First-Line Belzutifan/Cabozantinib Delivers Responses and Manageable Toxicities in ccRCC

Frontline belzutifan (Welireg) plus cabozantinib (Cabometyx) elicited durable responses and had a tolerable safety profile among patients with treatment-naive advanced clear cell renal cell carcinoma (ccRCC), according to findings from cohort 1 of the phase 2 LITESPARK-003 trial (NCT03634540), which were published in Lancet Oncology in January 2025.1

At a data cutoff date of May 15, 2023, and a median follow-up of 24.3 months (IQR, 13.9-32.0), 70% (95% CI, 55%-82%) of patients enrolled in cohort 1 (n = 50) achieved a confirmed overall response rate (cORR). The complete and partial response rates were 8% and 62%, respectively.

“Belzutifan plus cabozantinib has promising antitumor activity in treatment-naive patients with ccRCC,” lead study author Toni K, Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute in Boston, Massachusetts, and coauthors, wrote in the paper. “To our knowledge, this is the first trial in a first-line setting to show that the VEGFR-targeting combination of an HIF-2α inhibitor and a TKI has manageable toxicity.”

Trial Background and Design

The first-in-class HIF-2α inhibitor belzutifan has previously demonstrated antitumor activity in patients with pretreated advanced kidney cancer. In 2023, the FDA approved belzutifan for the treatment of patients with advanced RCC who have received prior treatment with a PD-1/PD-L1 inhibitor and a VEGF TKI.2 This regulatory decision was supported by findings from the phase 3 LITESPARK-005 trial (NCT04195750), in which belzutifan generated a statistically significant progression-free survival (PFS) improvement compared with everolimus (Afinitor; HR, 0.75; 95% CI, 0.63-0.90; 1-sided P =.0008).

“We hypothesized that use of a synergistic VEGFR-targeting approach involving belzutifan in combination with cabozantinib might offer enhanced clinical benefits to patients with ccRCC compared with using either drug in isolation,” investigators on the LITESPARK-003 trial noted in the publication.1

The ongoing, open-label, single-arm LITESPARK-003 trial investigated the efficacy and safety of belzutifan plus cabozantinib in patients with previously untreated advanced ccRCC (cohort 1) or those with ccRCC who had received prior immunotherapy (cohort 2). Preliminary data from cohort 2 have been previously reported.

Between September 27, 2018, and January 10, 2023, cohort 1 enrolled 50 patients at least 18 years of age with an ECOG performance status of 0 or 1 and measurable disease per RECIST 1.1 criteria who had received no prior systemic therapy for locally advanced or metastatic RCC. Eligible patients also needed to have adequate organ function, platelet counts, creatinine or transaminase levels, and bilirubin levels.

Patients were excluded from enrollment onto cohort 1 if they had received prior therapy with a HIF-2α inhibitor, cabozantinib, or both; had received radiotherapy for bone metastases within 2 weeks, or any other external radiotherapy lasting at least 5 days to sites other than bone within 4 weeks of receiving the first dose of study therapy; had clinically relevant ongoing major complications associated with prior radiotherapy; or if they had not recovered from the effects of prior anticancer therapy to baseline levels or grade 1 severity or lower. Notably, patients with treatable adverse effects (AEs) were permitted to enroll if their AEs were controlled with treatment.

Patients in cohort 1 received belzutifan at 120 mg orally once daily in combination with cabozantinib at 60 mg orally once daily until unacceptable AEs, disease progression, or patient withdrawal. To manage AEs, the dose of belzutifan could be reduced to 80 mg once daily and then to 40 mg once daily at investigators’ discretion. The dose of belzutifan could be re-escalated if the patient had resumed treatment with the agent at a given dose level for a minimum of 28 days with no reoccurrence of the original AE. Belzutifan was discontinued if the once-daily 40 mg dose led to unacceptable toxicity.

Reducing the dose of cabozantinib to 40 mg once daily and then to 20 mg once daily was also permitted. Cabozantinib was discontinued if the once-daily 20 mg dose led to unacceptable toxicity.

Interrupting treatment with belzutifan and cabozantinib due to toxicity was permitted for up to 3 weeks per investigator discretion. Patients who stopped either of the 2 drugs for reasons other than disease progression could continue to receive the other drug as a single agent. A protocol amendment permitted the continuation of study treatment for patients with disease progression who were clinically stable provided that the investigator thought the patient could derive benefit.

Investigator-assessed cORR per RECIST 1.1 criteria served as the trial’s primary end point. Secondary end points included time to response (TTR), duration of response (DOR), PFS, overall survival (OS), and safety. Prespecified exploratory pharmacokinetic end points will be reported at a later date.

Baseline Characteristics and Additional Efficacy Findings

Patients in cohort 1 had a median age of 64 years (interquartile range [IQR], 57-72). Eighty percent of patients were male, 96% of patients were White, and 66% of patients had an ECOG performance status of 0. Patients were categorized as International Metastatic RCC Database Consortium (IMDC) favorable- (56%), intermediate- (40%), and poor-risk (4%). Eighty percent of patients had undergone prior nephrectomy. All patients received at least 1 dose of the study regimen and were included in the efficacy and safety analyses.

At the data cutoff date, the median duration of treatment was 12.6 months (IQR, 9.2-25.3) with belzutifan and 12.4 months (IQR, 7.4-24.9) with cabozantinib. Forty-eight percent of patients had discontinued treatment; the primary reason for discontinuation was progressive disease, which occurred in 54% of the 24 patients who discontinued treatment.

According to data from a post-hoc analysis, the disease control rate was 98% (95% CI, 89%-100%). Post-hoc and subgroup analyses also showed similar efficacy with the combination across IMDC risk groups.

The median TTR was 1.9 months (IQR, 1.8-3.7). Forty-eight percent of patients had ongoing treatment, and the median DOR was 28.6 months (95% CI, 11.2-not reached [NR]).

Progression events or death occurred in 38% of patients. The median PFS was 30.3 months (95% CI, 16.6- NR). The respective estimated 12- and 24-month PFS rates were 69% (95% CI, 52.1%-81.0%) and 57% (95% CI, 38.5%-72.0%).

At the data cutoff date, 5 patients had died. The median OS was NR (95% CI, NR-NR), and the estimated 12- and 24-month OS rates were 96% (95% CI, 84.2%-98.9%) and 86% (95% CI, 68.2%-94.0%), respectively.

Safety Findings and Next Steps

Study authors noted that, “To our knowledge, this is the first trial in a first-line setting to show that the VEGFR-targeting combination of a HIF-2α inhibitor and TKI has manageable toxicity.”

The safety profile for belzutifan plus cabozantinib was consistent with individual profiles for each agent. All patients experienced at least 1 all-cause AE; grade 3 or higher AEs occurred in 60% of patients. One patient died from AEs of hepatic failure and spontaneous bacterial peritonitis. Neither AE was considered treatment related per the investigator.

Treatment-related AEs (TRAEs) were observed in all patients, and grade 3 TRAEs occurred in 44% of patients. One patient experienced grade 4 hypertension, which was considered cabozantinib related. No grade 5 TRAEs were observed.

The most common grade 3/4 TRAEs were hypertension (12%), anemia (10%), fatigue (8%), hypoxia (6%), and palmar-plantar erythrodysesthesia (6%). Belzutifan-related anemia was observed in 86% of patients (grade 1/2, 76%; grade 3, 10%), and belzutifan-related hypoxia occurred in 8% of patients (grade 2, 2%; grade 3, 6%).

Serious TRAEs were seen in 14% of patients. Furthermore, angina pectoris, abdominal abscess, colitis, dyspnea, dysarthria, decreased ejection fraction, hypertension, and pneumonia occurred in 1 patient each; notably, patients could have experienced more than 1 of these AEs. Additionally, 1 patient had an abdominal abscess and colitis (related to cabozantinib), and 1 patient had dyspnea and pneumonia (related to belzutifan).

AEs led to belzutifan dose reductions and interruptions in 28% and 48% of patients, respectively. The most common AEs that led to belzutifan dose reduction were hypoxia (8%), and fatigue (6%). The most common AEs that led to belzutifan dose interruption were diarrhea (12%), fatigue (10%), dyspnea (8%), nausea (8%), palmar-plantar erythrodysesthesia (6%), and pneumonia (6%).

AEs led to cabozantinib dose reductions and interruptions in 74% of patients, respectively. The most common AEs that led to cabozantinib dose reduction were fatigue (28%), palmar-plantar erythrodysesthesia (22%), diarrhea (16%), and increased alanine aminotransferase levels (6%). The most common AEs that led to belzutifan dose interruption were diarrhea (18%), fatigue (14%), and palmar-plantar erythrodysesthesia (10%).

AEs led to belzutifan discontinuation and cabozantinib discontinuation in 10% and 12% of patients, respectively. AEs that led to belzutifan discontinuation included angina pectoris, decreased ejection fraction, hypertension, hepatic failure, and spontaneous bacterial peritonitis (1 patient each). One patient had 2 AEs leading to belzutifan discontinuation: hepatic failure and spontaneous bacterial peritonitis. AEs that led to cabozantinib discontinuation in 1 patient each included angina pectoris, abdominal abscess, diarrhea, hypertension, hepatic failure, palmar-plantar erythrodysesthesia, and spontaneous bacterial peritonitis. One patient had both hepatic failure and spontaneous bacterial peritonitis.

The study authors stated that the limitations of this research include the lack of a comparator group, a relatively small sample size, and unmasked investigator assessment. Moreover, the high percentage of patients with IMDC favorable-risk disease may limit the generalizability of these findings to patients in all IMDC risk groups.

“Results from this study support further investigation of this regimen, including biomarker analysis, to select patients for whom belzutifan plus cabozantinib might be most effective,” study authors concluded.

References

1. Choueiri TK, Merchan JR, Figlin R, et al. Belzutifan plus cabozantinib as first-line treatment for patients with advanced clear-cell renal cell carcinoma (LITESPARK-003): an open-label, single-arm, phase 2 study. Lancet Oncol. 2025;26(1):64-73. doi:10.1016/S1470-2045(24)00649-1
2. FDA approves belzutifan for advanced renal cell carcinoma. FDA. December 14, 2023. Accessed January 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-advanced-renal-cell-carcinoma?utm_medium=email&utm_source=govdelivery