Approval Supported by Phase 3 LITESPARK-011 Data

The approval is based on findings from the Phase 3 LITESPARK-011 trial, which compared belzutifan plus lenvatinib with cabozantinib in patients with locally advanced or metastatic clear cell RCC previously treated with immune checkpoint inhibition.

At a preplanned interim analysis, the combination demonstrated a significant improvement in progression-free survival (PFS), reducing the risk of disease progression or death by 26% versus cabozantinib (HR 0.74; 95% CI, 0.61-0.89; p=0.001). Median PFS reached 14.6 months with the dual regimen compared with 10.6 months for cabozantinib.

The combination also significantly improved objective response rates (ORR), achieving responses in 53% of patients versus 40% in the comparator arm (p=0.0002). Data on duration of response were also reported. However, at final analysis, the study did not demonstrate a statistically significant improvement in overall survival (OS), the trial’s second primary endpoint.

Detailed study results are scheduled for presentation at the ESMO Congress 2026 in Madrid, Spain.

Addressing an Unmet Need After Immunotherapy

Treatment options remain limited for patients whose disease progresses after PD-1 or PD-L1–directed therapies, despite advances in first-line management of advanced kidney cancer. Investigators noted that the newly approved regimen provides an additional option for patients in the post-immunotherapy setting.

Belzutifan targets the HIF-2α pathway, a key driver of tumor growth and adaptation to low-oxygen conditions in many RCC tumors, while lenvatinib inhibits multiple receptor tyrosine kinases involved in angiogenesis and cancer progression. The combination is designed to attack complementary biological pathways associated with disease growth.

Safety Profile

The prescribing information for belzutifan includes a boxed warning regarding embryo-fetal toxicity, and clinicians are advised to confirm pregnancy status before treatment initiation and counsel patients on effective non-hormonal contraception.

Other important safety concerns associated with belzutifan include:

• Severe anemia, which may require blood transfusion
• Hypoxia requiring oxygen supplementation, hospitalization, or treatment discontinuation
• Cardiac dysfunction, including heart failure and reduced left ventricular ejection fraction when used with lenvatinib

Lenvatinib carries risks that include:

• Hypertension
• Cardiac dysfunction
• Arterial thromboembolic events
• Hepatotoxicity
• Renal impairment
• Proteinuria
• Gastrointestinal perforation or fistula formation
• Hemorrhagic events
• Thyroid dysfunction
• Osteonecrosis of the jaw
• Embryo-fetal toxicity

Dose interruptions, reductions, and discontinuations were common during treatment, reflecting the complexity of managing adverse events with the combination.

Key Safety Findings From LITESPARK-011

Among patients receiving belzutifan plus lenvatinib:

• 54% experienced serious adverse reactions.
• Serious events occurring in at least 2% of patients included hypoxia, pneumonia, hyponatremia, acute kidney injury, hemorrhage, anemia, cardiac failure, and diarrhea.
• 5% experienced fatal adverse reactions, including cases of sepsis, pneumonia, pneumonitis, respiratory failure, and other serious complications.
• Permanent discontinuation due to adverse events occurred in 17% of patients for belzutifan and 23% for lenvatinib.

Common adverse effects and laboratory abnormalities included decreased hemoglobin, fatigue, elevated liver enzymes, hypertension, musculoskeletal pain, diarrhea, nausea, hypothyroidism, appetite loss, proteinuria, rash, weight loss, abdominal pain, and stomatitis.

Trial Design

LITESPARK-011 enrolled 747 patients with advanced or metastatic clear cell RCC whose disease had progressed on or after PD-1/PD-L1 inhibitor therapy or within six months of completing adjuvant PD-1 treatment. Participants were randomized to receive either:

• Belzutifan 120 mg once daily plus lenvatinib 20 mg once daily, or
• Cabozantinib 60 mg once daily.

Patients with active hypoxia, significant recent cardiac disease, or active central nervous system metastases were excluded.

RCC Remains a Major Global Health Burden

Renal cell carcinoma represents approximately 90% of kidney cancer diagnoses, with clear cell RCC accounting for around 70% of RCC cases. Globally, an estimated 442,570 new kidney cancer cases and 144,871 deaths were reported in 2024. Approximately one-third of patients are diagnosed with regional or metastatic disease.

Expanding Roles for Belzutifan and Lenvatinib

The new approval further broadens the use of both agents in RCC. Belzutifan is already approved in the United States as monotherapy for certain patients with previously treated advanced clear cell RCC and in combination with pembrolizumab-based regimens in the adjuvant setting. Lenvatinib is also approved in combination with pembrolizumab for first-line advanced RCC and with everolimus after prior anti-angiogenic therapy.

The latest FDA decision establishes belzutifan plus lenvatinib as a new treatment option for patients with advanced clear cell RCC whose disease progresses after PD-1/PD-L1–based therapy, offering a novel mechanism-based approach in a setting where treatment choices remain limited.