Introduction

We have yet to have truly confirmatory data for a benefit for adjuvant immunotherapy in kidney cancer.  A large phase 3 trial produced conflicting results depending on whether a second immunotherapy agent was added. A biomarker sub-study clarified what ctDNA currently can and cannot tell clinicians. And a phase 2 trial offers one of the few solid options available for the historically understudied non-clear cell subtypes.

RAMPART: Positive data in combination immunotherapy, but not in monotherapy.  

The phase 3 RAMPART trial randomized patients with resected, intermediate- or high-risk renal cell carcinoma to active monitoring, one year of durvalumab monotherapy, or one year of durvalumab plus two doses of tremelimumab, testing whether checkpoint blockade could reduce recurrence after nephrectomy the way pembrolizumab already does per KEYNOTE-564.

The combination arm succeeded: 3-year disease-free survival was 81 percent with durvalumab plus tremelimumab versus 73 percent with active monitoring, a statistically significant 35 percent reduction in the risk of recurrence or death (hazard ratio 0.65). Durvalumab monotherapy, reported this year, did not: 3-year disease-free survival was 78 percent versus 72 percent with active monitoring, a hazard ratio of 0.74 that did not cross the pre-specified threshold for statistical significance, despite a similar-looking numerical trend. Overall survival data remain immature for both comparisons. Quality of life was preserved with durvalumab monotherapy but showed some new declines in pain and cognitive function with the combination at 15 months, alongside the expected increase in high-grade toxicity that comes with adding a second checkpoint inhibitor.

After two decades in which the overwhelming majority of adjuvant trials in this disease have been negative, pembrolizumab remains the only agent with a clearly positive result, and now a second positive signal exists only for the combination, not the single agent, in a similarly designed trial. Given the added toxicity of dual checkpoint blockade, this should be weighed carefully against the still-modest absolute benefit before becoming routine practice.

ctDNA in Kidney Cancer: Prognostic, But Not Yet a Treatment-Selection Tool

A pre-planned correlative analysis from the KEYNOTE-564 trial (the study that established adjuvant pembrolizumab) explored whether postoperative circulating tumor DNA could identify which patients benefit most from adjuvant immunotherapy. Only 5 percent of patients tested positive using the commercially available assay (8 percent with a more sensitive research-only assay), despite more than half of the overall study population eventually recurring, meaning the test's sensitivity for detecting patients who will go on to relapse is quite poor (10 to 15 percent) even though a positive result is highly specific for a worse outcome.

Critically, pembrolizumab benefited patients regardless of ctDNA status (hazard ratios of roughly 0.78 whether ctDNA-positive or -negative), meaning this biomarker cannot currently be used to select who should or shouldn't receive adjuvant treatment, even though it is clearly prognostic for risk. The presenting investigator's own conclusion was direct: this data does not support routine use of ctDNA to guide adjuvant treatment decisions in kidney cancer today. More sensitive assays and more mature data may change that, but the technology is not yet the solution some had hoped for.

Cabozantinib Plus Nivolumab Offers Real Activity in Non-Clear Cell Kidney Cancer

Non-clear cell renal cell carcinoma remains understudied, and current treatment decisions largely rest on small, single-arm response-rate studies rather than randomized trials. A single-institution phase 2 trial tested cabozantinib plus nivolumab in this population, building on activity already established for cabozantinib alone in non-clear cell disease.

Across 53 evaluable patients with a range of non-clear cell histologies, the overall response rate was 43 percent, rising to 46 percent in the first-line setting, a genuinely strong signal compared with the response rates traditionally seen with a tyrosine kinase inhibitor alone in this population, and one that looks much more like what is seen when combining a TKI with immunotherapy in clear cell disease. Responses occurred across multiple non-clear cell subtypes, including papillary, translocation-associated histologies, and in FH-deficient tumors, historically an especially difficult-to-treat group. Median duration of response was 17 months, median progression-free survival 11 months, and median overall survival about 28 months. Based on this data, cabozantinib plus nivolumab is now one of the preferred options listed in guidelines for non-clear cell renal cell carcinoma.

For Patients

If you or a family member has had surgery for kidney cancer at higher risk of recurrence, it's reasonable to ask your oncologist about the current, somewhat mixed evidence for adjuvant immunotherapy: one approved drug (pembrolizumab) has clear benefit, and a two-drug immunotherapy combination (not FDA approved) has shown benefit in one large trial, but comes with added side effects worth discussing directly. For patients with a rarer, non-clear cell type of kidney cancer, a combination of cabozantinib and nivolumab now has more supporting data and is a reasonable option to discuss, where until recently options were much more limited.

Key Takeaways

  • RAMPART showed durvalumab plus tremelimumab significantly improves 3-year disease-free survival after nephrectomy (81% vs 73%), but durvalumab monotherapy did not reach statistical significance in the same trial design, leaving pembrolizumab as the only single agent with a clearly positive adjuvant result in kidney cancer.

  • A ctDNA sub-study of KEYNOTE-564 found the test is highly specific but poorly sensitive for recurrence, and pembrolizumab benefited patients regardless of ctDNA status, meaning ctDNA cannot yet be used to select who needs adjuvant treatment.

  • Cabozantinib plus nivolumab produced a 43 percent overall response rate across non-clear cell renal cell carcinoma subtypes in a phase 2 trial, now supporting its use as a preferred guideline option in this understudied population.

  • Adding a second checkpoint inhibitor to adjuvant therapy meaningfully increases toxicity, and that tradeoff should be discussed explicitly with patients given the still-modest absolute benefit.

References

  1. Larkin J, Powles TB, Frangou E, et al. First results from RAMPART: an international phase III randomised-controlled trial of adjuvant durvalumab monotherapy or combined with tremelimumab for resected primary renal cell carcinoma. Presented ASCO 2026; Ann Oncol. 2025 (LBA93).

  2. Choueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma (KEYNOTE-564). N Engl J Med. 2021; ctDNA sub-analysis presented ASCO 2026.

  3. Feldman DR, et al. Phase 2 trial of cabozantinib plus nivolumab in non-clear cell renal cell carcinoma. Presented ASCO 2026.