Merck's Keytruda Pulled for SCLC as FDA Re-Evaluates Past Accelerated Approvals

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Merck’s Keytruda (pembrolizumab) is the dominant checkpoint inhibitor in the immuno-oncology space, approved for a laundry list of cancer indications. In the third quarter of 2020 alone, Keytruda had sales of $3.7 billion, an increase of 21% from the same period the previous year. So it can come as a surprise when the drug fails to hit a clinical trial endpoint.

On March 1, Merck announced it had voluntarily withdrawn the U.S. indication for Keytruda for metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other previous line of therapy.

This was done in consultation with the U.S. Food and Drug Administration (FDA). The complete process will take a few weeks. The company notes that this decision has no effect on other indications for Keytruda.

The checkpoint inhibitor received accelerated approval for this indication in June 2019 based on tumor response rate and durability of response data from KEYNOTE-158 (cohort G) and KEYNOTE-028 (cohort C1). The deal with the FDA was that the approval was contingent on completing a post-marketing evaluation proving Keytruda was superior to other products in extending overall survival (OS).

On January 2020, KEYNOTE-604, the confirmatory Phase III trial, hit one of the dual primary endpoints, progression-free survival (PFS), but didn’t reach statistical significance for the other primary endpoint of OS.

“The accelerated pathways created by the FDA have been integral to the remarkable progress in oncology care over the past five years and have helped many cancer patients with advanced disease, including small cell lung cancer, access new treatments,” said Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “Keytruda remains a foundational treatment for certain patients with metastatic non-small cell lung cancer. We will continue to rigorously evaluate the benefits of Keytruda in small cell lung cancer and other types of cancer, in pursuit of Merck’s mission to save and improve lives.”

Keytruda has been approved by the FDA to treat certain forms of bladder cancer, classical Hodgkin’s lymphoma, colorectal cancer, esophageal cancer, kidney cancer, liver cancer, melanoma skin cancer, non-small cell lung cancer, small cell lung cancer, and squamous cell head and neck cancer.

Keytruda is also approved to treatment forms of cervical cancer, Merkel cell cancer, primary mediastinal large B-cell lymphoma, gastric cancer, certain metastatic or unresectable solid tumors, triple-negative breast cancer, and endometrial cancer, in addition to treating pediatric colorectal cancer and other pediatric cancers.

The FDA is running an industry-wide evaluation of its accelerated approvals with a focus on determining which have not met post-marketing requirements. For example, last week AstraZeneca announced it was withdrawing its checkpoint inhibitor Imfinzi in bladder cancer over a similar response. Given the number of accelerated approvals in recent years, others are expected to follow.

The Imfinzi accelerated approval was for advanced bladder cancer with high PD-1 levels or in patients regardless of PD-1 status, and was to be confirmed by the DANUBE trial, but failed to meet the overall survival endpoints compared to standard of care.

For patients with extensive stage small cell lung cancer, Imfinzi is approved as a first line treatment, based on OS data from the Phase III CASPIAN clinical trial.

Merck has said it was notifying healthcare professionals about the withdrawal for this indication.