Novel Regimens Show Promise in Metastatic Kidney Cancer Treatment

More than half of patients with newly diagnosed metastatic kidney cancer (搜索)搜索该疾病 responded to a novel drug combination of pazopanib查看药品详情 and bevacizumab查看药品详情, 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 (搜索)搜索该疾病 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查看药品详情 (Votrient) plus bevacizumab查看药品详情 (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查看公司主页 in Buffalo, New York, noted that VEGF (搜索)搜索该靶点 upregulation is postulated to be a resistance mechanism against VEGF tyrosine kinase inhibitors. The hypothesis was that introducing bevacizumab查看药品详情 during scheduled breaks in pazopanib查看药品详情 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 (搜索)搜索该疾病 and hypoxia (搜索)搜索该疾病 emerged as the predominant severe toxicities associated with belzutifan查看药品详情 (Welireg), a first-in-class HIF-2α inhibitor, according to pooled data from four clinical trials in kidney cancer (搜索)搜索该疾病. 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查看药品详情 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 (搜索)搜索该疾病 and hypoxia (搜索)搜索该疾病 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查看药品详情 from 2018-2024, 22 each with VHL or sporadic RCC. Any-grade anemia (搜索)搜索该疾病 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 (搜索)搜索该疾病 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查看药品详情 could not be safely combined with the immunotherapy doublet of nivolumab查看药品详情 (Opdivo) and ipilimumab查看药品详情 (Yervoy) except with a lower dose of the CTLA-4 (搜索)搜索该靶点 inhibitor, according to a small phase I clinical trial of 22 patients with previously untreated advanced RCC.

Treatment began with sitravatinib查看药品详情 35 mg/day, nivolumab查看药品详情 3 mg/kg every 3 weeks and ipilimumab查看药品详情 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查看药品详情 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.