Key Ideas

HIF-2 alpha inhibition, first validated in metastatic clear cell renal cell carcinoma (RCC) with belzutifan, is now extending into new treatment settings. LITESPARK-022 showed adding belzutifan to adjuvant pembrolizumab improves disease-free survival after nephrectomy, while LITESPARK-011 demonstrated benefit for belzutifan plus lenvatinib after progression on immunotherapy, an important finding given that prior trials testing continued immunotherapy after IO progression have been negative. A next-generation HIF-2 alpha inhibitor, casdatifan, is showing encouraging early activity in this same post-treatment population.

The Biology Behind HIF-2 Alpha Targeting

Clear cell RCC is defined by VHL gene loss in more than 90% of cases, which leads to accumulation of HIF-1 and HIF-2 transcription factors and, downstream, increased angiogenesis and tumor growth. Historically, treatment has targeted this pathway downstream, largely through VEGF inhibitors. HIF-2 alpha inhibitors instead block the pathway upstream, at the transcription factor itself. Belzutifan, currently the only approved HIF-2 alpha inhibitor in kidney cancer, is approved in the metastatic setting; two recent trials examine whether its role can expand into the adjuvant and post-immunotherapy settings.

LITESPARK-022: Adding Belzutifan to Adjuvant Pembrolizumab

Adjuvant pembrolizumab is standard of care for clear cell RCC patients at increased recurrence risk following nephrectomy, based on KEYNOTE-564. The phase 3 LITESPARK-022 trial asked whether adding one year of belzutifan to adjuvant pembrolizumab could improve on that standard in patients with intermediate-high or high-risk disease, or M1 no-evidence-of-disease status after resection. Patients were randomized to pembrolizumab plus belzutifan or pembrolizumab alone.

The combination significantly improved disease-free survival, the primary endpoint, with a hazard ratio of 0.72. At the 30-month landmark, there was roughly a 7-percentage-point improvement in disease-free survival with the addition of belzutifan. Subgroup analysis showed benefit was broadly consistent, though in the M1 no-evidence-of-disease and M0 high-risk subgroups specifically, the numbers were small and the added benefit from belzutifan appeared less clear; sarcomatoid features and other markers of aggressive biology did not appear to negatively affect the ability to benefit from the combination. Overall survival data remain immature at this point.

On toxicity, adding belzutifan roughly doubled the rate of grade 3 adverse events compared to pembrolizumab alone, and treatment discontinuation due to adverse events was more common with the combination. Anemia, an expected on-target effect of belzutifan, occurred in roughly 84% of patients, with grade 3 or higher anemia in about 12%, translating to roughly one in ten patients seen in clinic. Most anemia was managed with dose modification; a smaller proportion of patients required blood transfusion or erythropoiesis-stimulating agents.

Two open clinical questions remain from this data: whether the disease-free survival benefit will translate into a meaningful overall survival benefit, given that data remain immature, and why the high-risk and M1 no-evidence-of-disease subgroups did not appear to derive clear benefit, an observation that warrants caution given the small subgroup sizes involved. In practice, this means discussing both pembrolizumab monotherapy and the belzutifan combination with appropriate patients, reserving the combination for select cases where the potential added benefit seems most likely to outweigh the added toxicity, factoring in that roughly half of adjuvant-eligible patients are already cured without any systemic treatment at all, an important reminder of the risk of overtreatment inherent to this setting. Better biomarkers to guide escalation or de-escalation decisions in this space remain an unmet need; circulating tumor DNA (ctDNA), useful in other tumor types, has been less helpful in kidney cancer because it is a low-shedding tumor. Ki-67 has shown some promise as a prognostic and potentially predictive biomarker in retrospective analysis of a separate negative adjuvant atezolizumab trial, with patients having high Ki-67 levels tending to do worse overall, but also appearing to derive more benefit from atezolizumab relative to placebo in that same analysis, suggesting potential predictive value worth further study.

Rethinking the Post-Immunotherapy Space

In the post-immunotherapy setting, prior data have generally not supported continuing or rechallenging immunotherapy after progression on an immunotherapy-based regimen; phase 3 trials, including CONTACT-03 (cabozantinib with or without atezolizumab) and a separate negative trial testing this question, both failed to show benefit from continuing immunotherapy after progression on immunotherapy in kidney cancer.

Against that backdrop, the phase 3 LITESPARK-011 trial evaluated a genuinely new mechanism in this space: belzutifan plus lenvatinib against cabozantinib, which has become something of a default standard after progression on first-line immunotherapy. The trial had dual primary endpoints of progression-free survival and overall survival, with objective response rate as a key secondary endpoint. LITESPARK-011 met its progression-free survival endpoint, with the curves separating early and remaining separated throughout follow-up; overall survival did not reach statistical significance at the interim analysis presented, though it trended favorably. Response rates and, notably, duration of response were meaningfully better with the belzutifan combination, with median duration of response nearly double that seen with cabozantinib alone.

The side effect profiles differed as expected based on each drug's individual toxicity: cabozantinib is associated with more hand-foot syndrome and diarrhea, while lenvatinib (and belzutifan) contribute more hypertension, anemia, and cardiac dysfunction. Reassuringly, patient-reported outcomes, including time to worsening symptoms and time to worsening global health status and quality of life, did not differ meaningfully between arms.

In practice, belzutifan plus lenvatinib is a reasonable option to consider after progression on immunotherapy, particularly for patients who need substantial tumor shrinkage and disease control. Because the combination carries meaningfully more toxicity than either drug alone, dose modifications should be anticipated, and the choice between this combination, cabozantinib alone, and other standard options such as everolimus or temsirolimus still depends heavily on prior treatment exposure, pace of disease, performance status, and individual patient preference.

What's Next: Casdatifan and Next-Generation HIF-2 Alpha Inhibition

Several next-generation HIF-2 alpha inhibitors are now in development. Casdatifan, evaluated in the phase 1 ARC-20 trial, is designed to be more potent and selective than belzutifan. In the 100mg once-daily cohort, the recommended dose selected for the ongoing phase 3 trial, casdatifan achieved a confirmed objective response rate of 35% in a heavily pretreated, refractory population. Elegant translational data from this trial also showed that more durable suppression of serum erythropoietin, the pharmacodynamic marker of HIF-2 alpha inhibition, correlated with improved clinical outcomes, including higher response rates, reinforcing the mechanistic rationale for this drug class and offering a potential biomarker to track treatment effect going forward.

For Patients

Kidney cancer, specifically the most common subtype called clear cell renal cell carcinoma, is often driven by a genetic pathway involving a protein called HIF-2 alpha. A newer drug that blocks this protein directly, rather than targeting blood vessel growth further downstream, is changing treatment in several settings.

After surgery to remove a kidney tumor, some patients at higher risk of recurrence now receive a year of immunotherapy. New research shows adding a HIF-2 alpha-blocking drug called belzutifan to that immunotherapy further reduces recurrence risk, though it adds side effects, most notably anemia, usually managed with medication adjustments or, less often, transfusions. Not every patient needs the added drug, and doctors weigh the added benefit against added side effects individually.

For kidney cancer that has spread and stopped responding to immunotherapy, doctors have generally moved away from continuing immunotherapy toward other options. New research shows combining belzutifan with lenvatinib works better than the prior standard, with responses lasting meaningfully longer. A newer version of this drug type, casdatifan, is showing promising early results in patients who have already tried multiple treatments. Anyone with advanced kidney cancer whose disease has progressed on immunotherapy should ask their oncologist about these newer combinations.

Key Takeaways

  • LITESPARK-022 showed adding one year of belzutifan to adjuvant pembrolizumab improved disease-free survival after nephrectomy (hazard ratio 0.72), though overall survival data remain immature and toxicity, especially anemia, roughly doubled.

  • Roughly half of adjuvant-eligible kidney cancer patients are already cured with pembrolizumab alone, underscoring the importance of individualized decision-making rather than universal treatment escalation.

  • ctDNA has limited utility as a biomarker in kidney cancer due to low tumor shedding; Ki-67 has shown early promise as both a prognostic and potentially predictive biomarker in retrospective analysis.

  • Prior trials continuing immunotherapy after progression on immunotherapy in kidney cancer, including CONTACT-03, have been negative, reinforcing that this is generally not an effective strategy.

  • LITESPARK-011 showed belzutifan plus lenvatinib improved progression-free survival and nearly doubled duration of response compared to cabozantinib after progression on immunotherapy-based therapy.

  • Casdatifan, a next-generation HIF-2 alpha inhibitor, achieved a 35% objective response rate at its selected phase 3 dose in a heavily pretreated population, with serum erythropoietin suppression correlating with clinical benefit.

References

  1. Choueiri TK, Motzer RJ, Karam JA, et al. Adjuvant Pembrolizumab plus Belzutifan versus Pembrolizumab for Clear Cell Renal Cell Carcinoma: The Randomized Phase 3 LITESPARK-022 Study. American Society of Clinical Oncology Genitourinary Cancers Symposium, 2026.

  2. Choueiri TK, Tomczak P, Park SH, et al. Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma (KEYNOTE-564). New England Journal of Medicine, 2024.

  3. Pal SK, Albiges L, Tomczak P, et al. Atezolizumab plus Cabozantinib versus Cabozantinib after Progression with Prior Immune Checkpoint Inhibitor Treatment (CONTACT-03). Lancet, 2023.

  4. Motzer RJ, et al. Belzutifan plus Lenvatinib versus Cabozantinib for Advanced Renal Cell Carcinoma After Anti-PD-(L)1 Therapy: Open-Label Phase 3 LITESPARK-011 Study. American Society of Clinical Oncology Genitourinary Cancers Symposium, 2026.

  5. Choueiri TK, et al. Activity and Biomarker Analyses with Casdatifan, a Next-Generation HIF-2 Alpha Inhibitor, in Refractory Clear Cell Renal Cell Carcinoma: Results from ARC-20. American Society of Clinical Oncology Genitourinary Cancers Symposium, 2026; Nature, 2026.