Targeted Combination Shows Promise in Metastatic Kidney Cancer

LOUISVILLE, Ky. — More than half of patients with newly diagnosed metastatic kidney cancer responded to a novel drug combination, which held disease progression at bay for 2 years, a small multicenter clinical study showed.

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%). AEs necessitated treatment delays in 30 patients, reported Saby George, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, at the International Kidney Cancer Symposium (IKCS).

“This novel regimen was well tolerated and demonstrated promising efficacy and safety in treatment-naive, predominantly favorable-risk patients,” said George. “None of the IO [immuno-oncology] combinations have been able to show a survival advantage in favorable-risk patients, so this may be relevant [for those patients] and also for patients who cannot receive checkpoint inhibitors.”

“We had some patients with proteinuria, but none of them required discontinuation,” he added. “We did not see any microangiopathic hemolytic anemia, as seen in various other trials that combined the two drugs. This novel regimen could be a viable option for patients with metastatic RCC [renal cell carcinoma].”

VEGF inhibitors are widely used in the treatment of metastatic RCC, and pazopanib received FDA approval on the basis of its ability to prolong PFS in metastatic RCC, George noted in his introductory comments. Single-agent pazopanib led to a median PFS of 11 months in untreated patients.

“VEGF upregulation is postulated to be a resistance mechanism against VEGF tyrosine kinase inhibitors,” he said. “We hypothesized that introducing bevacizumab during scheduled breaks in pazopanib treatment can bind and neutralize VEGF, thereby prolonging progression-free survival in metastatic RCC. Due to built-in breaks in this novel regimen, we anticipated lesser toxicity.”

Almost 70% of the patients enrolled in the trial had favorable-risk disease. They received pazopanib on days 1-28 and bevacizumab on days 36 and 56 of a 10-week cycle. The primary endpoint was 12-month CBR, and 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).

Exploring Belzutifan Safety

Anemia and hypoxia emerged as the predominant severe toxicities associated with recently approved first-in-class HIF-2α inhibitor belzutifan (Welireg), according to pooled data from four clinical trials in kidney cancer.

The data showed grade ≥3 anemia in 166 of 576 (28.8%) patients treated in the trials and grade ≥3 hypoxia in 70 (12.2%) patients. The median time to first occurrence of grade ≥3 anemia was 29 days and median time to resolution was 70 days. Median time to first occurrence of grade ≥3 hypoxia was 30 days. Median time to resolution was 11 days, and median duration of supplemental oxygen was 9 days, reported Pooja Ghatalia, MD, of Fox Chase Cancer Center in Philadelphia.

“Belzutifan had a generally manageable safety profile and few patients [6%] discontinued treatment due to adverse events [AEs],” she said. “AEs had a relatively early onset [median 3 months]. As expected, anemia and hypoxia were among the most frequent AEs. To date this is the largest pooled safety dataset for a HIF-2α inhibitor. Belzutifan has a unique mechanism of action from other approved RCC treatments and is the only treatment approved in patients with Von Hippel-Lindau [VHL] disease tumors.”

A second study reported at the IKCS showed 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, reported A.J. Winer, MD, of Vanderbilt University Medical Center in Nashville, Tennessee.

The analysis included 44 patients treated with belzutifan from 2018-2024, 22 each with VHL or sporadic RCC. The primary outcomes were incidence and time to onset of hypoxia and need for supplemental oxygen and the time to onset and incidence of anemia.

Any-grade anemia occurred in a similar proportion of patients with VHL (90.9%) or sporadic RCC (81.8%). Time to onset was substantially longer with VHL-associated RCC (82 vs 29 days). Grade ≥3 occurred in 54.5% of the sporadic group versus 36.4% of the VHL group.

Any-grade and grade ≥3 hypoxia occurred substantially more often in the sporadic group (59.1% vs 18.2%, 54.5% vs 9.1%). Median time to onset of grade ≥3 hypoxia was 29 days in patients with sporadic disease and 225 days in the VHL group. Subsequently, 40.9% of patients with sporadic RCC required supplemental oxygen as compared with 9.1% of the VHL group.

Median time on belzutifan was 30.9 months in the VHL group versus 3.4 months in the sporadic group. Patients with sporadic RCC were substantially older (median age 67 vs 41) and more likely to have chronic kidney disease (36.4% vs 4.5%). Those two factors likely contributed to the disparity in anemia and hypoxia, Winer acknowledged.

Challenges of 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, a small clinical trial showed.

The observation came from a phase I study of 22 patients with previously untreated advanced RCC. Sitravatinib inhibits VEGF, c-MET, and TAM, potentially offering an opportunity to augment response to nivolumab, said Pavlos Msaouel, MD, PhD, of the University of Texas MD Anderson Cancer Center.

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 treated with that regimen developed immune-related adverse events (irAEs), leading to discontinuation of nivolumab in six cases and ipilimumab in four. However, six patients had complete or partial responses and the seventh had stable disease.

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, one patient discontinued the targeted drug and three patients each discontinued nivolumab and ipilimumab.

The regimen remained active after the reduction in ipilimumab dose but did not achieve the same efficacy results as observed in the initial cohort.

“Sitravatinib could not be safely combined with ipilimumab 1 mg/kg due to irAEs,” said Msaouel. “Dose reduction of ipilimumab to 0.7 mg/kg allowed safe sitravatinib escalation, potentially at the cost of efficacy.”

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. Investigators also identified a tumor cell-specific transcriptomic signature linked to treatment resistance and poor outcomes. The observations may represent biomarkers for resistance that could guide future strategies to enhance immunotherapy effectiveness in RCC, Msaouel said in conclusion.