In kidney cancer, HIF-2α is believed to be a key oncogenic driver for development and progression of clear cell renal cell carcinoma (ccRCC), highlighting the therapeutic potential of HIF-2 antagonists in this disease. In order to learn more about the efficacy and safety of HIF-2α inhibition in RCC, research into belzutifan in this context has been initiated as part of a comprehensive strategy. The strategy involves multiple LITESPARK trials examining belzutifan alone and in combination with other therapies in treatment-naive and pretreated patients suffering from RCC. Based on the LITESPARK-004 study, belzutifan is already approved for the treatment of von Hippel-Lindau disease-associated RCC, central nervous system hemangioblastomas, and/or pancreatic neuroendocrine tumors not requiring immediate surgery. The drug has also shown anti-tumor activity in patients with previously treated advanced clear cell RCC in the Phase I LITESPARK-001 study. 

New findings from the LITESPARK clinical development program being presented at the ESMO Congress 2023 include Phase II results from the LITESPARK-003 and LITESPARK-013 trials evaluating WELIREG in advanced RCC. These results mark a notable advancement in renal cell cancer therapy. 

The LITESPARK-013 study compared belzutifan 200 mg and 120 mg doses in patients with advanced clear cell RCC that progressed on anti-PD-1/L1 therapy. The study was basically developed to determine if a higher dose of belzutifan could improve efficacy while maintaining an acceptable safety profile. The study's data were analyzed up to a median time of 20.1 months from randomization. 

Overall, there were no significant differences in efficacy outcomes between the two dosage groups. The overall response rate (ORR) was comparable in both arms, with 23.7% in the 120 mg group and 23.1% in the 200 mg group. It's worth noting that 5.1% of patients in the 200 mg group achieved a complete response, whereas none did in the 120 mg group. No clinically or statistically significant differences in PFS and OS were observed between the two dose groups. The median duration of response (DOR) was not reached for the 120 mg arm and was observed to be 16.1 months for the 200 mg arm. 

Adverse events of any grade and Grade 3-5 severity were equally common in both dose groups, occurring in 99% and 69% of cases, respectively. However, instances of adverse events leading to any dose modification were more prevalent in the 200 mg group (58% vs. 46%), as well as those causing treatment discontinuation (14% vs. 5%). The most frequent treatment-related adverse events included anemia, fatigue, and hypoxia, with similar patterns observed in both dosage groups.

On the other hand, the LITESPARK-003 study evaluated the efficacy and safety of belzutifan in combination with cabozantinib in participants with advanced ccRCC. The study comprised two groups: Cohort 1 with 50 patients who hadn't undergone previous systemic therapy for advanced RCC, and Cohort 2 with 52 patients who had received immunotherapy and up to two systemic regimens for advanced RCC. All patients were administered oral belzutifan at 120 mg and oral cabozantinib at 60 mg daily. Initial results from LITESPARK-003 demonstrated promising anti-tumor activity in patients in both the cohorts. At a median follow-up of 14.0 months, Cohort 1 showed a 57% overall response rate (ORR), while Cohort 2 exhibited a 31% ORR at a median follow-up of 24.6 months. Updated findings from both cohorts were presented at the 2023 ESMO Congress.

The primary end point was ORR while the secondary end points included DOR, PFS, OS, and safety. The efficacy results are given below in the table.

All patients in cohort 1 and 98% in cohort 2 experienced any-grade treatment-related adverse events (AEs). Grade 3 or higher treatment-related AEs were observed in 46% of cohort 1 and 64% of cohort 2, with no Grade 5 events in cohort 1 and one in cohort 2. The combination of belzutifan and cabozantinib continues to demonstrate enduring anti-tumor activity in patients with clear cell RCC who are treatment naïve or previously treated.

The findings from these ESMO results indicate that belzutifan, whether used independently or combined with cabozantinib, exhibited an impressive efficacy and safety profile, and a striking potential for significant clinical benefits.

KOL insights

“Belzutifan is a HIF-2α inhibitor, a first-in-class anti-cancer therapy that has shown strong early clinical results in renal cell carcinoma. For patients with advanced RCC, these results from LITESPARKS program marks a first step in helping to address the unmet medical need for additional treatment options for adult patients with advanced RCC following both prior VEGFR and PD-1/L1 targeted therapies –MD, United States” 

“Several ongoing studies are exploring the potential of belzutifan in combination with immunotherapy or TKIs. This is an agent that’s going to find its place in the RCC treatment armamentarium, the optimal usage is yet to be defined. When used alone, it will enhance our existing treatment approaches; however, in combination therapies, it could amplify the benefits observed with this agent” –MD, United States

Conclusion 

As per American Cancer Society in the United States, in 2023 there are approximately 82,000 new cases  whereas as per the European Association of Urology, in 2020, there were an estimated 138,611 new cases of RCC in Europe, indicating the need for additional effective treatment options.

The latest results from the LITESPARK trials, particularly LITESPARK-003 and LITESPARK-013, underscore the significant progress in renal cell cancer therapy. Belzutifan, both as a standalone treatment and in combination with cabozantinib, showcased remarkable efficacy in advanced clear cell renal cell carcinoma, highlighting belzutifan as a promising therapeutic option, offering hope to patients and clinicians alike. 

The LITESPARK-013 study displayed no significant disparities in effectiveness between the two dosage groups. The overall response rates were similar, standing at 23.7% in the 120 mg group and 23.1% in the 200 mg group. Whereas, in the LISTESPARK-003, ORR was 70% in treatment naïve patients and 31% in patients who had received immunotherapy and up to two systemic regimens for advanced RCC. 

Additionally, the safety profiles of belzutifan remained consistent with the previously established profile of the drug. In the LITESPARK-013 study, the safety of both the 200 mg and 120 mg daily doses of belzutifan was generally comparable. However, the 200 mg dose exhibited a higher rate of overall dose adjustments and treatment discontinuation. The LITESPARK-003 trial also indicated that the combination of belzutifan and cabozantinib was well tolerated. These findings further endorse the 120 mg once-daily dose of belzutifan as the preferred choice.

The findings from these ESMO results provide valuable insights into the changing paradigm of RCC treatment, underscoring the necessity for a range of treatment choices personalized to each patient's requirements. For more insight into the patient's burden/epidemiology, treatment, and changing market landscape-related advancements, refer to the Renal Cell Carcinoma Market Insight and Market Forecast Report and Renal Cell Carcinoma Pipeline Insight