Kidney Cancer Clinical Trials 2026 — 335 Recruiting Studies, 63 Phase 3 Programs

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 (2026)

63 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:

NCT ID	Trial / Agent	Sponsor	Status
NCT07489495	Belzutifan + zanzalintinib vs standard 2L+ RCC after prior IO/TKI (LITESPARK-034)	Merck / MSD	Not Yet Recruiting
NCT07227402	Belzutifan + zanzalintinib in RCC recurring after adjuvant therapy (MK-6482-033)	Merck / MSD	Recruiting
NCT07011719	Casdatifan (A2AR inhibitor) + cabozantinib vs placebo + cabozantinib, 2L+ advanced clear cell RCC	Arcus Biosciences	Recruiting
NCT07000149	Volrustomig (PD-1/TIGIT) ± casdatifan vs nivolumab + ipilimumab, 1L advanced ccRCC	AstraZeneca	Active (Enrollment Complete)
NCT04586231	Belzutifan + lenvatinib vs cabozantinib, 2L+ advanced RCC (LITESPARK-011)	Merck / MSD	Active (Enrollment Complete)
NCT06661720	Adjuvant tivozanib + pembrolizumab vs pembrolizumab alone after nephrectomy, high-risk RCC	Alliance for Clinical Trials in Oncology	Recruiting
NCT03873402	Nivolumab + ipilimumab vs nivolumab alone, advanced kidney cancer (CheckMate maintenance)	Bristol-Myers Squibb	Active (Enrollment Complete)
NCT03793166	PDIGREE: nivo + ipi → nivo vs nivo + cabozantinib by ctDNA/response, advanced RCC	National Cancer Institute (NCI)	Active (Enrollment Complete)
NCT02811861	Lenvatinib/everolimus or lenvatinib/pembrolizumab vs sunitinib, 1L advanced RCC (CLEAR)	Eisai	Active (Enrollment Complete)

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

How DataLookout works

We run a direct API connection to ClinicalTrials.gov every morning, collecting all new and updated trials. Our matching engine compares each trial against your profile — condition keywords, drug targets, phase, sponsor type, and study status. Only relevant trials reach your inbox.

Your daily digest includes: trial title, phase, sponsor, current status, enrollment target, primary endpoint, and a direct link to the ClinicalTrials.gov record. No noise, no duplicate alerts.

Pricing

Free: 1 disease/keyword profile, daily change tracking, ClinicalTrials.gov monitoring. No credit card required.

Starter — $29/month: 5 disease/keyword profiles, daily digest, phase and sponsor filters.

Pro — $99/month: Unlimited profiles, priority email delivery, digest frequency options. Best for BD teams and investors.

Frequently asked questions

How many kidney cancer clinical trials are currently recruiting?

As of March 2026, 335 kidney cancer and renal cell carcinoma (RCC) clinical trials are actively recruiting on ClinicalTrials.gov, with 63 Phase 3 programs active. The total active trial count (including active-not-recruiting and not-yet-recruiting) is 611.

What is belzutifan and how does it work in kidney cancer?

Belzutifan (Welireg, Merck) is an oral HIF-2α inhibitor that targets the transcriptional driver of clear cell RCC. VHL tumor suppressor loss leads to constitutive HIF-2α activation, which upregulates VEGF, PDGF, and oncogenic programs. Belzutifan binds directly to HIF-2α, preventing its dimerization with HIF-1β and halting downstream oncogenic transcription. It is approved for post-IO/TKI mRCC and VHL disease-associated tumors.

What is zanzalintinib?

Zanzalintinib (XL092, Exelixis) is a next-generation oral multi-kinase inhibitor targeting VEGFR1/2/3, MET, AXL, and MER. It was designed as a more selective and tolerable successor to cabozantinib for use in combination regimens. The lead Phase 3 program is LITESPARK-034 (NCT07489495) in combination with belzutifan vs standard 2L RCC, conducted in collaboration with Merck.

What comes after IO/TKI failure in metastatic RCC?

After progression on a first-line IO/TKI doublet (nivolumab + cabozantinib, pembrolizumab + axitinib, etc.), approved second-line options include belzutifan (LITESPARK-005), cabozantinib, sunitinib, axitinib, and everolimus. Phase 3 trials actively testing novel 2L strategies include belzutifan + zanzalintinib (LITESPARK-034) and casdatifan + cabozantinib (NCT07011719).

Is adjuvant therapy approved for RCC after nephrectomy?

Yes. Pembrolizumab (Keytruda) is FDA-approved for adjuvant treatment of adult patients at intermediate-high or high risk of RCC recurrence following nephrectomy, based on KEYNOTE-564 (significant DFS benefit; OS data maturing). In 2026, Phase 3 adjuvant trials include tivozanib + pembrolizumab vs pembrolizumab alone (NCT06661720) and the ATLAS-style belzutifan + zanzalintinib program for post-adjuvant recurrence (NCT07227402).

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