Real-world efficacy and safety of belzutifan in patients with metastatic renal cell carcinoma: a multicenter retrospective study in Japan

Technical Summary: Real-world Efficacy and Safety of Belzutifan in Metastatic Renal Cell Carcinoma

Problem Statement
Metastatic renal cell carcinoma (mRCC) remains a significant clinical challenge, with the majority of patients eventually experiencing disease progression despite advances in immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs). While the phase III LITESPARK-005 trial established belzutifan, a hypoxia-inducible factor-2α (HIF-2α) inhibitor, as a standard treatment for previously treated mRCC, there is a paucity of real-world evidence regarding its effectiveness and safety in routine clinical practice. Specifically, the Japanese patient population often receives belzutifan after multiple prior lines of systemic therapy, potentially differing from the highly selected cohorts in pivotal trials. Furthermore, clinical factors predicting durable benefit from HIF-2α inhibition remain poorly characterized.

Methodology
This study employed a multicenter, retrospective cohort design to evaluate consecutive patients with histologically confirmed mRCC treated with belzutifan across multiple institutions in Japan.

• Data Collection: Clinical data were extracted from institutional databases and electronic medical records, covering demographics, histological subtypes, prior nephrectomy, laboratory findings, metastatic sites, treatment history, and treatment outcomes.
• Study Population: 40 patients were included. Inclusion criteria required histologically confirmed mRCC and receipt of at least one dose of belzutifan. Patients with incomplete data or unassessable follow-up were excluded.
• Endpoints:
  • Primary: Progression-free survival (PFS), defined as the interval from initiation to radiographic progression or death.
  • Secondary: Overall survival (OS), objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (AEs).
• Statistical Analysis: Survival outcomes were estimated using the Kaplan–Meier method with log-rank tests for comparison. Exploratory univariable and multivariable Cox proportional hazards regression analyses were performed to identify clinical factors associated with PFS. Variables with a univariable P-value <0.10 or clinical relevance were included in multivariable models.

Key Contributions and Results
The study provides the first multicenter real-world evidence of belzutifan efficacy and safety in a Japanese cohort, characterized by a heavily pretreated population (80% received belzutifan as third-line therapy or later).

• Antitumor Activity:
  • In the overall cohort (n=40), the ORR was 10.0% and the DCR was 35.0%.
  • Among the 15 evaluable patients (those with completed radiographic assessments), the ORR was 26.7% and the DCR was 80.0%.
  • The median PFS was 6.0 months. The median OS was not reached at the time of analysis.
• Safety Profile:
  • Treatment-related adverse events occurred in 72.5% of patients, with 22.5% experiencing grade ≥3 events.
  • Anemia was the most common toxicity (55.0%), including grade ≥3 anemia in 10.0% of patients.
  • Grade ≥3 hypoxia occurred in 10.0% of patients. No unexpected safety signals were observed.
• Exploratory Analyses (Predictors of Outcome):
  • Histology: Non-clear-cell RCC was strongly associated with shorter PFS (Hazard Ratio [HR] 6.87; 95% CI 1.81–26.03; P=0.001).
  • Risk Stratification: Poor IMDC risk status at the initiation of belzutifan was associated with shorter PFS (HR 3.37; 95% CI 1.00–11.37; P=0.034).
  • Metastatic Pattern: Lymph node metastasis showed a potential association with shorter PFS (HR 3.45; 95% CI 0.91–13.11; P=0.061 in Cox model; P=0.049 in log-rank test).
  • Metastatic Burden: The number of involved metastatic organs was not significantly associated with PFS.

Significance and Claims
The authors conclude that belzutifan demonstrates clinical activity with a manageable safety profile in Japanese patients with previously treated mRCC, even in a setting of extensive prior therapy. The study highlights that patient and tumor characteristics at the time of initiation—specifically histological subtype, clinical risk status (IMDC), and metastatic pattern—may be more informative than metastatic burden alone in determining clinical activity.

The authors explicitly frame their findings on non-clear-cell histology, poor IMDC risk, and lymph node metastasis as hypothesis-generating. They emphasize that these associations require validation in larger prospective studies with longer follow-up to establish clinically useful biomarkers for patient selection. The paper acknowledges limitations including its retrospective nature, small sample size (particularly for subgroup analyses), short follow-up period, and the lack of molecular biomarker evaluation (e.g., VHL/HIF pathway alterations). Consequently, the authors caution against direct comparisons with prospective clinical trials and suggest that the observed outcomes may reflect the emergence of treatment-resistant clones in heavily pretreated patients, warranting further investigation into the optimal timing of belzutifan administration.