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Combination treatment with a hypoxia-inducible factor (HIF) 2α inhibitor and tyrosine kinase inhibitor induced responses in nearly a third of advanced renal cell carcinoma (RCC) patients previously treated with immunotherapy, a found.

In the study of 52 patients, 30.8% (95% CI 18.7-45.1) had a confirmed objective response following treatment with belzutifan (Welireg) plus cabozantinib (Cabometyx), including one complete response, reported Toni Choueiri, MD, of the Dana-Farber Cancer Institute in Boston, and colleagues.

And as described in , the median duration of response was 18.6 months (95% CI 8.3-22.8) following the combination.

"To our knowledge, this is the first trial to show that the combination of an HIF-2α inhibitor and a tyrosine-kinase inhibitor targeting VEGFR is tolerable and might offer more benefit than either drug as monotherapy," the authors wrote. "Results from this study provide a rationale for further randomized trials with HIF-2α inhibitors."

Over a follow-up of 24.6 months, the median progression-free and overall survival reached 13.8 month and 24.1 months, respectively, according to the findings.

In explaining the rationale behind the study, Choueiri and co-authors noted that effectively managing patients with RCC who have received prior therapies is "challenging."

While first-line treatment with anti-PD-1/L1-based combinations have improved clinical outcomes in advanced disease, "most patients will have their disease progress on first-line therapy," they explained.

Belzutifan is currently approved for cancers associated with von Hippel-Lindau (VHL) disease, while cabozantinib is approved in RCC, liver cancer, and thyroid cancer.

"This study represents a much needed treatment strategy in pretreated patients, considering the shortage of options after immunocombination therapy," wrote Veronica Mollica, MD, and Francesco Massari, MD, both of the University of Bologna in Italy, in a , adding that the results underline the "emerging role of the HIF inhibitor belzutifan, which is being widely investigated in different stages of renal cell carcinoma, from the adjuvant setting to metastatic disease."

The researchers noted that an ongoing phase III trial is comparing belzutifan in combination with lenvatinib (Lenvima) versus cabozantinib in clear cell RCC for patients who progressed after immunotherapy and up to two systemic regimens.

"Given its ambitious target and a plethora of promising preliminary evidence in support, belzutifan is a strong candidate to open a new therapeutic field," Mollica and Massari observed. "The right setting and combination drug, if needed, remains to be investigated, as well as whether belzutifan could supersede or be combined with cabozantinib as second or further line of therapy."

The study from Choueiri and colleagues enrolled 117 RCC patients at 10 sites in the U.S., including a cohort of 52 patients previously treated with immunotherapy-based regimens (current study) and a separate cohort involving treatment-naive disease (results to be reported at a later date).

In the previously treated group (up to two systemic regimens), patients had a median age of 63 years and about three-fourths were men. All had locally advanced or metastatic clear cell RCC and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.

A majority (54%) had previously received received immunotherapy only, while the rest had a combination that included immunotherapy and an anti-VEGF/VEGFR tyrosine kinase inhibitor.

Following treatment with belzutifan-cabozantinib, 15 patients had a confirmed partial response (29%) and one had a complete response (2%). Median time to response was 3.2 months. In addition, 32 patients (62%) had a best response of stable disease. Overall, 45 patients (87%) had a reduction in the sum of diameters of target lesions.

Treatment-related adverse events (TRAEs) occurred in 98% of patients, with grade 3 TRAEs occurring in 63% and serious TRAEs in 29%.

The most frequent grade 3 TRAEs were anemia (15%), fatigue (12%), and hypertension (27%). There were no grade 4 TRAEs and one grade 5 TRAE of respiratory failure.

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