Kidney Cancer Clinical Trial Monitor — RCC, IO/TKI Combinations & HIF-2α Programs

The RCC clinical trial landscape in 2026

Renal cell carcinoma treatment has been transformed by immunotherapy-TKI combinations. Nivolumab + ipilimumab, pembrolizumab + axitinib, nivolumab + cabozantinib, and pembrolizumab + lenvatinib are all approved first-line options — creating a complex competitive landscape and a genuine sequencing problem for second-line therapy.

The question "what comes after first-line IO/TKI?" is driving much of the current trial activity, alongside efforts to identify which patient subgroups benefit most from each frontline combination.

Key areas generating new RCC trials

Post-IO/TKI second-line treatment

With first-line IO/TKI combinations now standard, the second-line landscape after IO/TKI failure is largely uncharted. Active trial areas include:

• Cabozantinib or lenvatinib monotherapy after prior IO/TKI exposure
• HIF-2α inhibitors (belzutifan) in the post-IO/TKI setting
• IO rechallenge: whether patients who progress on one IO/TKI benefit from an alternative IO agent
• Novel immunotherapy strategies: LAG-3, TIGIT, and other checkpoint combinations

HIF-2α inhibitors: expanding belzutifan

Belzutifan (Welireg) established HIF-2α inhibition as a new modality in RCC and VHL disease. The expansion trials underway in 2025–2026 include:

• First-line RCC: belzutifan vs. sunitinib and vs. pembrolizumab + lenvatinib
• Belzutifan combinations with cabozantinib or everolimus
• Next-generation HIF-2α inhibitors with improved selectivity or oral bioavailability
• VHL disease: non-renal manifestations (retinal hemangioblastoma, CNS hemangioblastoma)

Adjuvant RCC: post-surgery recurrence prevention

Pembrolizumab is the only approved adjuvant therapy in RCC following KEYNOTE-564. Active trials are testing:

• Adjuvant IO combinations (IO + TKI) vs. IO monotherapy
• Adjuvant belzutifan in high-risk resected clear cell RCC
• Biomarker-selected adjuvant populations (ctDNA-positive post-surgery)
• Duration of adjuvant therapy: 12 months vs. 24 months

Non-clear cell RCC histologies

Papillary, chromophobe, collecting duct, and translocation RCC are distinct diseases with different biology than clear cell. Each generates specialized trials:

• Papillary RCC: MET inhibitors (savolitinib, tepotinib), VEGFR TKIs, IO combinations
• Translocation RCC: mTOR inhibitors, checkpoint inhibitors, combination approaches
• Sarcomatoid/rhabdoid differentiation: particularly immunotherapy-sensitive — dedicated enrollment arms

Novel immune targets beyond PD-1/VEGFR

Beyond the approved checkpoints, novel IO targets in RCC trials include:

• TIGIT antibodies in combination with PD-1 inhibition
• LAG-3 combination strategies for anti-PD-1 refractory patients
• CD27/CD70 pathway (CD70 is highly expressed in RCC) — bispecific and ADC approaches
• Tumor-infiltrating lymphocyte (TIL) therapy in clear cell RCC
• CAR-T targeting CD70 and other RCC-expressed antigens

Who monitors kidney cancer clinical trials?

• Oncology pharma and biotech teams with IO, TKI, or HIF-2α programs tracking the competitive landscape
• Clinical development leaders designing Phase 2/3 trials in second-line or adjuvant RCC settings
• GU oncology medical affairs teams tracking which new trials are opening for MSL preparation
• Healthcare investors covering companies with RCC pipeline assets
• Academic GU oncology groups reviewing what's enrolling for referral and participation decisions

Related urologic oncology and immunotherapy trial monitors

• Prostate cancer clinical trials — shared urologic oncology infrastructure and overlapping immunotherapy programs
• Melanoma clinical trials — overlapping checkpoint inhibitor combinations and combination IO approaches
• NSCLC clinical trials — shared checkpoint inhibitor programs and VEGFR/IO combination strategies