On April 19, the Food and Drug Administration approved the combination therapy of pembrolizumab (Keytruda), an immunotherapy, and axitinib (Inlyta), a tyrosine kinase inhibitor, for first-line treatment (those patients who have received no prior treatment for metastatic RCC). Approval was based on a trial of pembrolizumab and axitinib (pembro/axi) versus sunitinib (Sutent), which has been the standard first-line treatment for metastatic kidney cancer patients.

Approval by the FDA was based on the results of the Keynote-426 trial, which enrolled 861 clear cell only patients  with those on the pembro arm having received 200 mg of the therapy intravenously every three weeks in combination with 5 mg of axitinib orally twice daily. The sunitinib was administered at 50 mg daily, four weeks on and two weeks off.

The efficacy measurements were overall survival (OS) and progression-free survival (PFS). At the first interim analysis, at 12.8 months, patients on the pembro-axi arm were 48% less likely to die than those on the sunitinib arm. This result was statistically significant. The 12-month OS was 90% for the pembro/axi arm and 78% for the sunitinib arm. The median OS was not reached in either arm. The median PFS was 15 months and 11 months for the pembro/axi and sunitinib arms, respectively.

As for side effects, Grade 3 or 4 hepatotoxicity (drug induced liver damage) occurred in 20% of patients resulting in discontinuation of pembrolizumab or axitinib in 13% of patients. In addition to hepatotoxicity, the most common adverse events occurring in 20% of more patients on the pembro/axi arm were: diarrhea, fatigue, hypertension, hypothyroidism, decreased appetite, hand-foot syndrome, nausea, stomatitis, hoarseness, rash, cough, and constipation.

Compared to two previous trials of pembrolizumab and axitinib used as monotherapies for RCC, the objective response rate increased significantly, from 38% in a Phase 2 trial for pembrolizumab and 32% in a Phase 3 trial for axitinib to 59% for the pembro/axi combination. But there was also an increase in toxicity with Grade 3-5 adverse events in the axitinib monotherpy trial being 34%, the pembrolizumab being 23% but the pembro/axi combination increasing to 63%.

The take-away from this trial is the 48% survival advantage of pembro-axi versus sunitinib, which, according to the oncologists who commented on the trial results, will establish pembro/axi as the new standard therapy replacing sunitinib and even the nivolumab/ipilimumab combination for first-line (treatment naive) clear cell patients. Median overall survival has not yet been reached so it will be interesting to see how it will compare to other therapies and how many patients turn out to be long-term survivors. The increase in Grade 3 and 4 adverse reactions to the combination is concerning, and we expect and hope there will be other trials that will modify the doses and/or use them serially to reduce the toxicity and evaluate the efficacy in order to keep more patients on the therapy. This is the first combination therapy using immunotherapy and anti-angiogenic agents to be approved by the FDA. There will be more. But in order to turn metastatic kidney cancer into a chronic disease like AIDS, combination therapies with lower toxicity but equivalent or greater efficacy will have to be developed, not to mention dealing with non-clear cell RCC metastasis.

See full analysis of the trial with response and toxicities at pembro.