in the ongoing, open-label, phase 2 LITESPARK-003 study (NCT03634540).
Treatment-naïve pts with advanced clear cell RCC and ECOG PS of 0/1 received belzutifan 120 mg QD PO plus cabozantinib 60 mg QD PO. The primary end point was confirmed ORR (CR + PR) per RECIST v1.1 by investigator review. Secondary end points were DOR, PFS, OS, and safety.
Of 35 pts enrolled in cohort 1, 10 (29%) discontinued treatment; primarily due to progressive disease (n=8; 23%). Median age was 64 years (range, 33-89) and most pts had an ECOG PS of 0 (n=21; 60%), and IMDC favorable risk (n=21; 60%). Median follow-up was 14.0 mo (range, 0.2-33.0). Confirmed ORR was 57% (2 CRs, 18 PRs) and 13 pts (37%) had a best response of SD. Median DOR was 28.6 mo (range, 1.7+ to 28.6); 13 pts remained in response for ≥6 mo. Median PFS was 30.3 mo (95% CI, 9.4 to not reached); the estimated 12-mo PFS rate was 67%. Median OS was not reached; the estimated 12-mo OS rate was 96%. By IMDC risk category, ORR was 62% in 21 pts with favorable risk and 50% in 14 pts with intermediate/poor risk. In all pts, the most common any grade treatment-related AEs were anemia (n=25; 71%) and diarrhea (n=25; 71%). Grade 3 treatment-related AEs occurred in 13 pts (37%), most commonly hypertension (n=4; 11%) and fatigue (n=3; 9%). There were no grade 4 or 5 treatment-related AEs. 1 pt (3%) discontinued cabozantinib due to an AE (abdominal abscess). No pt discontinued belzutifan due to an AE.
Belzutifan plus cabozantinib had manageable safety with promising antitumor activity in treatment-naïve pts with advanced clear cell RCC.
Clinical trial identification
NCT03634540 Release date: August 16, 2018.