More than half of patients with newly diagnosed metastatic kidney cancer responded to a novel drug combination of pazopanib and bevacizumab, which held disease progression at bay for 2 years, according to a small multicenter clinical study. The research was presented at the International Kidney Cancer Symposium (IKCS). This regimen may be relevant for favorable-risk patients and those who cannot receive checkpoint inhibitors.
Pazopanib and Bevacizumab Combination
Frontline treatment with pazopanib (Votrient) plus bevacizumab (Avastin) led to an objective response rate (ORR) of 54.9% and a 12-month clinical benefit rate (CBR) of 78%. The 51-patient cohort had a median progression-free survival (PFS) of 23.3 months and median overall survival (OS) of 64 months. The most common grade 3/4 adverse events (AE) were hypertension (33%) and increased liver function tests (12-14%). Treatment delays due to AEs were reported in 30 patients.
Saby George, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, noted that VEGF upregulation is postulated to be a resistance mechanism against VEGF tyrosine kinase inhibitors. The hypothesis was that introducing bevacizumab during scheduled breaks in pazopanib treatment can bind and neutralize VEGF, thereby prolonging progression-free survival in metastatic RCC. The trial had statistical power to detect a CBR of 60% (equivalent to a median PFS of 15.7 months) versus 45% (equivalent to a median PFS of 11.1 months).
With a median follow-up of 35 months, the 12-month CBR (78%) and PFS (23.3 months) exceeded prespecified efficacy objectives (PFS 95% CI 17.1-28.5 months, OS 95% CI 47.6 months to not reached).
Belzutifan Safety Profile
Anemia and hypoxia emerged as the predominant severe toxicities associated with belzutifan (Welireg), a first-in-class HIF-2α inhibitor, according to pooled data from four clinical trials in kidney cancer. The data showed grade ≥3 anemia in 166 of 576 (28.8%) patients and grade ≥3 hypoxia in 70 (12.2%) patients.
Pooja Ghatalia, MD, of Fox Chase Cancer Center in Philadelphia, stated that belzutifan had a generally manageable safety profile, with few patients (6%) discontinuing treatment due to adverse events (AEs). A second study reported differences in the frequency and severity of anemia and hypoxia among belzutifan-treated patients with VHL-associated versus sporadic RCC, observations that emphasized a need for personalized monitoring and management of patients.
The analysis included 44 patients treated with belzutifan from 2018-2024, 22 each with VHL or sporadic RCC. Any-grade anemia occurred in a similar proportion of patients with VHL (90.9%) or sporadic RCC (81.8%), but time to onset was substantially longer with VHL-associated RCC (82 vs 29 days). Any-grade and grade ≥3 hypoxia occurred substantially more often in the sporadic group (59.1% vs 18.2%, 54.5% vs 9.1%).
Challenges with Triplet Regimens
The multikinase inhibitor sitravatinib could not be safely combined with the immunotherapy doublet of nivolumab (Opdivo) and ipilimumab (Yervoy) except with a lower dose of the CTLA-4 inhibitor, according to a small phase I clinical trial of 22 patients with previously untreated advanced RCC.
Treatment began with sitravatinib 35 mg/day, nivolumab 3 mg/kg every 3 weeks and ipilimumab 1 mg/kg every 3 weeks. Six of the first seven patients developed immune-related adverse events (irAEs), leading to discontinuation of nivolumab in six cases and ipilimumab in four. After the ipilimumab dose was reduced to 0.7 mg/kg, no irAEs occurred in the next three patients. Investigators increased the sitravatinib dose to 70 mg, and no irAEs occurred in the next three patients. After investigators escalated the sitravatinib to the final planned dose of 100 mg, three patients developed dose-limiting toxicities.
Pavlos Msaouel, MD, PhD, of the University of Texas MD Anderson Cancer Center, noted that the regimen remained active after the reduction in ipilimumab dose but did not achieve the same efficacy results as observed in the initial cohort. Translational studies showed that emergence of treatment resistance in the tumor microenvironment was associated with a shift from cytotoxic to exhausted T-cell states and an increase in M2-like myeloid cells.
