Editor’s Note: The 2024 American Society of Clinical Oncology (ASCO) Annual Meeting was held from May 31 to June 4 in Chicago, USA, showcasing the latest advancements in urological oncology research. Among them, a phase I clinical study led by Professor Guo Jun from Peking University Cancer Hospital on belzutifan combined with lenvatinib for previously treated advanced renal cell carcinoma (RCC) was selected (Abstract No. 4537). "Oncology Frontier" invited Professor Xinan Sheng from Peking University Cancer Hospital to share insights on the study.Study Overview
Background:
Belzutifan is a “first-in-class” HIF-2α inhibitor that has shown durable antitumor activity when used alone or in combination with VEGFR-TKI in the first-line and subsequent treatment of advanced clear cell renal cell carcinoma (ccRCC). LITESPARK-010 (NCT05030506) is a phase I, two-cohort, open-label study investigating belzutifan combined with lenvatinib (with or without pembrolizumab) in Chinese patients with advanced ccRCC. This study presents the preliminary results from Cohort 1.
Methods:
Chinese adult patients with histologically confirmed ccRCC who had received 1-3 prior treatments were administered belzutifan 120 mg PO QD for 3 weeks, followed by belzutifan 120 mg combined with lenvatinib 20 mg PO QD until intolerable toxicity, disease progression, or study withdrawal. The study included a dose-limiting toxicity (DLT) phase for 21 days post-initiation of combination therapy. The dual primary endpoints were safety and pharmacokinetics (PK). Secondary endpoints included objective response rate (ORR) assessed by investigators using RECIST v1.1, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).
Results:
As of August 29, 2023, 24 patients were enrolled in Cohort 1, with 23 receiving combination therapy; one patient discontinued during monotherapy due to non-study anticancer treatment. The median age was 61 years, with 17 male patients (71%) and 14 patients (58%) with intermediate/poor IMDC risk stratification. Fourteen patients (58%) had received one prior line of therapy, and ten patients (42%) had received ≥2 prior lines. Five patients (21%) had prior PD-(L)1 inhibitor treatment.
At the data cutoff, 11 patients (46%) remained on treatment. The median follow-up was 14.4 months. During the DLT phase, ten patients were assessed, with one experiencing a DLT (grade 2 treatment-related transient ischemic attack). All 24 patients (100%) experienced treatment-related adverse events (TRAEs) of any grade, with the most common being anemia (100%) and proteinuria (88%). Seventeen patients (71%) had grade 3/4 TRAEs, most commonly anemia (29%) and hypertension (29%). One patient (4%) experienced grade 3 hypoxia. There were no TRAE-related deaths (grade 5). The median Tmax for belzutifan monotherapy was 1.8 hours (range, 0.6-8.0), with a geometric mean AUC0-24 of 22,400 h·ng/mL (90% CI, 19,600-25,500) and a geometric mean Cmax of 1640 ng/mL (90% CI, 1490-1820). Belzutifan reached steady-state concentration after 14 days of monotherapy; the accumulation ratio for AUC0-24 was 1.7 (90% CI, 1.5-1.9). The PK profile of belzutifan combined with lenvatinib was similar to that of belzutifan monotherapy. Among all 24 patients, the confirmed ORR was 50% (95% CI, 29%-71%; all PRs). The median DOR was not reached (NR; range, 3.5-20.4+ months); Kaplan-Meier estimates showed that 50% of responders had a DOR ≥12 months. The median PFS was 13.7 months (95% CI, 8-NR), and the median OS was not reached (95% CI, NR-NR). The 12-month PFS and OS rates were 57% and 75%, respectively.
Conclusion:
Preliminary data indicate that belzutifan combined with lenvatinib exhibits good antitumor activity in previously treated Chinese ccRCC patients. The safety profile of belzutifan 120 mg combined with lenvatinib 20 mg is consistent with the known safety profiles of each drug.
Researcher’s Insights
This phase I clinical study on belzutifan combined with lenvatinib aimed to preliminarily evaluate the safety and efficacy of the combination in patients with advanced renal cell carcinoma who had failed multiple lines of treatment, while also collecting relevant PK and pharmacodynamic (PD) data.
According to the study protocol, patients first received belzutifan monotherapy for three weeks, followed by the combination of belzutifan and lenvatinib. In the final cohort of 24 patients, an objective response rate of 50% was observed, with a median PFS of 13.7 months, comparable to data from similar studies involving belzutifan combined with cabozantinib. These results suggest that this combination therapy has promising preliminary efficacy for patients who have failed multiple lines of treatment.
Currently, research on treatment strategies for patients who have failed multiple lines of tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitor combinations is still lacking. Although belzutifan has been approved in the United States for patients who have failed targeted and immune therapy, its monotherapy ORR is only 20-30%, with a median PFS of just 5.6 months, indicating a significant gap in meeting patient needs. Therefore, exploring combination therapy options for these patients is of great significance. Studies like this one, as well as similar international research, provide valuable treatment options for patients who have failed targeted and immune therapy.
This clinical study found that the combination therapy had a high safety profile, with manageable overall safety. However, the incidence of grade 3/4 adverse reactions was as high as 71%, mainly due to hypertension, proteinuria, and anemia. Hypertension and proteinuria are common adverse reactions of TKIs. Despite the 29% incidence of anemia, these complications were generally manageable during the clinical trial, making the overall tolerability acceptable. The dose of lenvatinib used was 20 mg daily, the same as for Western populations. Previous studies have shown that East Asian populations have poorer tolerance to this dose, suggesting that a dose reduction might benefit patients from a safety perspective. This requires dose-escalation phase I clinical studies to explore the optimal dose level.
As belzutifan gains approval for relevant indications in China, more patients may adopt combination therapy. Additionally, in clinical practice, safety management is crucial, including regular monitoring of hemoglobin levels, blood pressure, and urine protein, and managing any adverse reactions to maximize efficacy. This phase I clinical trial’s main contribution is providing a combination therapy option for Chinese patients, offering a new treatment pathway for those who have failed immune-targeted therapy.
