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NASHVILLE, Tenn. -- A higher dose of belzutifan (Welireg) being investigated for advanced clear cell renal cell carcinoma (ccRCC) did not improve outcomes as compared with the usual dose in other settings, a randomized trial showed.

A fourth of patients in each treatment group met the primary endpoint of objective response rate (ORR), and two thirds of patients in each group had a reduction in target lesion size. Time to response, duration of response (DOR), and progression-free survival also did not differ significantly between the 120- and 200-mg groups.

However, the higher dose was associated with more dose modification and discontinuation for any reason as well as discontinuation because of treatment-related adverse events (TRAEs), reported Pooja Ghatalia, MD, of Fox Chase Cancer Center in Philadelphia, during the International Kidney Cancer Symposium.

"These results, together with results from the phase III LITESPARK-005 study, continue to support the 120-mg once-daily dose of belzutifan in patients with clear cell renal cell carcinoma," said Ghatalia.

A first-in-class oral hypoxia-inducible factor (HIF)-2α inhibitor, belzutifan has for several von Hippel-Lindau disease-associated tumors, including RCC, with treatment at a recommended dose of 120 mg. HIF-2α is a of ccRCC, and belzutifan showed antitumor activity in a of previously treated advanced ccRCC. A fourth of patients had objective responses across the dose range evaluated, and no dose-limiting toxicities occurred at doses as high as 160 mg/day, Ghatalia noted.

The phase I results provided the rationale for continued evaluation of belzutifan in a phase II study, . That randomized comparison of 120- and 200-mg doses in previously treated ccRCC included patients who had received as many as three prior therapies but no more than one anti-PD1/L1 agent.

Investigators randomized 154 patients to the two belzutifan doses, and all patients received at least one dose of assigned therapy. Median follow-up was 20.1 months.

Median ages were 62-65 years across groups; men accounted for three fourths of all patients. Half the patients had received one prior tyrosine kinase inhibitor (TKI), and another 28% had received none.

Ghatalia reported that 18 patients in each group responded to belzutifan (23.1% and 23.7% in the 200- and 120-mg arms, respectively), including four complete responses in the 200-mg arm. An additional 61 patients randomized to the higher dose and 57 to the 120-mg dose had stable disease, resulting in disease control rates of 78.2% and 75.0%, respectively.

The data showed that 51 of 78 (65%) patients in the 200-mg arm had some degree of tumor shrinkage, as did 52 of 76 (68%) in the 120-mg group. A subgroup analysis showed comparable response rates by age, sex, race, prior TKI regimens, and prior lines of therapy. Median time to response was 3.6 months in both groups.

For the key secondary endpoints, median DOR was 16.1 months with the 200-mg dose but not yet reached with the 120-mg dose, and median progression-free survival was numerically but not statistically higher with the 200-mg dose (9.1 vs 7.3 months, HR 0.94, P=0.3861).

Survival data remained immature, and the median overall survival had yet to be reached in either group. The lower value of the 95% confidence intervals numerically favored the 120-mg dose (22.0 vs 20.6 months).

Grade ≥3 AEs occurred in a similar proportion of patients allocated to 200 mg (69.2%) and 120 mg (68.4%) of belzutifan, as did serious AEs (42.3% vs 43.4%). Dose modification occurred more often with the higher dose (57.7% vs 46.1%), and more patients assigned to the higher dose discontinued treatment because of AEs (14.1% vs 5.3%). TRAEs occurred in a similar proportion of patients in each group, but more patients in the 200-mg arm discontinued treatment because of TRAEs (9.0% vs 2.6%).

The most common TRAEs (any grade) with 200 mg or 120 mg of belzutifan were anemia (80.8% vs 75.0%), fatigue (41.0% vs 43.4%), and hypoxia (26.9% vs 23.7%). The same three AEs were the most common grade ≥3 events in both arms.

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