FDA Grants Priority Review to Keytruda-Inlyta Combo for Untreated, Advanced Kidney Cancer Patients

The U.S. Food and Drug Administration has granted priority review to Merck‘s application requesting the approval of Keytruda (pembrolizumab) in combination with Inlyta (axitinib) for the initial treatment of advanced renal cell carcinoma (RCC) patients, with a final decision expected June 20, the company announced.

The application is based on data from the Phase 3 KEYNOTE-426 trial (NCT02853331), where the combination was shown to be significantly better than standard treatment Sutent (sunitinib) at extending survival and delaying disease progression or death.

“Many patients with advanced renal cell carcinoma face a poor prognosis and there remains a need for new and effective treatment options in the first-line setting,” Roger M. Perlmutter, president of Merck Research Laboratories, said in a press release. “KEYNOTE-426 demonstrated that an anti-PD-1 combination therapy significantly improved overall survival and progression-free survival versus [Sutent] in the first-line treatment of advanced renal cell carcinoma.”

Keytruda, developed by Merck (known as MSD outside the U.S. and Canada), is an immunotherapy that counteracts a mechanism used by cancer cells to evade anti-cancer immune responses. This mechanism involves the production of PD-L1 by tumor cells to interact with the PD-1 receptor on the surface of specific immune cells, which “shuts down” the immune response against them.

By suppressing PD-1/PD-L1 interactions, Keytruda restores the body’s capacity to activate an anti-tumor response and fight cancer cells.

Inlyta, by Pfizer, is a protein kinase inhibitor that mainly prevents new blood vessels from forming in growing tumors. This reduces the oxygen and nutrient supply reaching tumors, halting their proliferation. Inlyta is already approved for RCC patients who failed one prior treatment.

Building on findings from the Phase 1b KEYNOTE-035 trial, showing that a combination of Keytruda and Inlyta had promising anti-tumor activity in patients with untreated, advanced RCC, Merck designed the open-label KEYNOTE-426 trial to determine if the combination improved the outcomes of these patients, compared with Sutent.

The trial included 861 patients, with a median age 62 years, who had clear-cell metastatic RCC and had not received any prior treatment for their metastatic condition. Participants were randomly assigned a combination of Keytruda (given as an infusion every three weeks) and Inlyta (given orally twice a day), or oral Sutent once a day.

Treatment was continued until patients experienced disease progression, showed signs of unacceptable toxicity, or dropped out of the study.

KEYNOTE-426’s primary goals were to determine if the combination extended patients’ survival and delayed the time to disease progression or death. Secondary measures included overall response rate, duration of response, disease control rate, and safety.

Researchers had already reported that KEYNOTE-426 met both its primary objectives and the secondary measure of objective response rate.

More recently, at the 2019 Genitourinary Cancers Symposium, they presented updated findings from this trial, in the study “Study to Evaluate the Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Axitinib Versus Sunitinib Monotherapy in Participants With Renal Cell Carcinoma (MK-3475-426/KEYNOTE-426).”

After a median follow-up of 12.8 months, 59% of patients in the combination group were still receiving treatment, versus 43.1% of those on Sutent.

A total of 59.3% of patients responded to the combination, compared with 35.7% of patients on Sutent. Responses were also longer: While more than half of responders were still benefiting from the combination, responses to Sutent lasted a median of 15.2 months.

Researchers found that the combination reduced the risk of death by 47%, with 89.9% of patients on the combination living past the one-year mark, compared with 78.3% of those on Sutent.

Similarly, the risk of disease progression or death was lowered by 31%, with patients on the Keytruda-Inlyta combination living without signs of disease worsening for a median of 15.1 months, versus 11.1 months for Sutent.

These benefits were seen regardless of risk group or PD-L1 status — a biomarker that often predicts responses to Keytruda.

The proportion of patients experiencing severe adverse events was similar in both groups — 62.9% for the combination versus 58.1% for Sutent. However, more patients on Sutent discontinued treatment due to severe adverse events — 6.3% versus 10.1%.

The combination of Keytruda plus Inlyta provided superior overall survival, progression-free survival, and overall response rate compared to Sutent, “and had manageable safety in patients with previously untreated, advanced or metastatic clear-cell RCC,” the researchers concluded. “These data suggest that [the combination] should be a new standard of care for this population.”

In addition to KEYNOTE-426, Merck also included supporting data from KEYNOTE-035 in its application to the FDA.

“We look forward to working with the FDA to bring this Keytruda combination to patients,” Perlmutter said.