LITESPARK-013 Data Support RP2D of Belzutifan as Standard Option in Advanced ccRCC


Administration of the hypoxia-inducible factor–2α inhibitor belzutifan (Welireg) at the recommended phase 2 dose of 120 mg daily produced comparable toxicities and efficacy outcomes to that of a daily 200-mg dose of the agent in patients with advanced clear cell renal cell carcinoma.

Pooja Ghatalia, MD

Pooja Ghatalia, MD

Administration of the hypoxia-inducible factor (HIF)–2α inhibitor belzutifan (Welireg) at the recommended phase 2 dose (RP2D) of 120 mg daily produced comparable toxicities and efficacy outcomes to that of a daily 200-mg dose of the agent in patients with advanced clear cell renal cell carcinoma (ccRCC), according to findings from the randomized phase 2 LITESPARK-013 study (NCT04489771).1

Results presented at the 2023 International Kidney Cancer Symposium showed that patients in the 200-mg dose group experienced an overall response rate (ORR) of 23.1% by blinded independent central review (BICR), which included a complete response (CR) rate of 5.1% and a partial response (PR) rate of 17.9%. Similarly, the overall response rate with the 120-mg dose was 23.7% and was comprised entirely of partial responses. This resulted in an estimated difference of -0.5% (range, -14.0-12.9) between response rates (one-sided P = .5312).

“The ORRs by subgroup analysis were also very similar regardless of the various characteristics including age, race, gender, geographic region, [International Metastatic Disease Consortium; (IMDC] risk factors, and prior lines of therapy,” lead study author Pooja Ghatalia, MD, of Fox Chase Cancer Center, said in an oral presentation of the data.

More than half of patients in both arms experienced stable disease (55.1% in the 200-mg arm, 51.3% in the 120-mg arm). Progressive disease occurred in 15.4% and 19.7% of patients in the 200-mg and 120-mg arms, respectively. Disease control rates (DCR) were 78.2% and 75.0% in each respective arm. Notably, 6.4% of patients in the 200-mg arm and 5.3% in the 120-mg arm did not undergo assessment.

Assessment of secondary end points showed that the median duration of response (DOR) was 16.1 months (range, 2.1+-23.5+) with the 200-mg dose and not reached with the 120-mg dose (range, 2.6+-16.1+). The median time to response was 3.6 months for both groups (range, 1.7-5.5; range, 1.8-16.8).

Regarding survival outcomes, belzutifan led to a median progression-free survival of 9.1 months (95% CI, 5.5-12.0) at 200-mg and 7.3 months (95% CI, 5.6-9.5) at 120 mg (HR, 0.94; 95% CI, 0.63-1.4; P = .3861). The median overall survival was not reached (NR) in either arm (HR, 1.1; 95% CI, 0.65-1.90; P = .6448).

Moreover, 65% and 68% of patients in the 200-mg and 120-mg arms, respectively, experienced a reduction in target lesions from baseline. The response rates were comparable across subgroups between the 2 dose groups.

“If you compare the best percentage change from baseline in target lesions between the two groups… [the percentages] were very similar…” Ghatalia remarked during her presentation.

Belzutifan is currently approved by the FDA for the treatment of adult patients with von Hippel-Lindau disease with associated RCC, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors that do not require immediate surgery. The approval was based on results from the phase 2 LITESPARK-004 study (NCT03401788).2

“Belzutifan has also shown antitumor activity in patients with previously treated advanced RCC in the phase 1 LITESPARK-0013 study,” Ghatalia stated.

Previously reported data from the phase 1 LITESPARK-001 trial (NCT02974738) demonstrated the antitumor activity and manageable safety of belzutifan in pretreated patients with advanced ccRCC. At doses ranging from 20 mg to 240 mg, the agent produced an ORR of 25% and a DCR of 80% in patients with advanced ccRCC who were previously exposed to a median of 3 prior lines of therapy. The ORR included 1 complete response and 13 partial responses.

In patients with favorable risk disease (n = 13), the ORR was 31% with a DCR of 92%, while those with intermediate- or poor-risk disease (n = 42), had an ORR was 24% with a DCR of 76%. The maximum-tolerated dose of belzutifan was not reached. Based on the safety, pharmacokinetic, and pharmacodynamic data from this study, a daily 120-mg dose of belzutifan was selected as the RP2D.3

The LITESPARK-013 trial was conducted to further evaluate the safety and efficacy of belzutifan in patients who progressed on prior anti–PD-L1 therapy.The trial enrolled patients with histologically confirmed advanced/metastatic ccRCC who were previously treated with no more than 3 systemic therapies and had received only 1 prior PD-L1 inhibitor.Patients were randomized to receive either the RP2D of belzutifan or 200 mg of belzutifan once daily. Tumor assessments were conducted at week 9 and were then conducted every 8 weeks until week 49, followed by every 12 weeks thereafter.

Stratification factors included IMDC risk prognostic score (O vs 1-2 vs 3-6) and the number of prior TKI regimens received.

The primary end point was objective response rate assessed by BICR according to RECIST v1.1 criteria. Key secondary end points included PFS, DOR, OS, and safety. The data cutoff for the current analysis was 20.1 months.

A total of 154 patients were enrolled onto the study 78 of whom received the 200-mg dose of belzutifan and 76 of whom received the 120-mg dose. Twenty-one patients in the higher-dose arm and 18 in the lower-dose arm are still on treatment, while 57 and 58 patients in each respective arm discontinued treatment. Reasons for treatment discontinuation include progressive disease (37 in the 200-mg arm; 45 in the 120-mg arm), adverse effects (AEs; 11 and 4, respectively), clinical progression (5 and 6), patient withdrawal (3 and 2), and physician’s decision (1 and 1).

The median age of patients enrolled onto the study was 65.0 years (range, 37-82) in the 200-mg arm and 62.0 years (range, 31-82) in the 120-mg arm. The majority of patients in both arms were male (75.6% in 200-mg arm; 84.2% in 120-mg arm), had an ECOG performance status of 0 (52.6%, 53.9%), and were considered intermediate/poor risk (83.3%; 81.6%). In both arms, 51.3% of patients received 1 prior TKI regimen. In the 200-mg arm, 28.2% received no prior TKIs and 20.5% received 2 to 3 previous regimens. These percentages were 28.9% and 19.7% in the 120-mg arm.

A safety analysis revealed that 98.7% of patients in both arms experienced any-grade AEs. Grade 3 to 5 AEs occurred in 69.2% of patients in the 200-mg arm and 68.4% of patients in the 120-mg arm. Serious AEs occurred in 42.3% and 43.4% of patients, respectively. AEs led to dose modification, dose interruption, dose reduction, treatment discontinuation and death in 57.7%, 34.6%, 32.1%, 14.1% and 3.8% of patients at the 200-mg dose level, respectively. Corresponding percentages in the 120-mg arm were 46.1%, 28.9%, 25.0%, 5.3% and 0.0%.

“The safety profiles of the 2 doses are generally similar and are consistent with the known safety profile of belzutifan. [However], the 200-mg dose was associated with a higher rate of overall dose modifications and drug discontinuation.”

Any-grade treatment-related AEs (TRAEs) were seen in 92.3% of patients in the 200-mg arm and 92.1% of patients in the 120-mg arm. Grade 3/4 AEs occurred in 46.2% of patients in the 200-mg arm and 46.1% of patients in the 120-mg arm. Serious TRAEs occurred in 21.8% and 17.1% of patients, respectively. TRAEs were responsible for dose interruptions (20.5% in the 200-mg arm vs 13.2% with 120-mg), dose reductions (28.2% vs 23.7%), and treatment discontinuations (9.0% vs 2.6%). No patients died due to TRAEs.

TRAEs observed in at least 5% of patients across both arms included anemia (80.8% in the 200-mg arm vs 75% in the 120-mg arm), fatigue (41.0% vs 43.4%, respectively), hypoxia (26.9% vs 23.7%), peripheral edema (15.4% vs 11.8%), dyspnea (15.4% vs 9.2%), headache (11.5% vs 13.2%), dizziness (10.3% vs 10.5%), nausea (9.0% vs 21.1%), decreased appetite (9.0% vs 6.6%), hemoglobin decrease (9.0% vs 6.6%), alkaline phosphatase increase (7.7% vs 9.2%) , aspartate aminotransferase increase (6.4% vs 11.8%), pruritis (6.4% vs 1.3%), asthenia (5.1% vs 1.3%), diarrhea (5.1% vs 1.3%), weight increase (5.1% vs 0.0%), myalgia (2.6% vs 7.9%), constipation (2.6% vs 5.3%), and cough (1.3% vs 7.9%).

“The take-home message is that the results of the study indicate that the 120-mg dose of belzutifan is appropriate for patients with ccRCC,” Ghatalia concludes.


  1. Ghatalia P, Agarwal N, Brugarol J, et al. LITESPARK-013: Randomized phase 2 study of two doses of belzutifan in patients with advanced clear cell renal cell carcinoma (ccRCC). Presented at: 2023 International Kidney Cancer Symposium; November 9-11, 2023. Accessed November 10, 2023. Abstract 33.
  2. FDA approves belzutifan for cancers associated with von Hippel-Lindau disease. News release. FDA. August 13, 2021. Accessed November 10, 2023.
  3. Jonasch E, Bauer TM, Papadopoulos KP, et al. Phase 1 LITESPARK-001 (MK-6482-001) study of belzutifan in advanced solid tumors: update of the clear cell renal cell carcinoma (ccRCC) cohort with more than 3 years of total follow-up. J Clin Oncol. 2022;40(suppl 16):4509. doi:10.1200/JCO.2022.40.16_suppl.4509

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