(UroToday.com) The 2026 American Society of Clinical Oncology (ASCO) Annual Meeting was host to a kidney and bladder cancers poster session. Dr. Cristina Suarez presented LITESPARK-033, an ongoing phase III trial of belzutifan + zanzalintinib versus cabozantinib for recurrent clear cell renal cell carcinoma (RCC) during or after adjuvant anti-PD-(L)1 therapy.
Adjuvant pembrolizumab is the current standard of care for patients with RCC at increased risk of recurrence following nephrectomy. However, there remains no established standard treatment for patients who recur during or after adjuvant anti–PD-(L)1 therapy, highlighting an important unmet clinical need. Belzutifan, a potent and selective hypoxia-inducible factor-2α (HIF-2α) inhibitor, is approved in the United States for patients with advanced ccRCC following prior PD-(L)1 inhibitor and VEGFR tyrosine kinase inhibitor (TKI) therapy, and in the European Union for advanced ccRCC after progression on PD-(L)1- and VEGFR-targeted therapies.
Zanzalintinib is a multitargeted kinase inhibitor of VEGFR, MET, and the TAM family kinases (TYRO3, AXL, and MER). Given the established activity of VEGFR-TKIs in RCC and the encouraging results seen with HIF-2α/VEGFR-targeted combinations, the combination of belzutifan plus zanzalintinib is being investigated in this disease setting. Notably, the phase III LITESPARK-011 trial previously demonstrated superior progression-free survival and objective response rate for belzutifan plus lenvatinib versus cabozantinib following prior anti–PD-(L)1 therapy. 1
LITESPARK-033 is a global, multicenter, open-label phase III trial comparing belzutifan plus zanzalintinib versus cabozantinib in patients with advanced ccRCC who experience recurrence during adjuvant anti–PD-(L)1 therapy or within 24 months of the last adjuvant dose. Patients are randomized to:
- Arm A: belzutifan 120 mg orally once daily plus zanzalintinib 60 mg orally once daily
- Arm B: cabozantinib 60 mg orally once daily
Treatment continues until disease progression, unacceptable toxicity, or treatment discontinuation. Randomization is stratified according to:
- Timing of recurrence after adjuvant anti–PD-(L)1 therapy (≤6 months versus >6 months after the last dose)
- IMDC risk category (favorable versus intermediate versus poor)
- Presence of sarcomatoid features (yes versus no)
Key eligibility criteria include:
- Age ≥18 years
- Histologically confirmed unresectable advanced RCC with a clear cell component
- Measurable disease per RECIST v1.1
- Disease recurrence during adjuvant anti–PD-(L)1 therapy or within 24 months after the last dose
- No prior systemic therapy for metastatic disease
- Not considered a candidate for, or declined, anti–PD-(L)1 retreatment
- Karnofsky Performance Status ≥70%
Major exclusion criteria include:
- Prior treatment with a HIF-2α inhibitor or VEGFR-TKI
- Oxygen saturation <92% at rest or requirement for supplemental oxygen
- Clinically significant cardiovascular disease within 12 months
- Requirement for hemodialysis or peritoneal dialysis
- Active CNS metastases or carcinomatous meningitis
- Active infection requiring systemic therapy
- Concurrent strong CYP3A4 inhibitors or inducers that cannot be discontinued
- Therapeutic anticoagulation
The dual primary endpoints are:
- Progression-free survival (PFS) per RECIST v1.1 assessed by blinded independent central review (BICR)
- Overall survival (OS)
The key secondary endpoint is objective response rate (ORR) per RECIST v1.1 by BICR. Additional secondary endpoints include:
- Duration of response (DOR)
- Safety and tolerability
- Patient-reported outcomes (PROs)
Tumor assessments with CT or MRI of the chest, abdomen, and pelvis are performed every 12 weeks, with bone imaging required at screening. Safety assessments include continuous adverse event monitoring with grading according to CTCAE v5.0. Patient-reported outcomes include FKSI-DRS, EORTC QLQ-C30, FACIT GP5, and EQ-5D-5L collected longitudinally throughout treatment and follow-up.
Efficacy analyses will be conducted in the intention-to-treat population. Comparisons of PFS and OS will use stratified log-rank testing, with hazard ratios and 95% confidence intervals estimated using stratified Cox proportional hazards models. Time-to-event endpoints will be analyzed using Kaplan-Meier methodology, while ORR will be evaluated using exact Clopper-Pearson methods. Safety analyses will be performed in all treated participants.
At the time of presentation, LITESPARK-033 was actively enrolling participants globally, with study sites open across Argentina, Australia, Austria, Belgium, Brazil, Croatia, Czechia, Denmark, France, Germany, Greece, Hong Kong, Ireland, Italy, Mexico, Poland, the Republic of Korea, Singapore, Spain, Taiwan, and the United States.
The LITESPARK-033 study is designed to address a growing therapeutic challenge in RCC: management of patients who recur during or shortly after adjuvant immunotherapy. By evaluating combined HIF-2α inhibition and VEGFR-targeted therapy against cabozantinib, this trial will help define the optimal treatment strategy for this increasingly common clinical scenario.
Presented by: Cristina Suarez Rodriguez, MD, PhD, Attending Physician, Vall d'Hebron University Hospital, Barcelona, Spain
Written by: Rashid K. Sayyid, MD, MSc, Assistant Professor, Urologic Oncologist, Department of Urology at The University of Arizona and Banner University Medical Center, Tucson, AZ – @rksayyid on X during the American Society of Clinical Oncology Genitourinary (ASCO) Annual Meeting held in Chicago, IL between May 29th and June 1st, 2026
Reference: