FDA Grants sBLA to Advanced Hepatocellular Carcinoma

The US Food and Drug Administration (FDA) has accepted and granted priority review for a new supplemental Biologics License Application (sBLA) for pembrolizumab (KEYTRUDA) for previously treated patients with advanced hepatocellular carcinoma (HCC).

The anti-PD-1 therapy, pembrolizumab, is a humanized monoclonal antibody designed strengthen the immune system’s ability to detect and fight tumor cells. By blocking the interaction between PD-1 and its ligands—PD-L1 and PD-L2—it activates T lymphocytes which influence tumor cells as well as healthy ones.

“There continues to be a significant need for new options in the treatment of advanced hepatocellular carcinoma, which is the most common type of liver cancer,” said Scot Ebbinghaus, MD, vice president of clinical research at Merck Research Laboratories, in a recent statement. “The data supporting our application provide a clear rationale for the advancement of the KEYTRUDA clinical program for hepatocellular carcinoma, and we are grateful for the opportunity to work with the FDA to potentially bring KEYTRUDA to patients living with this difficult-to-treat cancer.”

The sBLA was based largely on data yielded from the phase 2 KEYNOTE-224 trial, which has been evaluating pembrolizumab in patients with HCC. In the trial update presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting held in Chicago, Illinois, and simultaneously published in The Lancet Oncology, single-agent pembrolizumab induced an overall response rate of 16.35% among 104 patients with advanced HCC who had previously been treated with sorafenib.

In the 2 experimental arms, subjects were administered a pembrolizumab 200 mg intravenous (IV) infusion on day 1 of each 3-week cycle for up to 35 administrations.

A complete response rate was noted in 1% of participants, while a partial response rate was noted in 15.4%. The disease control rate was 61.5%, which was complemented by a median progression-free survival of 4.8 months and a 6-month progression-free survival rate of 43.1%.

The safety profile of the drug proved consistent with findings yielded in previous studies. Pruritus was the most commonly reported (21.2%) treatment-related adverse event, followed by fatigue (12.5%), increased aspartate aminotransferase (9.6%), and diarrhea (9.6%). Grade 3 to 5 treatment-related adverse events were reported in 25% of patients and 1 associated death was reported. Furthermore, In 2.9% of patients, immune-mediated adverse events were experienced.

An objective response rate measured in the time frame of approximately 3 years serves as the primary outcome measure for the trial. Secondary outcome measures include duration of response, disease control rate, time to disease progression, progression-free survival, and overall survival.

Pembrolizumab has previously been indicated for the treatment of other rare cancers such as refractory primary mediastinal large B-cell lymphoma (PMBCL) for patients who have relapsed after 2 or more previous lines of therapy and an expanded indication for unresectable or metastatic melanoma, regardless of BRAF mutations. It was also granted an orphan drug designation for the treatment of cutaneous T-cell lymphoma (CTCL).

In addition to those specific rare diseases, pembrolizumab has also been indicated for rare variants of melanoma, lung cancer, head and neck cancer, classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, gastric cancer, cervical cancer, and microsatellite instability-high (MSI-H) cancer.

Currently, the FDA has set a Prescription Drug User Fee Act (PDUFA), or target action, date of Nov. 9, 2018.