Data from the phase 2 LITESPARK-003 trial demonstrated antitumor activity and a well-tolerated safety profile with belzutifan plus cabozantinib in patients with clear cell renal cell carcinoma.
According to data from Cohort 1 of the phase 2 LITESPARK-003 trial (NCT03634540) presented at the 2022 European Society for Medical Oncology Congress (ESMO), belzutifan (Welireg) plus cabozantinib (Cabometyx) was well tolerated and demonstrated promising antitumor activity in patients with treatment-naïve advanced clear cell renal cell carcinoma (RCC).1
At a median follow-up of 14.0 months, the objective response rate (ORR) per investigator assessment was 57% among 35 treated patients. The complete response (CR) and partial response (PR) rates were 6% and 51%, respectively, with stable disease (SD) reported in 13 patients (37%). Combined, this resulted in a disease control rate (DCR) of 94%. No patients experienced disease progression. Two patients did not have an opportunity for assessment postbaseline but were reported as remaining on treatment at data cutoff.
“Responses occurred across all International mRCC Database Consortium risk groups—both in the favorable and intermediate/poor risk groups,” Jamie R. Merchan, MD, said in a presentation of the data. “The data have led us to preliminarily conclude that dual targeting of HIF-2α and VEGF pathways may be an effective treatment strategy in advanced clear cell RCC.” Merchan is medical oncologist with the University of Miami Health System.
In the favorable-risk group (n = 21), the ORR was 62%, with 2 patients (10%) having a CR and 11 patients (52%) having a PR to treatment. Stable disease was reported in 29% of patients for a DCR of 90%. In the intermediate/poor-risk group (n = 14), the ORR was 50% with patients either having a PR (50%) or SD (50%), translating to a DCR of 100%.
The median time to response was 1.9 months (range, 1.7-9.2) and the median duration of response was 28.6 months (range, 1.7+ to 28.6), with 78% of responders having a response of at least 12 months. At the time of data cutoff, 25 patients (71%) remained on treatment.
Belzutifan, a potent and selective HIF-2α inhibitor, was initially evaluated in heavily pretreated patients in early-phase studies and demonstrated encouraging response and DCR rates across risk groups, according to Andre Fay, MD, an invited discussant of the abstract. He pointed to data from the phase 1/2 trial (NCT02974738), which showed that single-agent belzutifan elicited an ORR of 24% with a DCR of 24% among 55 treated patients.2
“Anti-VEGF increases HIF-2α concentration, providing a rationale for the combination of the  inhibitors,” said Fay, who is a professor of medicine PUCRS School of Medicine and chief of the Medical Oncology Department at the Hospital Sírio-Libanês in Brazil.
LITESPARK-003 enrolled patients with locally advanced or metastatic clear cell RCC who were either treatment-naïve (cohort 1) or had received treatment with no more than 2 prior lines of immunotherapy for advanced or metastatic RCC (cohort 2). Patients must have had an ECOG performance status of 0 or 1.1
In cohort 1, patients received belzutifan at 120 mg plus cabozantinib at 60 mg, both administered orally once daily.
The median age of the patients was 64.0 years (range, 33-89) and most were men (83%). The majority had an ECOG performance status of 0 (60%) and favorable-risk disease (60%). Twenty-six patients (74%) received prior nephrectomy.
In an analysis of best percentage change from baseline in tumor lesions, Merchan noted that 1 patient with a CR had an 88% reduction in both nodal and non-nodal lesions, with the non-nodal lesion having 100% reduction in size and the lymph node being reduced to fewer than 10 mm in diameter.
Progression-free survival (PFS) and overall survival (OS) estimates were also presented. The median PFS was 30.3 months (95% CI, 9.4–not reached [NR]), with 67% of patients free of progression at 12 months. At the time of data cutoff, 2 patients died, and the median OS was not reached. The 12-month OS rate was 96%.
Treatment-related adverse effects (TRAEs) were reported in 97% of patients. Grade 3 or higher TRAEs occurred in 37% of patients with no grade 4 or 5 TRAEs reported. One patient discontinued cabozantinib due to a TRAE and no patients discontinued belzutifan due to a TRAE. Serious TRAEs occurred in 2 patients. Dose reductions were reported at rates of 20% and 74% for belzutifan and cabozantinib, respectively.
The most common any-grade TRAEs included anemia (71%), diarrhea (71%), fatigue (63%), dysgeusia (46%), nausea (43%), palmar-plantar erythrodysesthesia (37%), hypertension (34%), increased alanine aminotransferase (31%), increased aspartate aminotransferase (29%), decreased appetite (29%), thrombocytopenia (26%), hypophosphatemia (26%), stomatitis (20%), hypothyroidism (20%), and decreased weight (20%).
Grade 3 TRAEs were reported for anemia, fatigue, palmar-plantar erythrodysesthesia, hypertension. One grade 3 TRAE was reported in each of the following: colitis, abdominal abscess, decreased weight, decreased platelet count, hypoxia, and dyspnea.
“Anemia and hypoxia are 2 AEs of clinical or special interest because they are associated with belzutifan therapy,” Merchan noted. “HIF-2α upregulated erythropoietin expression, and therefore, inhibition of this transcription factor results in reductions in erythropoietin and may result in anemia.”
Of the 25 patients with anemia, 7 patients received erythropoiesis-stimulating agents and 1 patient received a blood transfusion.
“The mechanism of belzutifan hypoxia is not well understood, however, what hypothesis states is that HIF-2α inhibition may impair the pulmonary arterial vasoconstrictive response to ventilation/perfusion mismatch, which may result in hypoxia,” Merchan added. Hypoxia was managed in the 2 individuals, with supplemental oxygen given to 1 patient and dose reduction in the second patient.
“Only 1 patient discontinued treatment, and it was [identified as being related to TRAEs with] cabozantinib, so this seem to be a safe combination, but we still need to be careful with hypoxia in other specific characteristics of belzutifan,” Fay said. “Cabozantinib plus belzutifan results in encouraging activity in treatment-naïve clear cell RCC, but longer follow-up is needed for survival outcomes. There is a rationale for higher responses in an angiogenesis-driven population and randomized trials evaluating the combination of belzutifan in different stages of the disease are ongoing.”
The phase 3 LITESPARK-011 trial (NCT04586231) will investigate belzutifan plus lenvatinib in patients with previously treated advanced clear cell RCC and is open for enrollment.