Belzutifan/lenvatinib improves PFS and ORR in LITESPARK-011 trial in RCC

Treatment with belzutifan (Welireg) plus lenvantinib (Lenvima) demonstrated improvements in progression-free survival (PFS) and objective response rate (ORR) compared with cabozantinib (Cabometyx) in patients with previously treated clear cell renal cell carcinoma (RCC), according to data presented at the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium.^1,2

The findings, from the phase 3 LITESPARK-011 study (NCT04586231), were by Robert J. Motzer, MD, section head, Kidney Cancer, Genitourinary Oncology Service and the Jack and Dorothy Byrne Chair in Clinical Oncology at Memorial Sloan Kettering Cancer Center in New York, New York.

“No standard of care exists for patients with advanced RCC after disease progression following anti-PD-1 or L1 therapy.^3,4 Targeted therapies commonly used include cabozantinib; lenvatinib and everolimus [Afinitor]; and others, but most were established before checkpoint inhibitors were standard of care in the adjuvant first-line advanced RCC setting. None have been compared to a contemporary VEGFR-TKI in a randomized phase 3 trial,” Motzer explained.

The phase 3, open-label LITESPARK-011 trial included patients with unresectable, locally advanced, or metastatic clear cell RCC who had a Karnofsky Performance Status score of at least 70%, had progression on or after anti-PD-(L)1 monoclonal antibody as first- or second-line therapy or progression 6 months or sooner after the last dose adjuvant anti-PD-(L)1 monoclonal antibody. Patients were still eligible for inclusion if they had received prior treatment with a VEGFR-TKI. Patients were randomly assigned 1:1 to either belzutifan/lenvatinib 120 mg orally once daily plus lenvatinib 20 mg orally once daily or cabozantinib 60 mg orally once daily. The dual primary end points were PFS per RECIST 1.1 by blinded independent central review (BICR) and overall survival (OS). The key secondary end point was objective response rate (ORR) per RECIST 1.1 by BICR. Other secondary end points included duration of response (DOR) per RECIST 1.1 by BICR and safety. Time to deterioration in patient-reported outcomes was an exploratory end point.

A total of 747 patients were randomly assigned between March 5, 2021, and September 1, 2023. All but 1 patient in the belzutifan/lenvatinib arm were treated, and 5 patients in the cabozantinib arm did not receive treatment. Treatment was ongoing in 37.6% of the belzutifan/lenvatinib arm and 22.6% of the cabozantinib arm. Progressive disease was the biggest factor in discontinuing treatment in both arms, with 39.2% of discontinuations in the belzutifan/levantinib arm and 50.9% of discontinuations in the cabozantinib arm due to this reason. Median follow-up was 29 months (range, 19.3-49.2 months).

Looking at baseline characteristics, Motzer discussed prior lines of therapy across the study participants. Four percent of the belzutifan/lenvatinib arm had received adjuvant therapy only prior the study, compared with 4.8% in the cabozantinib arm. In the belzutifan/lenvatinib arm, 67.9% 27.0%, and 1.1% of patients had received 1, 2, or 3 prior lines of therapy, respectively. In the cabozantinib arm, 66.8%, 28.5%, and 0% of patients had received 1, 2, or 3 prior lines of therapy, respectively. More than 50% of patients in each arm had received 1 prior VEGFR-TKI therapy.

Motzer then presented results from interim analysis 1 and interim analysis 2.

“For both of these analyses, there was statistically superior benefit in progression-free survival for belzutifan plus lenvatinib compared to cabozantinib. ORR was studied only at the first interim analysis, and showed a statistically higher rate of objective response for the combination as well. Overall survival did not meet statistical boundary at the second interim analysis, and the final overall analysis is pending for OS,” Motzer said.

The remainder of Motzer’s presentation focused on interim analysis 2. Treatment with belzutifan/levantinib was associated with longer PFS, with a median 14.8 months (95% CI, 11.2-16.6) vs 10.7 months (95% CI, 9.2-11.1) in the cabozantinib arm (HR: 0.70; 95% CI, 0.59-0.84; P = .00007). When stratified by subgroups including age, sex, race, region, ECOG Performance Status, IMDC risk category, and prior lines of therapy, PFS generally remained favorable toward the belzutifan/lenvatinib arm.

Median OS was also greater with belzutifan/lenvatinib at 34.9 months (95% CI, 27.5-not reached) vs 27.6 months (95% CI, 24.0-31.4) in the cabozantinib arm (HR: 0.85; 95% CI, 0.68-1.05; 1-sided P = .06075). Motzer noted that this did not reach statistical significance.

“This will be studied again in the final OS analysis,” he said.

ORR was 52.6% in the belzutifan/lenvatinib arm (95% CI, 47.3-57.7) vs 40.2% in the cabozantinib arm (95% CI, 35.2-45.3) (estimated difference, 12.4% [95% CI, 5.3-19.3]). Twenty complete responses were observed in the belzutifan/lenvatinib arm vs 4 in the cabozantinib arm.

Median DOR was 23.0 months (range, 2.0-44.3+ months) vs 12.3 months (range, 1.8+ to 35.9+) in the cabozantinib arm.

“Some of the responses on the combination arm are ongoing for more than 3 years. To me, these are some of the most striking aspects of the results of this trial—the durability of response that we see,” Motzer said.

Motzer then discussed treatment exposure and safety. Median duration of therapy was 16.8 months (range, 0.03-46.9 months) for patients receiving belzutifan/lenvatinib compared with 13.2 months (range, 0.4-41.9 months) in the cabozantinib arm. Nearly all patients in each arm had a treatment-emergent adverse event (AE); specifically, 99.7% of the belzutifan/lenvatinib arm and 99.5% of the cabozantinib arm, “but the numbers with grade 3 or higher were nearly identical between the 2 arms. In fact, more patients had dose reduction of cabozantinib than they did of lenvatinib, and about a third of patients had a dose reduction of belzutifan,” Motzer noted. The rate of treatment-emergent AEs resulting in discontinuation of all study drugs was 11.1% in the belzutifan/lenvatinib arm and 11.3% in the cabozantinib arm. Two treatment-related AEs led to death in the belzutifan/lenvatinib arm, and 1 AE led to death in the cabozantinib arm.

“The most common adverse events in the belzutifan plus lenvatinib arm were diarrhea, hypertension, and anemia, and the most common ones in the cabozantinib arm were diarrhea, hypertension, and skin toxicity, with palmar plantar erythrodysesthesia syndrome,” Motzer said.

Hypoxia was observed in 15.4% of patients receiving belzutifan/lenvatinib and 0% of patients receiving cabozantinib. Of the hypoxia observed in the belzutifan/lenvatinib arm, 11.9% was high grade.

Time to deterioration in patient-reported outcomes was measured using the Functional Assessment of Cancer Therapy–Kidney Symptom Index—Disease-Related Symptoms as well as the EORTC QLQ-C30 GHS/QOL. The HR for the former was 1.02 (95% CI, 0.82-1.28) and 1.07 (95% CI, 0.86-1.34) for the latter.

“Belzutifan plus lenvatinib demonstrated superior PFS and objective response rate vs cabozantinib in patients with advanced clear cell RCC following anti-PD-1 or L1 therapy. Overall survival favored belzutifan plus lenvatinib, but did not reach statistical significance and will be tested further at final analysis…LITESPARK-011 is the first phase 3 study of a HIF-2α inhibitor plus a VEGFR-TKI, and the first phase 3 study in RCC in the post-checkpoint inhibitor setting to show improved outcomes vs a contemporary VEGFR-TKI. Most importantly, belzutifan plus lenvatinib addresses an unmet clinical need and represents a potential new treatment option for patients with RCC that progressed after PD 1 or-L1 therapy,” Motzer said in closing.

REFERENCES

1. Motzer RJ, Park SH, McDermott RS, et al. Belzutifan (bel) plus lenvantinib (lenva) versus cabozantinib (cabo) for advanced renal cell carcinoma after anti-PD-(L)1 therapy: Open-label phase 3 LITESPARK-011 study. Presented at: 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium. February 26-28, 2026. San Francisco, California. Abstract LBA417. https://meetings.asco.org/meetings/2026-asco-genitourinary-cancers-symposium/334/16925?presentation=256659

2. WELIREG® (belzutifan) plus LENVIMA® (lenvatinib) reduced the risk of disease progression or death by 30% compared to cabozantinib in certain previously treated patients with advanced renal cell carcinoma (RCC). News release. Merck. February 28, 2026. Accessed February 28, 2026. https://www.businesswire.com/news/home/20260228417897/en/WELIREG-belzutifan-Plus-LENVIMA-lenvatinib-Reduced-the-Risk-of-Disease-Progression-or-Death-by-30-Compared-to-Cabozantinib-in-Certain-Previously-Treated-Patients-With-Advanced-Renal-Cell-Carcinoma-RCC

3. National Comprehensive Cancer Network. Kidney Cancer (Version 1.2026). NCCN Clinical Practice Guidelines in Oncology. Accessed February 28, 2026. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1440

4. Powles T, Albiges L, Bex A, et al. Renal cell carcinoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2024;35(8):692-706. doi:10.1016/j.annonc.2024.05.537