Clinical trialPhase 3Kidney cancer

Adjuvant Pembrolizumab plus Belzutifan for Renal-Cell Carcinoma

N Engl J Med · 20261841 patients (921 pembrolizumab + belzutifan, 920 pembrolizumab + placebo)

Choueiri TK, Motzer RJ, Karam JA, Yip W, Suárez C, Ye D, et al. N Engl J Med. 2026. 395:32-43

Study type: Clinical trial
Study name: LITESPARK-022
Phase: Phase 3
Design: Randomised, double-blind trial (1:1 ratio)
Sample size: 1841 patients (921 pembrolizumab + belzutifan, 920 pembrolizumab + placebo)
Source: N Engl J Med · 2026
Trial registration: NCT05239728

In plain words

This study looked at whether adding belzutifan tablets to the immunotherapy pembrolizumab after kidney surgery lowers the risk of the cancer coming back further. After two years, about 81 out of every 100 patients in the combination group were free of recurrence, compared with about 74 with pembrolizumab alone. But it has not yet been proven that the combination helps people live longer, and severe side effects were more common with it, so its benefits and harms should be weighed with the doctor.

Key results

80.7% vs 73.7%

24-month disease-free survival

HR for recurrence or death 0.72; 95% CI 0.59–0.87; P<0.001 (two-sided)

96.2% vs 95.7%

24-month overall survival (interim analysis)

HR 0.78; 95% CI 0.51–1.19; P=0.24; at 29% of the events for the final analysis; not significant

52.1% vs 30.2%

Grade 3 or higher adverse events

Drugs in this study:Pembrolizumab (Keytruda)

Dose and schedule cards

Adjuvant pembrolizumab + belzutifan (LITESPARK-022)

Same criteria as KEYNOTE-564 (RCC with a clear-cell component at intermediate-high or high risk, or M1 NED); a newer combination whose overall survival benefit has not yet been shownEach drug’s schedule in the tableOn the page “Kidney cancer” · Adjuvant therapy regimens after nephrectomy

Same criteria as KEYNOTE-564 (RCC with a clear-cell component at intermediate-high or high risk, or M1 NED); a newer combination whose overall survival benefit has not yet been shown

Drug	Dose	Route	Schedule
Pembrolizumab	400 mg (or 200 mg every 3 weeks)	IV, 30-minute infusion	Day 1 every 6 weeks
Belzutifan	120 mg once daily	Oral, with or without food	Daily, continuously

Cycle schedule: Pembrolizumab every 6 weeks (or every 3 weeks with the 200 mg dose); belzutifan daily and continuously
Duration: Pembrolizumab up to 12 months (in the trial, up to 9 doses of 400 mg); belzutifan up to 54 weeks, or until recurrence or unacceptable toxicity

Doses per the FDA labels and the trial. Belzutifan as adjuvant therapy: withhold for haemoglobin <9 g/dL or if a blood transfusion is needed; oxygen saturation <88%: withhold.

On the page “Kidney cancer” · Adjuvant therapy regimens after nephrectomy

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Pembrolizumab + belzutifan

Belzutifan 120 mg (three 40 mg tablets) orally once daily for up to about 54 weeks + pembrolizumab 400 mg IV infusion every 6 weeks for up to 9 doses (about 54 weeks), or until recurrence or unacceptable toxicity.

2Pembrolizumab + placebo

Oral placebo once daily for up to about 54 weeks + pembrolizumab 400 mg IV infusion every 6 weeks for up to 9 doses (about 54 weeks).

Source of the regimen details: Published abstract (NEJM 2026), ClinicalTrials.gov NCT05239728 and the FDA label (WELIREG)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with renal cell carcinoma with a clear-cell component (with or without sarcomatoid features) after complete resection of the primary tumour (partial or radical nephrectomy) no more than 12 weeks before randomisation, with ECOG 0 or 1 and one of the following: intermediate-high risk (pT2 grade 4 or sarcomatoid, N0 M0; or pT3 any grade, N0 M0), high risk (pT4 N0 M0 or any pT with N+‎ M0), or M1 NED (solitary soft-tissue metastasis resected at the same time as nephrectomy or up to 2 years after it) (ClinicalTrials.gov).

Endpoints

Primary endpoint: investigator-assessed disease-free survival. Secondary endpoints: overall survival and safety.

Safety and side effects

Grade 3 or higher adverse events occurred in 52.1% of pembrolizumab + belzutifan patients and 30.2% of pembrolizumab + placebo patients. According to the FDA label, with the combination decreased haemoglobin was seen in 95% of patients (grade 3 or higher in 11%) and hypoxia in 7% (grade 3 or higher in 5%).

Clinical significance and place in guidelines

According to specialist news reports (ASCO Post, June 2026), in June 2026 the FDA approved belzutifan with pembrolizumab for the adjuvant treatment of adults with renal cell carcinoma with a clear-cell component at intermediate-high or high risk of recurrence after nephrectomy (or nephrectomy and resection of metastatic lesions); overall survival data were not yet complete at the time of approval. Approval status in other jurisdictions (including the EMA) and its place in current guidelines should be checked separately; the EAU 2022 and NCCN 3.2022 guidelines were written before this trial.

Limitations

The results are from an interim analysis and overall survival data are immature (29% of final events); notably more grade 3 or higher adverse events; relatively short follow-up (median 28.4 months); results apply only to patients with a clear-cell component.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.