Pembro plus axitinib is new standard in advanced RCC

On the basis of findings from the KEYNOTE-426 study, the combination of pembrolizumab (KEYTRUDA) plus axitinib (Inlyta) represents a new standard as front-line treatment for metastatic clear cell renal cell carcinoma, said Thomas Powles, MD, at the Genitourinary Cancers Symposium in San Francisco.

Data from the first interim analysis of KEYNOTE-426 showed that pembrolizumab plus axitinib significantly improved the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) compared with sunitinib (Sutent) in patients with advanced or metastatic clear-cell RCC. (The FDA recently approved pembrolizumab in combination with axitinib for the first-line treatment of patients with advanced RCC; for more, see “FDA approves first-line treatment for advanced renal cell carcinoma.")

Previous findings suggesting synergy between the combination of pembrolizumab and axitinib provided the rationale for KEYNOTE-426, said Dr. Powles, professor of urology oncology at Barts Cancer Institute in London. The study randomized 861 patients to oral sunitinib, 50 mg once daily for the first 4 weeks of each 6-week cycle, or to combination therapy with intravenous pembrolizumab, given at 200 mg every 3 weeks for up to 35 cycles, along with oral axitinib, 5 mg twice daily. Treatment continued until disease progression, unacceptable toxicity, or patient withdrawal. The median patient age was 62 years and 73% were male. The International Metastatic Renal Cell Carcinoma Database Consortium risk category was intermediate in 55.1% of patients assigned to combination therapy and 57.3% assigned to sunitinib monotherapy, and favorable in 31.9% and 30.5%, respectively. About 60% of patients in each arm had a PD-L1 combined positive score ≥1. Co-primary endpoints were OS and PFS.

At a median follow-up of 12.8 months, combination therapy was associated with a 47% reduction in the risk of death compared with sunitinib (HR: 0.53; p<.0001). The 12-month OS rate was 89.9% in the combination arm versus 78.3% in the sunitinib arm. The advantage in OS with pembrolizumab plus axitinib was observed irrespective of risk group or PD-L1 status.

Median PFS was 15.1 months in the combination patients and 11.1 months in sunitinib patients, corresponding to a 31% reduction in the risk for progression (HR: 0.69; p=.0001). The ORR was 59.3% and 35.7%, respectively. PFS favored pembrolizumab and axitinib across subgroups, including those for PD-L1 expression and risk group. About 11% in the pembrolizumab/axitinib arm and 17% in the sunitinib arm had progressive disease.

Median duration of response was not reached in patients assigned to combination therapy compared with 15.2 months in those assigned to sunitinib.

Treatment is ongoing in 59% of patients in the combination arm versus 43.1% in the sunitinib arm. Among the patients who discontinued pembrolizumab/axitinib, 50% have received subsequent treatment, and of those discontinuing sunitinib, 60.7% received subsequent anticancer treatment.

Treatment-related grade 3-5 side effects were observed in 62.9% of patients on the combination therapy compared with 58.1% who received sunitinib. These side effects led to discontinuation of all treatment in 8.2% versus 10.1%, respectively. The rates of increases in the levels of alanine aminotransferase and aspartate aminotransferase each exceeded 20% in the pembrolizumab plus axitinib arm.

Next:"A major step forward"

“We have a number of unanswered questions at this point, particularly the absence of biomarkers to predict response. PD-L1 levels, which have been markers for immunotherapy success in other cancers, remain unproven in renal cancer. It is possible that by combining pembrolizumab with axitinib, the predictive value of PD-L1 is being masked,” Dr. Powles said. “Overall, we have not previously seen a renal cancer study which has improved response, PFS, and OS. This is therefore a major step forward in renal cancer.”

Invited discussant Lori Wood, MD, associate professor of medical oncology at Dalhousie University, Halifax, Nova Scotia, called the results of KEYNOTE-426 “practice changing,” and applauded the low death rate but said that in the real world “we have to follow the protocols very consistently” to obtain the same survival benefit that was observed in the study.

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She observed that resource utilization will be high with the pembrolizumab/axitinib combination, with visits every 3 weeks to administer the regimen for a total of 18 physician visits, 18 nurse visits, and 18 infusion visits, and many unscheduled visits for side effects, over the course of 1 year.

KEYNOTE-426 was funded by Merck. Dr. Powles has a financial or other relationship with Bristol-Myers Squibb, Merck, Roche/Genentech, AstraZeneca/MedImmune, Novartis, and Ipsen. For full disclosures, go to bit.ly/keynote426disclosures.