Kidney Cancer Clinical Trial Landscape

Why kidney cancer trial monitoring matters in 2026

Renal cell carcinoma (RCC) treatment has been transformed since 2018 by immunotherapy-TKI combinations. Nivolumab + ipilimumab (CheckMate 214), pembrolizumab + axitinib (KEYNOTE-426), nivolumab + cabozantinib (CheckMate 9ER), and pembrolizumab + lenvatinib (CLEAR) are all approved first-line doublets — creating a genuine sequencing problem: what comes after IO/TKI failure?

In 2026, the RCC pipeline is addressing this sequencing question with three converging strategies: HIF-2α inhibition (belzutifan + combinations), next-generation TKIs (zanzalintinib), and novel immune mechanisms including adenosine A2A receptor blockade (casdatifan) and PD-1/VEGF bispecifics.

Active Phase 3 kidney cancer / RCC trials

Multiple Phase 3 programs are active in kidney cancer, spanning 1L IO combinations, post-IO/TKI sequencing, HIF-2α inhibitors, novel immunotherapy mechanisms, and adjuvant settings:

Belzutifan (LITESPARK program) — HIF-2α inhibition redefining RCC

Belzutifan (Welireg, Merck) is an oral HIF-2α inhibitor that targets hypoxia-inducible factor 2 alpha — a transcription factor that drives clear cell RCC oncogenesis through VHL loss. Unlike TKIs that block VEGF signaling downstream, belzutifan targets the upstream transcriptional driver. It holds two FDA approvals:

• VHL disease-associated RCC: First systemic therapy approved for hereditary VHL tumors (hemangioblastoma, pancreatic neuroendocrine tumor, RCC)
• Post-IO/TKI mRCC: Approved based on LITESPARK-005 — belzutifan vs everolimus in adults who progressed after prior anti-PD-1/PD-L1 and a VEGFR TKI. OS benefit confirmed

In 2026, Merck's LITESPARK expansion program is testing belzutifan in earlier settings and novel combinations:

• LITESPARK-034 (NCT07489495): Belzutifan + zanzalintinib vs standard of care in 2L+ RCC after prior IO/TKI — the first Phase 3 combining HIF-2α inhibition with a next-generation TKI designed to complement belzutifan's mechanism
• LITESPARK-011 (NCT04586231): Belzutifan + lenvatinib vs cabozantinib in 2L+ RCC — enrollment complete, results expected 2026
• MK-6482-033 (NCT07227402): Belzutifan + zanzalintinib in RCC recurring after adjuvant therapy — expanding the belzutifan indication into post-adjuvant disease

Zanzalintinib (Exelixis) — next-generation VEGFR/MET/AXL TKI

Zanzalintinib (XL092, Exelixis) is a next-generation oral multi-kinase inhibitor targeting VEGFR1/2/3, MET, AXL, and MER — a broader and optimized selectivity profile compared to cabozantinib. Exelixis designed zanzalintinib specifically to combine with HIF-2α inhibitors and immune checkpoint agents, addressing the tolerability constraints of first-generation cabozantinib in combination settings.

Key development program in RCC:

• LITESPARK-034 (NCT07489495, with Merck): Phase 3 combination with belzutifan vs standard 2L RCC — the flagship combination in the LITESPARK/Exelixis collaboration
• Neuroendocrine tumors (NCT06943755): Phase 3 vs everolimus — separate indication from RCC
• Earlier RCC combos with nivolumab and ipilimumab in Phase 1/2 — data being generated before potential Phase 3

Casdatifan (Arcus Biosciences) — adenosine A2A receptor blockade in RCC

Casdatifan (AB928) is an oral selective adenosine A2A receptor (A2AR) antagonist. In the RCC tumor microenvironment, hypoxia and VHL loss drive high adenosine production, which suppresses T-cell anti-tumor activity by binding A2AR on immune effector cells. Casdatifan blocks this immunosuppressive signal without interfering with the VHL/HIF axis.

In Phase 3, casdatifan is being tested in combination with cabozantinib vs placebo + cabozantinib in patients with advanced clear cell RCC who have received prior IO-containing therapy (NCT07011719, Recruiting). This trial represents the most advanced adenosine-pathway program in kidney cancer — a completely distinct mechanism from both HIF-2α inhibitors and TKIs.

Separately, AstraZeneca's Phase 3 trial (NCT07000149) tests volrustomig (a PD-1/TIGIT bispecific) with and without casdatifan vs nivolumab + ipilimumab as first-line therapy in clear cell RCC — evaluating whether PD-1/TIGIT co-blockade plus adenosine blockade can outperform the approved doublet IO regimen.

Post-IO/TKI sequencing — the defining challenge in 2026

The approval of four first-line IO/TKI doublets has created a significant clinical problem: virtually no randomized Phase 3 data exists for second-line therapy after IO/TKI failure. Current practice involves sequential TKI or belzutifan, but the optimal approach — and the correct choice for patients who failed each specific 1L regimen — remains undefined.

Active Phase 3 trials in the post-IO/TKI setting in 2026:

• Belzutifan + zanzalintinib (LITESPARK-034, NCT07489495): HIF-2α + next-gen TKI doublet vs standard (likely cabozantinib or sunitinib)
• Casdatifan + cabozantinib (NCT07011719): A2AR blockade + VEGFR/MET TKI vs cabozantinib alone
• Belzutifan + lenvatinib (LITESPARK-011): Results pending — HIF-2α + multikinase TKI

The IO/TKI sequencing problem also means first-line trial design is being revisited: PDIGREE (NCT03793166) uses an adaptive design where patients responding to nivo + ipi continue on nivo, while inadequate responders cross over to nivolumab + cabozantinib — a ctDNA-guided sequential approach that could define personalized 2L sequencing.

Non-clear cell RCC: distinct diseases, distinct trials

Non-clear cell RCC histologies — papillary (type 1 and 2), chromophobe, collecting duct, medullary, and translocation — collectively represent approximately 25% of RCC and are biologically distinct from clear cell. They have different driver mutations (MET amplification in papillary type 1, FH mutation in type 2, TFEB fusion in translocation RCC) and respond differently to approved therapies.

• Papillary RCC: MET inhibitors (savolitinib, capmatinib, tepotinib) are being evaluated in MET-amplified/mutated papillary RCC Phase 1/2 cohorts; pembrolizumab monotherapy has shown modest activity in unselected pRCC
• Translocation RCC: TFEB/TFE3 rearrangements activate mTOR pathway; mTOR inhibitors and newer approaches including CDK4/6 inhibitors are being tested
• Sarcomatoid/rhabdoid differentiation: Present in any histology; these high-grade features predict benefit from IO-based therapy (CheckMate 214 sarcomatoid subgroup: 36-month OS ~56% with nivo + ipi)
• Collecting duct and medullary RCC: Cisplatin-based and gemcitabine regimens are tested; IL-2-based approaches continue in medullary RCC

DataLookout monitors ClinicalTrials.gov for all RCC histologies. You can configure separate alert profiles for "papillary RCC," "non-clear cell," "translocation RCC," or specific biomarker terms like "MET exon 14" or "TFEB fusion" to receive targeted alerts for rare histology programs.

What we monitor for kidney cancer

Our system pulls from the ClinicalTrials.gov API every day. For a kidney cancer / RCC watch profile, you can configure alerts for:

• Condition keywords: "renal cell carcinoma", "kidney cancer", "clear cell RCC", "papillary RCC", "non-clear cell RCC", "VHL disease", "sarcomatoid RCC"
• Drug/target keywords: "belzutifan", "HIF-2alpha", "zanzalintinib", "casdatifan", "cabozantinib", "VEGFR", "A2AR", "CD70 RCC" — any compound or target you're tracking
• Phase filter: Phase 1 for early programs, Phase 2/3 for competitive commercial data
• Sponsor type: Industry only or all sponsors including NCI, cooperative groups, and major academic centers
• Status changes: New registrations, enrollment opens, results postings, and any update to trial records

Who uses kidney cancer trial monitoring

• GU oncology BD teams — tracking HIF-2α, A2AR, TKI, and IO programs in RCC for business development and competitive intelligence
• Clinical development leaders — designing Phase 2/3 trials in 1L, 2L, or adjuvant RCC settings where precedent data is sparse
• Oncology investors — monitoring belzutifan expansion, zanzalintinib milestones, and emerging A2AR program readouts
• GU oncology medical affairs and MSL teams — staying current on which Phase 3 trials are enrolling for key opinion leader and site engagement
• Academic GU oncology researchers — following non-clear cell and rare histology trials globally, including cooperative group and international programs

Frequently asked questions

Related kidney and urologic oncology trial monitors

• Renal cell carcinoma (ccRCC) clinical trials — deep dive into clear cell RCC programs, LITESPARK data, and post-IO/TKI sequencing
• Prostate cancer clinical trials — shared GU oncology infrastructure; AR, PSMA, and PARP programs
• Bladder cancer clinical trials — EV/pembro, sacituzumab, and FGFR3 programs in urothelial carcinoma
• Melanoma clinical trials — overlapping IO combinations and checkpoint inhibitor biology