Belzutifan in 2026: Three Phase 3 Trials, Two Likely Approvals, and One Negative Surprise

Belzutifan in 2026: Three Phase 3 Trials, Two Likely Approvals, and One Negative Surprise

Three Phase 3 trials of belzutifan — an oral HIF-2α inhibitor targeting the near-universal VHL loss in clear cell renal cell carcinoma — reported results in 2026. Two trials are positive and poised for FDA approval; a third delivers an unexpected negative result in the frontline metastatic setting. Dr. Scott Tykodi breaks down the data and what it means for clinical practice.

Introduction: The Belzutifan Story Reaches Its Phase 3 Chapter

Belzutifan has been available as a late-line single agent for clear cell renal cell carcinoma since its initial FDA approval in 2023 based on the LITESPARK-005 study that represents proof of concept for HIF2α targeting. The story of 2026 in kidney cancer is what happens when you take this oral HIF-2α inhibitor as part of combination regimens and in earlier settings. Three phase 3 LITESPARK trials are all reporting results within this calendar year. Two are positive; one delivers a surprise negative result that preserves the current frontline standard of care.

Understanding Belzutifan: Why HIF-2α Is the Right Target in Clear Cell RCC

To understand why belzutifan has activity in kidney cancer, it helps to understand the biology. Von Hippel Lindau (VHL) gene loss is present in nearly all clear cell RCC tumors — by mutation, deletion, or epigenetic silencing. VHL normally functions as part of an oxygen sensing complex that ubiquitinates HIF-1α and HIF-2α transcription factors, targeting them for proteasomal degradation.

When VHL is lost, HIF-1α and HIF-2α are no longer degraded. They accumulate and activate gene expression programs that drive angiogenesis, proliferation, and metabolic reprogramming, creating what is often called a state of “pseudohypoxia”. The tumor behaves as though it is chronically oxygen-deprived, even when it is not.

Belzutifan is an oral inhibitor of HIF-2α that disrupts its heterodimerization with its binding partner, blocking the transcription factor's activity. HIF-2α is not mutated in kidney cancer; it is dysregulated. Targeting that dysregulation is a mechanistically sound approach, and the LITESPARK program has now tested HIF-2α targeting by belzutifan across three disease settings.

LITESPARK-022: Adjuvant Pembrolizumab Plus Belzutifan — Positive for DFS

The LITESPARK-022 trial enrolled nearly 1,000 patients per arm in a randomized comparison of 1-year of adjuvant pembrolizumab monotherapy (the current adjuvant standard following KEYNOTE-564) versus the doublet of pembrolizumab plus belzutifan. The study enrolled clear cell histology only, stratified by three risk categories: intermediate-high risk (T2 and T3 tumors), high risk (T4 tumors and node-positive disease), and stage IV M1 NED (stage IV patients with all visible disease surgically resected).

Primary endpoint: Disease-Free Survival: Hazard ratio 0.72, statistically significant, with early curve separation that was sustained. The doublet outperformed pembrolizumab monotherapy.

The subgroup that matters: A post-hoc analysis by risk category revealed a striking pattern. Intermediate-high risk patients — T2 and T3 tumors — derived the DFS benefit from the doublet. High-risk patients (T4, N+) and stage IV M1 NED patients showed a hazard ratio approximately equal to 1.0 suggesting no added benefit for belzutifan in those highest-risk subsets.

This is clinically important because 85% of patients enrolled fall into the intermediate-high risk category. These T2 and T3 patients are who we see every day in clinic. The doublet appears to benefit the largest and most commonly encountered adjuvant population, while the highest-risk patients — who might intuitively seem most in need of intensification — do not appear to benefit from adding belzutifan.

Overall survival: A trend favoring the doublet was not yet significant. The study is ongoing; follow-up will continue.

Toxicity: Grade 3 or higher adverse events occurred in 42% of doublet patients versus 18% of monotherapy patients — more than double. However, the dropout rate was not substantially different: approximately 10% versus 7.3%. Patients seemed able to dose-adjust and sustain therapy. Belzutifan-specific toxicities emerged predictably: anemia (managed with erythropoiesis-stimulating agents without apparent loss of efficacy signal), hypoxia, and a range of additional toxicities - not always intuitive for belzutifan toxicities — including increased liver enzyme elevations, diarrhea, headaches, and nausea.

Patient selection consideration: The adjuvant patient is different from the metastatic patient. Patients who have just had a tumor removed feel cancer-free. The last thing many of them want is to feel sick from treatment. In real-world practice, the 42% grade 3+ rate may translate to a higher dropout rate than seen in the trial. For a healthy younger patient in their 40s or 50s with a T3 tumor, the doublet is a clear recommendation. For an elderly or frail patient — even one technically meeting T2-T3 eligibility — the two-drug regimen may not be appropriate. Clinical judgment will matter.

A note on adjuvant therapy completion: Duration of therapy is associated with outcomes in kidney cancer adjuvant trials with PD1 inhibitors. The negative adjuvant nivolumab trials used either 6 or 9 months of therapy; whereas pembrolizumab and durvalumab (RAMPART arm C), both positive, used a full year. I keep this in mind if I encounter patients near the end of adjuvant pembrolizumab who begin experiencing side effects such as itching or fatigue, for example. The temptation is to stop early to help the patient feel better sooner. However, I encourage my patients to complete the full course when clinically possible.

LITESPARK-012: Frontline Metastatic — A Negative Result That Clarifies the Standard

The LITESPARK-012 trial evaluated three regimens in the frontline metastatic setting: pembrolizumab plus lenvatinib (the backbone control), pembrolizumab plus lenvatinib plus belzutifan, and pembrolizumab plus quavonlimab (a CTLA-4 antibody co-formulated with pembrolizumab for simultaneous dosing).

A press release issued just a few weeks ago reported negative top line outcomes for this trial. Both experimental regimens failed to improve PFS or OS versus the doublet comparator. The current four frontline options for metastatic clear cell RCC — ipilimumab/nivolumab, pembrolizumab/axitinib, pembrolizumab/lenvatinib, and cabozantinib/nivolumab — therefore remain the standard and will not be displaced by a newly emerging triplet regimen.

The data will be presented at ESMO in fall 2026. Understanding the nuances of why the triplets failed will be informative for future trial design.

LITESPARK-011: Belzutifan Plus Lenvatinib as Salvage; Positive, OS Likely to Follow

LITESPARK-011 evaluated belzutifan plus lenvatinib versus cabozantinib as salvage therapy for previously treated clear cell RCC. Patients required at least one prior IO-containing regimen; approximately half had not received a prior VEGF-pathway inhibitor (likely treated with ipilimumab/nivolumab frontline) and the rest had received only a single prior targeted therapy. This trial is therefore best understood as testing a second-line or second-targeted-therapy.

Results:

• PFS: 14.8 months vs 10.7 months, hazard ratio 0.70, significant
• OS: 34.9 months vs 27.6 months, hazard ratio just below significance at p=0.06
• ORR: 52.6% vs 39.6%, significant
• Median duration of response: 23.0 months vs 12.3 months — nearly double

The duration of response finding is striking. When responses last nearly twice as long with the doublet, a more robust survival advantage is likely to emerge with longer follow-up. My prediction is that the next OS analysis will cross the significance threshold.

Subgroup finding: Poor-risk patients showed a hazard ratio of approximately 1.0 for PFS — no benefit for the doublet in this subset. Poor-risk patients may also be less fit, and adding a second drug to patients who are already struggling may not serve them well regardless of the biology.

Toxicity management:

• Dose reductions were common in both arms (lenvatinib 66%, belzutifan 33%, cabozantinib 77%) but dropout rates were identical at 11% each.
• Anemia with belzutifan: ESA support appears safe and effective; does not appear to compromise antitumor activity based on available data.
• Hypoxia: stop therapy, allow recovery, then dose reduce. Not a drug to push through if a patient needs supplemental oxygen.
• Cardiac signal: the FDA required cardiac monitoring to be added to the study protocol mid-enrollment. A small cardiac dysfunction signal emerged — 7% all-grade, 4.6% high-grade in the belzutifan arm. No automatic monitoring protocol has been advised, but worth clinical vigilance.
• Cabozantinib has higher rates of hand-foot syndrome and liver enzyme elevations; whereas lenvatinib has higher rates of proteinuria. Prior frontline toxicity experience can also help inform the choice of second-line agent.

Looking Ahead: Two Trials Worth Watching

B9400004 (personalized neoantigen vaccine plus pembrolizumab vs pembrolizumab monotherapy, adjuvant): Completed enrollment in early 2025. This is an mRNA vaccine personalized to each patient's tumor neoantigens — the same technology that has generated excitement in the melanoma adjuvant space. Positive results would be intriguing by showing the addition of a biologic to pembrolizumab can enhance clinical activity in contrast to a targeted drug (belzutifan) addition to pembrolizumab in this setting.

EA8252 (pembrolizumab vs surveillance in non-clear cell RCC, adjuvant): Opening soon through a cooperative group mechanism. Currently, patients with non-clear cell RCC receive surveillance after nephrectomy. This trial will provide the first prospective evidence on whether adjuvant pembrolizumab benefits non-clear cell patients.

For Patients

If you have been diagnosed with kidney cancer, the treatment landscape has advanced substantially in the past few years. For patients who have had surgery for kidney cancer, adjuvant immunotherapy — and now potentially a combination of immunotherapy and a new targeted drug called belzutifan — can reduce the risk of your cancer returning. For patients with metastatic kidney cancer that has progressed after prior treatment, belzutifan in combination with another targeted drug is showing better disease control than current standards and FDA approval is anticipated. Ask your oncologist about your specific risk category, your history of prior treatments, and whether a clinical trial might be appropriate for your situation.

Key Takeaways

• Belzutifan (HIF-2α inhibitor) targets the VHL-loss → HIF-2α overexpression biology present in nearly all clear cell RCC.
• LITESPARK-022 (adjuvant): pembro + belzutifan DFS HR 0.72, significant; benefit concentrated in intermediate-high risk (T2-T3, 85% of patients); no benefit in high-risk or M1 NED subsets; grade 3+ AEs doubled (42% vs 18%) but dropout rates similar; FDA approval anticipated 2026.
• LITESPARK-012 (frontline metastatic): negative trial; pembro + lenvatinib + belzutifan and pembro + quavonlimab both failed to improve PFS or OS; current four frontline regimens remain standard.
• LITESPARK-011 (salvage): belzutifan + lenvatinib vs cabozantinib; PFS HR 0.70 significant; OS just missing (p=0.06) but likely to cross at next analysis given DOR nearly doubled (23 vs 12.3 months); poor-risk patients showed no PFS benefit.
• Adjuvant therapy duration may matter: complete the full course of pembrolizumab when possible; shorter duration associated with negative adjuvant trials.
• Belzutifan toxicity management: ESA support for anemia is safe; stop for hypoxia and dose reduce; vigilance for cardiac side effects is warranted given small signal.
• Non-clear cell RCC: no adjuvant treatment available currently; EA8252 trial will provide prospective evidence.

About the Author

Scott Tykodi, MD, PhD is an Associate Professor of Medicine at the University of Washington School of Medicine and Fred Hutchinson Cancer Center in Seattle, Washington, where he is a member of the Kidney Cancer and Melanoma Program. He serves as Director of Kidney Cancer Research and Co-Director of the Kidney Cancer Multidisciplinary Clinic. He specializes in the care of patients with kidney cancer and has led more than 35 clinical trials evaluating novel immune-based and targeted therapies for kidney cancer and other solid tumors.

References

1. LITESPARK-022. Pembrolizumab plus belzutifan vs pembrolizumab in adjuvant clear cell RCC. Presented at ASCO GU, 2026.
2. LITESPARK-012. Triplet regimens vs pembrolizumab/lenvatinib in frontline metastatic clear cell RCC. Press release, 2026. Data to be presented at ESMO 2026.
3. LITESPARK-011. Belzutifan plus lenvatinib vs cabozantinib in previously treated clear cell RCC. Presented at ASCO GU, 2026.
4. KEYNOTE-564. Adjuvant pembrolizumab in RCC. New England Journal of Medicine, 2021; OS update 2024.
5. RAMPART trial (arm C). Adjuvant durvalumab plus tremelimumab in RCC. Presented at ESMO, 2025.
6. LITESPARK-005. Belzutifan versus Everolimus for Advanced Renal-Cell Carcinoma. New England Journal of Medicine, 2024; FDA approval basis.
7. Tykodi S. "Kidney Cancer Updates." Presented at the 2026 Alaska Hematology Oncology Conference, Anchorage, AK, May 2026.