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July 6, 2017

After Deaths, FDA Places Clinical Holds on Keytruda Combo Trials

  • Following reports of patient deaths, the FDA has placed clinical holds on three trials assessing Merck & Co.’s approved cancer immunotherapy Keytruda® (pembrolilzumab) in combination with other therapies to treat multiple myeloma, the company said.

    The clinical holds follow a review of data by the trials’ Data Monitoring Committee that showed more deaths among patients treated with Keytruda in two Phase III studies, KEYNOTE-183 and KEYNOTE-185—an occurrence that prompted Merck to halt enrollment in both trials last month.

    KEYNOTE-183 was designed to assess the combination of Keytruda with Celgene’s Pomalyst® (pomalidomide) and low-dose dexamethasone in patients with refractory or relapsed and refractory multiple myeloma. KEYNOTE-183 (NCT02576977) has an estimated enrollment of 300 patients, an estimated primary completion date of August 31, 2018, and an estimated study completion date of October 31, 2019, according to ClinicalTrials.gov.

    KEYNOTE-185 was to study the combination of Keytruda with another Celgene marketed cancer drug, Revlimid® (lenalidomide), and low-dose dexamethasone in newly diagnosed and treatment-naïve multiple myeloma. KEYNOTE-185 (NCT02579863) has an estimated enrollment of 640 patients, an estimated primary completion date of August 31, 2019, and an estimated study completion date of July 31, 2021, according to ClinicalTrials.gov.

    “The FDA has determined that the data available at the present time indicate that the risks of Keytruda plus pomalidomide or lenalidomide outweigh any potential benefit for patients with multiple myeloma,” Merck acknowledged yesterday.

    As a result, KEYNOTE-183 and KEYNOTE-185 have been placed on full clinical hold, and all patients enrolled in both studies will end treatment with Keytruda. So, too, will patients in the Keytruda/lenalidomide/dexamethasone cohort in a third trial, the Phase I KEYNOTE-023 study.

  • Phase I Trial on Partial Hold

    A partial clinical hold has been placed on KEYNOTE-023, designed to assess the Keytruda/ lenalidomide/dexamethasone combination in patients who received prior anti-multiple myeloma treatment with an immunomodulatory (IMiD) treatment (lenalidomide, pomalidomide, or thalidomide). KEYNOTE-023 (NCT02036502) has an estimated enrollment of 115 patients, and an estimated study completion date of August 9, 2018, according to ClinicalTrials.gov.

    The clinical hold does not apply to other studies of Keytruda, Merck said.

    “Patient safety is Merck’s primary concern, and we are grateful to the study investigators and patients involved in these studies for their commitment to this important research,” stated Roger M. Perlmutter, M.D., Ph.D., president, Merck Research Laboratories. “Merck’s development program for Keytruda, spanning more than 30 different tumor types, has one priority: helping patients suffering from cancer.”

    Keytruda is a humanized monoclonal antibody that works by blocking interaction between the programmed cell death protein 1 (PD-1) and its receptor ligands, PD-L1 and PD-L2, thus increasing the immune system’s ability to fight cancer. Keytruda is a blockbuster drug, having generated $1.402 billion in revenue last year (148% above 2015) and $584 million in the first quarter alone (up 134% from Q1 2016).

    The FDA approved Keytruda in 2014 as the first PD-1 inhibitor indicated to treat unresectable or metastatic melanoma following treatment with Bristol-Myers Squibb’s marketed cancer immunotherapy Yervoy® (ipilimumab).

    Since then, Keytruda has won approval for additional indications in non-small-cell lung cancer, head and neck squamous cell cancer, classical Hodgkin's lymphoma, urothelial carcinoma—and, most recently in May, pediatric and adult patients with unresectable or metastatic microsatellite instability-high or mismatch repair solid tumors, for which Merck won accelerated FDA approval.

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