FDA Rejects Merck's 6-Week Dosing Schedule for Keytruda


It doesn’t happen that often, but Merck’s checkpoint inhibitor Keytruda (pembrolizumab) received a rejection from the U.S. Food and Drug Administration (FDA). Six all at once, as a matter of fact.

The company had submitted six supplemental Biologics License Applications (sBLAs) to update the dosing frequency of Keytruda to include every-six-weeks (Q6tW) dosing. It was seeking approval of a 400 mg Q6W dose infused over 30 minutes for indications in melanoma, classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, gastric cancer, hepatocellular carcinoma and Merkel cell carcinoma.

The agency issued a Complete Response Letter (CRL), which Merck indicates it is reviewing and will discuss their next plans with the FDA.

The applications were based on pharmacokinetic modeling and simulation data that the company presented at the 2018 ASCO Annual meeting. They also supported a March 28, 2019 approval for the 400 mg Q6W dosing for Keytruda as a monotherapy by the European Commission.

Just last week, Merck positive results from the pivotal Phase III KEYNOTE-355 trial of Keytruda in combination with chemotherapy in patients with metastatic triple-negative breast cancer (mTNBC) whose tumors expressed PD-L1. The trial met one of its dual primary endpoints, progression-free survival (PFS).

An independent Data Monitoring Committee (DMC) ran an interim analysis on the trial, showing that first-line treatment with Keytruda with nab-paclitaxel, paclitaxel or gemcitabine/carboplatin had a statistically significant and clinically meaningful improvement in PFS compared to chemotherapy alone. The DMC recommended the trial continue without changes to evaluate the other dual primary endpoint, which is overall survival (OS).

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“Triple-negative breast cancer is an aggressive malignancy,” said Roger M. Perlmutter, president, Merck Research Laboratories. “It is very encouraging that Keytruda in combination with chemotherapy has now demonstrated positive results as both a first-line treatment in the metastatic setting with this trial, and as neoadjuvant therapy in the KEYNOTE-522 trial. We look forward to sharing these findings with the medical community at an upcoming congress and discussing them with the FDA and other regulatory authorities.”

TNBC is a particularly aggressive form of breast cancer. It has a high recurrence rate within the first five years after diagnosis. The triple-negative refers to testing negative for all three hormone receptors, estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER2). Many cancer therapies target one or more of these hormone receptors, and this lack of all three makes it difficult for therapies to target the cancer. TNBC affects about 15-20% of breast cancer patients.

The company is having a busy year so far. In addition to these two stories, last week four African countries, including the Democratic Republic of the Congo (DRC), approved Ervebo, the company’s Ebola vaccine.

And as part of its 2019 full-year and fourth-quarter reporting, Merck announced it is spinning off products from its Women’s Health, Legacy Brands, and Biosimilars businesses. It plans to launch a new, independent, publicly-traded company to handle those products. No name for the new company has been announced.

“Over the past several years, we have purposefully shifted the focus of our efforts and resources to our best opportunities for growth,” said Kenneth C. Frazier, chairman and chief executive officer of Merck.

Those key pillars are Oncology, Vaccines, Hospital and Animal Health. And it’s clear that the foundation of the Oncology pillar is Keytruda.

The new company will decrease Merck’s Human Health manufacturing footprint by about 25% and the number of Human Health products by about 50%.

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