Editor’s Note:
The treatment of advanced renal clear cell carcinoma (ccRCC) has evolved from the cytokine era to the era of targeted therapy, immunotherapy, and immunotherapy combinations, expanding survival options for patients. However, results from the CONTACT-03 study suggest that continuing with immunotherapy combinations after immunotherapy failure may not be a preferred option, highlighting the need for exploration of subsequent treatment options for this patient population. Two significant studies presented at this year’s ESMO conference (LBA87, LBA88) [2,3] indicate that, compared to everolimus, the HIF-2α inhibitor Belzutifan significantly improves the PFS and ORR of advanced ccRCC patients. Additionally, Belzutifan in combination with cabozantinib demonstrates persistent anti-tumor activity and safety consistent with previous observations. At the conference, “Oncology Frontier” had the privilege of inviting Professor Xinan Sheng from Peking University Cancer Hospital to provide in-depth insights.
Efficacy of Belzutifan vs. Everolimus in the Treatment of Previously Treated Advanced ccRCC: A Randomized, Open-label, Phase III LITESPARK-005 Study (Abstract No: LBA88)
Background: Belzutifan is the first orally administered HIF-2α inhibitor approved in the United States for the treatment of VHL-related renal cell carcinoma, pNET, and CNS hemangioblastoma patients. It exhibits anti-tumor activity in renal cell carcinoma. The Phase III LITESPARK-005 study (NCT04195750) aimed to evaluate the efficacy of Belzutifan compared to everolimus in previously treated advanced ccRCC.
Methods: Patients aged ≥18 years with advanced ccRCC and KPS ≥70% who had received 1-3 lines of systemic treatment, including anti-PD-(L)1 and VEGF-TKI, were randomized in a 1:1 ratio to the Belzutifan group (120 mg QD) or the everolimus group (10 mg QD). Treatment continued until progression or intolerable toxicity. The study had dual primary endpoints, including PFS and OS assessed by blinded independent central review (BICR). Secondary endpoints included ORR assessed by BICR according to RECIST 1.1, safety, and time to deterioration (TTD) based on FKSI-DRS. The first interim analysis (IA1) reported PFS and ORR results.
Results: The Belzutifan and everolimus groups included 374 and 372 patients, respectively. At IA1, with a median follow-up of 18.4 months (range 9.4–31.7), Belzutifan showed superior PFS and ORR compared to everolimus, with no statistically significant difference in OS. At IA2, with a median follow-up of 25.7 months (range 16.8–39.1), PFS, OS, and ORR results were consistent with IA1. The Belzutifan group had 13 patients (3.5%) achieve complete response (CR), while no patients in the everolimus group achieved CR. The 12-month PFS rate (33.7% vs. 17.6%) and 18-month PFS rate (22.5% vs. 9.0%) were higher in the Belzutifan group than the everolimus group.
Belzutifan and everolimus groups had 22.6% and 5.0% of patients under treatment, 5.9% and 14.7% of patients discontinued treatment due to any adverse events (AE), and 38.7% and 39.4% of patients experienced grade 3-5 treatment-related adverse events (TRAEs). The TTD was superior in the Belzutifan group compared to the everolimus group (NR vs. 2.0 months, HR 0.53, 95% CI: 0.41–0.69; P < 0.0001).
Conclusion: After immunotherapy and anti-angiogenic therapy, Belzutifan significantly improves the PFS and ORR of advanced ccRCC patients compared to everolimus. The safety profile of Belzutifan is consistent with previous reports, with no new safety signals.
Phase II LITESPARK-003 Study: Belzutifan in Combination with Cabozantinib for the Treatment of Advanced ccRCC (Abstract No: LBA87)
Background: Preliminary results from the Phase II LITESPARK-003 study (NCT03634540) showed that Belzutifan in combination with cabozantinib has good anti-tumor activity in both first-line (Cohort 1) and second-line (Cohort 2) treatment of advanced ccRCC patients. This study analyzed the latest results from Cohorts 1 and 2.
Methods: Eligible patients with ECOG PS 0 or 1 advanced ccRCC were enrolled. Cohort 1 patients had not previously received systemic treatment for advanced renal cancer, while Cohort 2 patients had received ≤2 lines of systemic treatment, including immunotherapy. All patients received 120 mg belzutifan and 60 mg cabozantinib orally once daily. The primary endpoint was investigator-assessed ORR (RECIST v1.1). Secondary endpoints included DOR, PFS, OS, and safety.
Results: Cohort 1 had 50 patients, and Cohort 2 had 52 patients. Most Cohort 1 patients (n=28, 56%) were IMDC low-risk, while most Cohort 2 patients (n=41, 79%) were IMDC intermediate/high-risk. The median follow-up was 24.3 months (range 4.1-48.2) for Cohort 1 and 39.8 months (range 33.1-55.0) for Cohort 2. The overall ORR was 70% for Cohort 1 and 31% for Cohort 2. The median DOR was 28.6 months (range 1.9+ to 35.8) for Cohort 1 and 31.5 months (range 4.2+ to 36.8) for Cohort 2. The ≥24-month sustained response rate was 57% for Cohort 1 and 51% for Cohort 2.
Cohort 1 had a median PFS of 30.3 months (95% CI, 16-NR), while Cohort 2 had a median PFS of 13.8 months (95% CI, 9-19). Cohort 1 had a median OS of NR (95% CI, NR-NR), and Cohort 2 had a median OS of 26.7 months (95% CI, 20-41).
Overall, 23 patients (46%) in Cohort 1 experienced grade 3-5 treatment-related adverse events (TRAEs), while 33 patients (63%) in Cohort 2 did. No patients in Cohort 1 died from TRAEs, while one patient (2%) in Cohort 2 died from TRAE (respiratory failure).
Conclusion: In the latest analysis of the LITESPARK-003 study, Belzutifan in combination with cabozantinib demonstrated persistent anti-tumor activity and safety consistent with previous observations. These results further support the potential use of HIF-2α inhibitors and VEGFR-TKIs in combination as a treatment option for first-line and subsequent therapy in advanced renal cell carcinoma.
Expert Commentary:
Currently, advanced renal cancer has entered the era of immunotherapy and immunotherapy combination. The ASCO conference revealed a study on cabozantinib in combination with immunotherapy for patients who failed immunotherapy, showing negative results. However, two studies in the field of kidney cancer presented at this year’s ESMO conference are worth noting. One is the announcement of the LITESPARK-005 study, which compared Belzutifan with everolimus in a randomized controlled phase III clinical trial for patients who had previously failed targeted and immunotherapy. This provides a basis for the use of HIF inhibitors after the failure of immunotherapy and targeted therapy. The other is the LITESPARK-003 study on the treatment of advanced ccRCC with Belzutifan in combination with cabozantinib. It includes two cohorts, one for first-line and one for multiple-line treatment. Although it is a phase II clinical study, preliminary data has already shown significant efficacy. This year’s ESMO conference updated the complete data for these studies. Both studies aim to address the challenge of how to choose treatment after the failure of immunotherapy.
The KEYNOTE-426 [4] and CLEAR [5] studies at the ASCO conference explored patients who failed first-line immunotherapy, showing that continuing immunotherapy did not have a clear advantage. In contrast, the Belzutifan presented at the ESMO conference focuses on post-immunotherapy selection, including patients who have received TKIs or immunotherapy. The results of the LITESPARK-003 [2] and LITESPARK-005 [3] studies indicate that Belzutifan has good anti-tumor activity in advanced ccRCC. After the failure of immunotherapy and targeted TKI treatment, mTOR inhibitor everolimus is usually used. The LITESPARK-005 study [3] suggests that, compared to everolimus, the HIF-2α inhibitor can also be a beneficial weapon for the treatment of advanced ccRCC. With further research, it is believed that the use of HIF-2α inhibitors in the treatment of advanced ccRCC will continue to advance.
Compared to single-agent Belzutifan, combination with VEGFR-TKI seems to achieve better efficacy. A phase II study of Belzutifan in combination with cabozantinib has been conducted abroad [2], whether in the first line or after multiple lines of treatment, including a small-sample study in China on Belzutifan in combination with lenvatinib for previously treated ccRCC. All studies suggest that combination data is better than Belzutifan alone. Therefore, in the future, HIF-2α inhibitors are likely to continue the path of combination therapy. The combination of Belzutifan and TKI is expected to be a major application scenario after the failure of immunotherapy. Although cabozantinib is currently a preferred monotherapy for patients who have failed immunotherapy, theoretically, combining it with HIF-2α inhibitors may achieve better efficacy. At the same time, we also hope that in the future, Belzutifan can be combined with existing drugs (including cabozantinib, lenvatinib, etc.) for more clinical research to improve efficacy and advance the treatment line. We hope that similar clinical trial data will be available soon, providing better treatment options for patients after the failure of immunotherapy combination treatment.
Reference :
1.Pal,Sumanta Kumar,et al.”Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment(CONTACT-03):a multicentre,randomised,open-label,phase 3 trial.”The Lancet(2023).
2.T.K.Choueiri,T.Bauer,J.R.Merchan et al.LBA87-Phase II LITESPARK-003 study of belzutifan in combination with cabozantinib for advanced clear cell renal cell carcinoma(ccRCC).ESMO 2023
3.L.Albiges,B.I.Rini,K.Peltola,et al.LBA88-Belzutifan versus everolimus in participants(pts)with previously treated advanced clear cell renal cell carcinoma(ccRCC):Randomized open-label phase III LITESPARK-005 study.ESMO 2023.
4.Rini,Brian I.,et al.Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma:5-year analysis of KEYNOTE-426.(2023):LBA4501.
5.Motzer R J,Porta C,Eto M,et al.Final prespecified overall survival(OS)analysis of CLEAR:4-year follow-up of lenvatinib plus pembrolizumab(L+P)vs sunitinib(S)in patients(pts)with advanced renal cell carcinoma(aRCC)[J].J Clin Oncol 41,2023(suppl 16;abstr 4502)
Professor Xinan Sheng
Chief Physician, Professor, Ph.D. Supervisor
Deputy Director of the Department of Urological Oncology, Peking University Cancer Hospital
Deputy Director of the Integration and Rehabilitation Professional Committee of China Anti-Cancer Association Genitourinary Tumors
Standing Committee Member of the Professional Committee on Genitourinary Tumors of China Anti-Cancer Association
Deputy Leader of the Rare Types of Kidney Cancer Collaboration Group of the Professional Committee on Genitourinary Tumors of China Anti-Cancer Association
Member of the Bladder Cancer Quality Control Expert Committee of the National Cancer Quality Control Center
Director of the Chinese Society of Clinical Oncology (CSCO)
Standing Committee Member and Secretary-General of the Kidney Cancer Expert Committee of the Chinese Society of Clinical Oncology
Standing Committee Member of the Urothelial Carcinoma Expert Committee of the Chinese Society of Clinical Oncology
Chairman-designate of the Urological Oncology Sub-Committee of the Beijing Cancer Prevention and Treatment Research Association
Chairman of the Youth Committee of the Genitourinary Tumors Sub-Committee of the Beijing Anti-Cancer Association
