Clinical trialPhase 3Kidney cancer

Pembrolizumab plus axitinib versus sunitinib for advanced clear cell renal cell carcinoma: 5-year survival and biomarker analyses of the phase 3 KEYNOTE-426 trial

Nat Med · 2025861 patients

Rini BI, Plimack ER, Stus V, Gafanov R, Waddell T, Nosov D, et al. Nat Med. 2025. 31:3475-3484

Study type: Clinical trial
Study name: KEYNOTE-426
Phase: Phase 3
Design: Randomised, open-label trial; minimum follow-up of 5 years
Sample size: 861 patients
Source: Nat Med · 2025
Trial registration: NCT02853331

In plain words

After more than 5 years of follow-up, the combination of the immunotherapy drug pembrolizumab with the tablet axitinib still gave patients with advanced kidney cancer longer survival than sunitinib, and the tumour responded in about 60% of patients.

Key results

HR 0.84

Overall survival

95% CI 0.71–0.99

HR 0.69

Progression-free survival

0.59–0.81

60.6% vs 39.6%

Objective response

Drugs in this study:Lenvatinib (Lenvima)Pembrolizumab (Keytruda)

Dose and schedule cards

Pembrolizumab + axitinib (KEYNOTE-426)

Advanced RCC, first line, all IMDC risk groupsEach drug’s schedule in the tableOn the page “Kidney cancer” · First-line regimens for advanced RCC

Advanced RCC, first line, all IMDC risk groups

Drug	Dose	Route	Schedule
Pembrolizumab	200 mg (or 400 mg)	IV, 30-minute infusion	Day 1 every 3 weeks (400 mg dose: every 6 weeks)
Axitinib	5 mg twice daily (12 hours apart)	Oral, with or without food	Daily, continuously

Cycle schedule: Pembrolizumab every 3 weeks (or every 6 weeks with the 400 mg dose); axitinib daily and continuously
Duration: Pembrolizumab up to 24 months; axitinib until progression or unacceptable toxicity

Per the FDA labels and the trial. If the patient has had no adverse reaction above grade 2 for at least 2 consecutive weeks, is normotensive and is not taking antihypertensive medication, the axitinib dose in this combination may be increased at intervals of 6 weeks or longer to 7 mg and then 10 mg twice daily; dose reductions: 3 mg, then 2 mg twice daily. In moderate hepatic impairment (Child-Pugh B), reduce the starting dose by about half. ALT or AST increase to 3 to <10 × ULN without bilirubin ≥2 × ULN: withhold both drugs until grade 0–1 (consider corticosteroids); ≥10 × ULN, or >3 × ULN with bilirubin ≥2 × ULN: permanently discontinue both. Monitor thyroid function and urine protein before starting and periodically.

On the page “Kidney cancer” · First-line regimens for advanced RCC

Pembrolizumab + axitinib

Advanced clear cell kidney cancer, first lineEach drug’s schedule in the tableOn the page “Immunotherapy regimens in kidney cancer: pembrolizumab-axitinib, nivolumab-ipilimumab and adjuvant pembrolizumab”

Advanced clear cell kidney cancer, first line

Drug	Dose	Route	Schedule
Pembrolizumab	200 mg	IV	Every 3 weeks
Axitinib	5 mg twice a day (increase to 7 and 10 if tolerated)	Oral	Daily

Cycle schedule: Pembrolizumab every 3 weeks; axitinib daily and continuously
Duration: Until progression; pembrolizumab up to 35 cycles

As in KEYNOTE-426.

Dose source:.

On the page “Immunotherapy regimens in kidney cancer: pembrolizumab-axitinib, nivolumab-ipilimumab and adjuvant pembrolizumab”

Combination with oral targeted drugs

Advanced RCC (KEYNOTE-426 / CLEAR); pMMR endometrial (with lenvatinib); adjuvant ccRCC (with belzutifan)Cycle length: Every 3 or 6 weeksOn the page “Pembrolizumab (Keytruda)” · Standard doses and combination regimens (FDA label)

Advanced RCC (KEYNOTE-426 / CLEAR); pMMR endometrial (with lenvatinib); adjuvant ccRCC (with belzutifan)

Drug	Dose	Route	Schedule
Pembrolizumab	200 mg every 3 weeks or 400 mg every 6 weeks	IV infusion over 30 minutes	Day 1
RCC
Axitinib	5 mg twice a day (escalation at intervals of 6 weeks or more can be considered)	Oral	Daily
RCC or endometrial
Lenvatinib	20 mg once a day	Oral	Daily
Adjuvant ccRCC
Belzutifan	120 mg once a day	Oral	Daily

Cycle length: Every 3 or 6 weeks
Duration: Advanced disease: pembrolizumab up to 24 months; adjuvant with belzutifan: up to 12 months

With axitinib: ALT/AST 3 to less than 10 × ULN without bilirubin 2 ×, withhold both drugs until grade 0 to 1 (consider corticosteroids); ALT/AST above 3 × with bilirubin 2 × or more, or 10 × or more: stop both permanently.

On the page “Pembrolizumab (Keytruda)” · Standard doses and combination regimens (FDA label)

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 + axitinib

Pembrolizumab 200 mg IV every 3 weeks for up to 35 cycles (about 2 years) + axitinib 5 mg orally twice daily continuously; until progression, unacceptable toxicity or physician/patient decision. If one drug was stopped for toxicity, the other could be continued. Per the FDA label, the axitinib dose in this combination can be increased at intervals of 6 weeks or more to 7 and then 10 mg twice daily, and reduced for adverse events to 3 and then 2 mg twice daily.

2Sunitinib

Sunitinib 50 mg orally once daily, 4 weeks on and 2 weeks off, continuously until progression or unacceptable toxicity.

Source of the regimen details: Full text of the paper (PMC12532709), ClinicalTrials.gov NCT02853331; axitinib dose escalation and reduction rules from the FDA label (INLYTA)

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

Adults with newly diagnosed or recurrent stage IV clear cell renal cell carcinoma, without previous systemic therapy for advanced disease, with a Karnofsky performance status of 70% or more, at least one measurable lesion per RECIST 1.1 and a tumour sample for biomarker analysis; randomisation was stratified by IMDC risk group and geographic region.

Endpoints

Overall survival, progression-free survival, objective response and prespecified exploratory biomarker analyses.

Safety and side effects

Safety data are not reported in the abstract; details in the full text of the paper.

Clinical significance and place in guidelines

This report confirms the durability of the combination's benefit, although the size of the overall survival benefit has narrowed with longer follow-up (HR from 0.53 in the first report to 0.84).

Limitations

The trial is open-label; the biomarker analyses are exploratory.

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.