Clinical trialPhase 3Kidney cancer

Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma

N Engl J Med · 2019861 patients (432 pembrolizumab + axitinib, 429 sunitinib)

Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. N Engl J Med. 2019. 380:1116-1127

A newer report of this study has been published: 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 (2025)

Study type: Clinical trial
Study name: KEYNOTE-426
Phase: Phase 3
Design: Randomised, open-label trial
Sample size: 861 patients (432 pembrolizumab + axitinib, 429 sunitinib)
Source: N Engl J Med · 2019
Trial registration: NCT02853331

In plain words

This study compared a combination of an injected immunotherapy drug (pembrolizumab) and a tablet that blocks the growth of the tumour's blood vessels (axitinib) with the tablet sunitinib in patients with advanced kidney cancer. After one year, about 90 of every 100 patients in the combination group were alive, compared with about 78 in the sunitinib group, and the tumour shrank in more patients. This benefit was seen in all risk groups.

Key results

89.9% vs 78.3%

12-month overall survival

HR for death 0.53; 95% CI 0.38–0.74; P<0.0001

15.1 vs 11.1 months

Median progression-free survival

HR 0.69; 95% CI 0.57–0.84; P<0.001

59.3% vs 35.7%

Objective response

P<0.001

75.8% vs 70.6%

Grade 3 or higher adverse events of any cause

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 or unacceptable toxicity; 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 for 4 weeks followed by 2 weeks off (6-week cycle).

Source of the regimen details: Published abstract (NEJM 2019), ClinicalTrials.gov NCT02853331 and the full text of the 5-year report (PMC12532709); axitinib dose-modification 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

Patients with advanced or metastatic renal cell carcinoma with a clear cell component (with or without sarcomatoid features), without previous systemic therapy for advanced disease, with measurable disease and a Karnofsky performance status of at least 70% (ClinicalTrials.gov); all IMDC risk groups.

Endpoints

Primary endpoints: overall survival and progression-free survival in the intention-to-treat population. Key secondary endpoint: objective response rate.

Safety and side effects

Grade 3 or higher adverse events of any cause occurred in 75.8% of patients in the pembrolizumab + axitinib group and 70.6% of the sunitinib group (details of specific adverse events in the full text of the paper).

Clinical significance and place in guidelines

On the basis of this trial, the FDA approved axitinib with pembrolizumab for first-line treatment of advanced renal cell carcinoma in April 2019. NCCN (version 3.2022) lists this combination as a preferred option with category 1 evidence in all risk groups, and in the EAU 2022 guideline it is also one of the standard first-line treatments in all IMDC risk groups (level of evidence 1b).

Limitations

Open-label design; results are from the first interim analysis with relatively short follow-up (median 12.8 months); the comparator was sunitinib and there is no direct comparison with other immunotherapy-based combinations.

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.