ESMO 2023: LITESPARK-003 Phase 2 Study of Belzutifan in Combination With Cabozantinib for Advanced Clear Cell Renal Cell Carcinoma (ccRCC)

( The 2023 European Society of Medical Oncology (ESMO) Annual Congress held in Madrid, Spain between October 20th and 24th, 2023 was host to a non-prostate genitourinary proffered paper session. Dr. Toni Choueiri presented the late-breaking abstract results of the phase 2 LITESPARK-003 study of belzutifan in combination with cabozantinib for patients with advanced clear cell renal cell carcinoma (ccRCC).

The inactivation of the Von Hippel Lindau (VHL) gene leads to the overexpression of hypoxia-inducible factors (HIF), which drive the expression of multiple oncogenes, including vascular endothelial growth factors (VEGF). Constitutively active HIF-2a is a key oncogenic driver in ccRCC, with VHL inactivated in ccRCC.

The initial results from the phase 2 LITESPARK-003 trial showed promising anti-tumor activity with the HIF-2a inhibitor belzutifan when combined with the multi-kinase inhibitor cabozantinib in patients with advanced ccRCC who were either treatment-naïve (Cohort 1) or previously treated with immunotherapy (Cohort 2).1,2 As demonstrated in the table below, the objective response rates (ORRs) were 57% and 31% for treatment-naïve and previously treated patients, respectively, at median follow-up of 14 and 24.6 months, respectively. The objective of this analysis was to report the updated results from Cohorts 1 and 2.

The study design of LITESPARK-003 is illustrated below. In brief, this phase II trial assigned patients with locally advanced or metastatic ccRCC (treatment-naïve or previously treated) to belzutifan 120 mg orally once daily plus cabozantinib 60 mg orally once daily. The primary endpoint was investigator-determined ORR per RECIST v1.1, with secondary outcomes of progression-free survival (PFS), duration of response (DOR), time-to-response (TTR), overall survival (OS), and safety/tolerability.


There were 50 and 52 patients included in Cohorts 1 and 2, respectively. The median follow-up in Cohort 1 was 24.3 months (additional 10.3 months from last updated) and 39.8 months in Cohort 2 (additional 15.2 months follow-up). At the data cut-off date of May 15, 2023, 26 and 6 patients were still receiving ongoing study drug therapy.


The baseline patient characteristics are summarized below. There was a higher proportion of patients with IMDC intermediate/poor risk disease in the previously treated cohort (79% versus 44% in Cohort 1). Approximately 80% had underwent a prior nephrectomy. 56% of patients in Cohort 2 had received 1 prior line of anti-cancer therapy, and 44% had received 2. All patients in Cohort 2 had previously received immunotherapy (immunotherapy + anti-VEGF therapy in 46%).


With regards to the primary outcome of investigator-assessed ORR, 70% of patients in Cohort 1 had an ORR (complete or partial response). As expected, this was higher for those with favorable risk disease (79% versus 59%). Only 1 patient had evidence of progressive disease as best response (DCR: 98%). Conversely, in Cohort 2, the ORR was 31%, with DCR of 92%. Similar ORRs were observed by IMDC risk in this cohort.


When ORR was analysed by prior anti-cancer therapy received, there was a similar ORR irrespective of whether patients had received immunotherapy only (32%) or immunotherapy + anti-VEGF therapy (29%). Similarly, ORR was consistent irrespective of the number of prior therapy lines.


The median TTR was 1.9 months in Cohort 1 and 3.2 months in Cohort 2. The median DOR in Cohort 1 was 28.6 months and 57% of patients remained in response for at least two years by Kaplan Meier estimates. These figures for Cohort 2 were 31.5 months and 51%, respectively.


Investigator-assessed PFS is summarized for each cohort in the Kaplan Meier curves below. The median PFS was 30.3 months in Cohort 1 and 13.8 months in Cohort 2.


The median OS was not reached in Cohort 1 and was just over two years in Cohort 2 (26.7 months). At two years, 86% of patients in Cohort 1 were still alive, compared to 55% of those in Cohort 2.


With regards to treatment-related adverse events (TRAE), grade 3 or worse events were observed in 46% and 64% of patients in Cohorts 1 and 2, respectively. 14% and 21% of patients discontinued either drug secondary to a TRAE, respectively.


The most common TRAEs were anemia, diarrhea, and fatigue as summarized below:


Dr. Choueiri concluded as follows:

  • Belzutifan plus cabozantinib continues to show durable anti-tumor activity for patients with advanced ccRCC who were either treatment-naïve (Cohort 1) or were previously treated with immunotherapy (Cohort 2)
    • Cohort 1
      • ORR=70% (4 complete and 31 partial responses); consistent across IMDC risk categories
      • The median duration of response was 28.6 months, with 58% having an estimated response beyond 24 months
    • Cohort 2
      • ORR=31% (2 complete and 14 partial responses); consistent across IMDC risk categories and prior anti-cancer therapy
      • The median duration of response was 31.5 months, with 51% having an estimated response beyond 24 months
  • Safety was consistent with prior observations and with individual profiles of each agent
  • These results provide a scientific rationale for the continued investigation of belzutifan plus a VEGFR TKI for advanced ccRCC
  • The phase 3 LITESPARK-011 study (NCT04586231) is being conducted to investigate belzutifan plus lenvatinib versus cabozantinib in patients with advanced ccRCC who had received prior immunotherapy and up to two prior systemic therapy regimens
Presented by: Toni K. Choueiri, MD, Jerome and Nancy Kohlberg Professor of Medicine, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA

Written by: Rashid K. Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 European Society of Medical Oncology (ESMO) Annual Meeting, Madrid, Spain, Fri, Oct 20 – Tues, Oct 24, 2023.


  1. Choueiri TK, et al. Phase II study of belzutifan plus cabozantinib as first-line treatment of advanced renal cell carcinoma (RCC): Cohort 1 of LITESPARK-003. Ann Oncol 2022;33:S660-S680.
  2. Choueiri TK, et al. Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study. Lancet Oncol 2023;24:553-562.