Key Ideas

Kidney cancer had a quieter year than some other genitourinary cancers, but three questions dominate current decision-making: whether adjuvant therapy is worth its toxicity in high-risk clear cell disease, how to choose a first-line regimen as biomarker-driven selection slowly matures, and how to sequence therapy once frontline immunotherapy stops working. Across all three, the honest answer is that the field is still building the evidence to guide truly individualized decisions, and overall survival remains the outcome that matters most.

Three Questions, Not a Slam Dunk

Kidney cancer did not see the volume of practice-changing news that prostate or bladder cancer did this year, but three areas are worth attention: adjuvant therapy for the highest-risk clear cell renal cell carcinoma (RCC), first-line treatment selection and how that choice constrains later options, and second-line decisions between tyrosine kinase inhibitors (TKIs), TKI-based doublets, and HIF-2alpha inhibitors. Across all three, the same question is worth asking for every patient, every trial, and every cancer type: what is the primary endpoint, and is it clinically meaningful to this specific patient? Overall survival is the outcome that ultimately matters, even when disease-free or progression-free survival looks encouraging.

Adjuvant Therapy for High-Risk Clear Cell RCC: Real Benefit, Real Trade-offs

Adjuvant pembrolizumab, based on KEYNOTE-564, remains the standard for the intermediate and high-risk clear cell RCC after nephrectomy, and it is the only adjuvant immunotherapy strategy in kidney cancer that has shown both disease-free and overall survival benefit; a meta-analysis of adjuvant immunotherapy trials in this setting found that KEYNOTE-564 alone is driving that signal, since adjuvant atezolizumab and adjuvant nivolumab-ipilimumab combinations both failed to show benefit in their respective trials. Even with KEYNOTE-564, only a minority of patients are cured by adjuvant treatment, so the benefit has a low effect size and no adjuvant strategy so far has produced a slam-dunk result. Pending at least one recent completed trial, RAMPART durvalumab plus tremelimumab arm, which improved DFS in resected RCC, with benefit concentrated in Leibovich high-risk patients; but not seen for the durvalumab alone, presented at ASCO 2026, if that reading is confirmed on publication. 

LITESPARK-022 built on that foundation by adding belzutifan, a HIF-2alpha inhibitor, to adjuvant pembrolizumab in roughly 1,800 patients with high-risk clear cell RCC, comparing that combination against pembrolizumab alone. The trial met its primary endpoint: the disease-free survival hazard ratio was 0.72, with 24-month disease-free survival of about 80% with the combination versus about 73% with pembrolizumab alone, a 7-percentage-point absolute gain. Whether that gain is clinically significant enough to justify added toxicity is a genuine question to work through with each patient rather than a settled answer. The secondary endpoint of overall survival, with a hazard ratio around 0.78, crossed 1.0 and was not statistically significant. Grade 3 or higher toxicity increased by roughly 22 percentage points with the combination, adding anemia, hypoxia, and other effects that require closer monitoring, though these are generally reversible with dose holds. It is already a difficult conversation to ask a patient with no evidence of disease to accept immunotherapy toxicity; adding a second drug's toxicity on top of that, in a population that by definition does not yet have a proven survival benefit, deserves discussion rather than default acceptance.

In practice, the case for adding belzutifan is strongest in patients at truly high risk: pT4 disease at any grade, N1 or M1 disease with no evidence of remaining disease after resection. For patients closer to pT2 grade 4 or pT3 any grade, where risk is more moderate, the decision is less clear given that overall survival benefit has not yet been established, and using a validated risk calculator to estimate five-year risk can help frame that conversation.

Choosing First-Line Therapy: Toward Biomarker-Driven Selection

Right now, first-line treatment selection in kidney cancer is guided mostly by IMDC risk category and general treatment goals, similar to prostate and bladder cancer, but without a comparably mature biomarker framework yet. The BIONIKK trial was an early, genuinely prospective attempt to change that: using a 35-gene expression classifier, patients were divided into four molecular groups and treated accordingly, with immune-low tumors randomized to nivolumab alone versus nivolumab plus ipilimumab, angiogenic and normal-like tumors randomized between a TKI and nivolumab-ipilimumab, and immune-high tumors again randomized between nivolumab alone and the combination. The results, from a small trial, are hypothesis-generating rather than decision-changing: one group showed a numeric but not statistically significant advantage for adding ipilimumab, another showed no real difference between a TKI and the combination, and a third had too few patients to interpret. These results are not something to act on directly, but they are worth following, because a follow-on biomarker-driven trial, built on molecular clusters identified in the earlier IMmotion151 trial, is testing a similar hypothesis in an immunotherapy-responsive cluster and has already cleared its first efficacy hurdle on response rate, with progression-free and overall survival data still pending.

Until that kind of biomarker selection matures, first-line decisions in the clinic still come down to disease pace, patient frailty, and stated goals. A rapidly progressing disease or a patient who wants to maximize response typically points toward an immunotherapy-TKI combination; a frail, largely asymptomatic patient, or one who prioritizes avoiding TKI-related toxicity, may be steered toward immunotherapy alone. Most patients end up on an immunotherapy-TKI combination in practice, with immunotherapy-only combinations reserved for a smaller group of patients with a lower disease burden who prefer to avoid TKI toxicity.

After First-Line Immunotherapy: What Not to Do, and What's Next

Once frontline immunotherapy stops working, the data are fairly clear on one point: re-trying immunotherapy generally is not helpful and may cause harm outside of a clinical trial, based on trials that specifically tested adding immunotherapy back after prior immunotherapy exposure and found no benefit (Contact 03 and Tinivo-3). Cabozantinib remains the established second-line standard and the comparator against which newer regimens are measured.

Belzutifan's role is expanding beyond the adjuvant setting. LITESPARK-011, a phase 3 trial in patients with clear cell RCC that had progressed after anti-PD-(L)1 therapy, compared belzutifan plus lenvatinib against cabozantinib, deliberately using cabozantinib as an active, reliable comparator rather than a weaker option like everolimus that older lenvatinib trials had used. The combination met its primary endpoint, with median progression-free survival of 14.8 months versus roughly 10 months for cabozantinib; response rate 52.6% vs 40.2% statistically; significant, and overall survival numerically favored the combination without reaching statistical significance, and patient-reported quality of life was similar between arms. The combination has been submitted to the FDA, and if it is approved around the anticipated timeline, it will become available as another second-line-and-beyond option. On another blow to cabozantinib, LenCabo, the first head-to-head randomized comparison of contemporary post-immunotherapy regimens, showed that lenvatinib plus everolimus improved PFS versus cabozantinib in previously treated metastatic ccRCC (15.7 vs 10.2 months). Toxicity with lenvatinib-based combinations are higher but manageable with the same tools used for other TKI regimens: closer monitoring, more frequent dose holds, and attention to added combination expected toxicities. A separate exploratory combination of cabozantinib and belzutifan has shown a promising response rate as well, though progression-free survival data are not yet available to judge how it compares in the 2nd line setting.

These developments leave clinicians with a roughly three-way branch point after first-line therapy: patients who received ipilimumab-ipilimumab frontline therapy generally move to cabozantinib, lenvatinib-everolimus or a newer option lenvatinib-belzutifan combination; patients who received nivolumab-cabozantinib frontline therapy have lenvatinib-based set of options; and patients who received pembrolizumab-lenvatinib combinations frontline may move to cabozantinib or belzutifan alone. A frontline triplet combining an immunotherapy backbone with belzutifan is being studied and will need to clear a high bar to justify a three-drug combination in this disease. 

Managing the Real-World Side Effects of These Regimens

Anemia from HIF-2alpha inhibitors like belzutifan is a manageable toxicity, but it benefits from a structured approach rather than ad hoc decisions made with each new patient. Having a standard threshold in place, rather than deciding case by case whether a hemoglobin of 9.8 versus 9.2 warrants holding treatment, keeps the approach consistent: pursuing erythropoiesis-stimulating agent authorization proactively when treatment starts, holding definitively below a hemoglobin of 8 with dose reduction considered, and starting supportive measures below 10 to keep levels from dropping further. In practice, insurance authorization for these supportive measures has generally not been a barrier. 

For Patients: What These Kidney Cancer Updates Mean for You

If you have had surgery for high-risk kidney cancer, ask your oncologist directly about the actual size of the benefit from additional treatment after surgery, and what added side effects come with it. The benefit from these treatments is modest, and the right decision depends heavily on how you personally weigh a limited chance of preventing recurrence against a chance of side effects in a period when you have no evidence of remaining cancer.

If your kidney cancer is metastatic, know that treatment selection today is still guided mostly by risk category and general goals of care rather than a precise biomarker test, though that is an active area of research. It is reasonable to ask what your specific goals are for treatment, whether that is length of life, quality of life, or both, since that conversation should directly shape which combination of drugs your oncologist recommends.

Key Takeaways

  • Adjuvant pembrolizumab (KEYNOTE-564) remains the only adjuvant immunotherapy approach in high-risk clear cell RCC with a proven overall survival benefit; adding belzutifan (LITESPARK-022) improves disease-free survival further, but overall survival benefit is not yet established, and toxicity increases meaningfully although reversible.

  • Biomarker-driven first-line treatment selection (as explored in the BIONIKK/OPTIC trial and its successors) remains investigational; today's first-line decisions still rely primarily on IMDC risk, disease pace, patient frailty, and stated goals of care.

  • Re-challenging with immunotherapy after progression on frontline immunotherapy is not recommended outside a clinical trial; cabozantinib and Lenvatinib-everolimus remain the standard second-line options.

  • Belzutifan combined with lenvatinib (LITESPARK-011) improves progression-free survival compared with cabozantinib after prior immunotherapy, with an FDA submission pending, expanding belzutifan's role beyond its original later-line, single-agent approval.

  • Proactive, protocol-driven management of anemia and other regimen-specific toxicities, rather than ad hoc, case-by-case decisions, helps patients stay on effective treatment longer.

References

  1. Choueiri TK, Tomczak P, Park SH, et al. Overall survival with adjuvant pembrolizumab in renal-cell carcinoma. N Engl J Med. 2024;390:1359-1371.

  2. Choueiri TK, Motzer RJ, et al. Adjuvant pembrolizumab plus belzutifan for renal-cell carcinoma (LITESPARK-022). N Engl J Med. 2026.

  3. Vano YA, Elaidi R, Bennamoun M, et al. Nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): a biomarker-driven, open-label, non-comparative, randomised, phase 2 trial. Lancet Oncol. 2022.

  4. Motzer RJ, McDermott R, Park SH, et al. Belzutifan plus lenvatinib versus cabozantinib in patients with previously treated advanced renal cell carcinoma (LITESPARK-011): an open-label, randomised, controlled, phase 3 trial. Lancet. 2026.