PD-1 Targeted Antibody Lambrolizumab Receives FDA Breakthrough Designation

Gary Gilliland, MD, PhD

Lambrolizumab, an investigational antibody designed to target the programmed death-1 (PD-1) pathway in patients with melanoma, received a breakthrough therapy designation from the FDA after promising results from a small single-arm study.

The PD-1 pathway has been of considerable interest to researchers developing therapies to treat melanoma and other tumor types. The PD-1 receptor is expressed on the surface of activated T cells and binds to ligands on the surface of antigen-presenting cells (PD-L1 and PD-L2), an interaction that causes the T cells to switch off. Cancer cells express high levels of PD-L1 on their surface to gain control of the PD-1 pathway and cause T cells to switch off, rendering them unable to enter the tumor microenvironment and generate an antitumor response.

Developed by Merck, lambrolizumab, formerly known as MK-3475, is a humanized monoclonal IgG4 antibody that acts against PD-1. In the results of a phase I trial that were presented at the American Society of Clinical Oncology (ASCO) annual meeting in 2012, the antibody was studied in nine patients with a variety of tumor types, including two patients with melanoma. The drug was well-tolerated and generated antitumor activity in three different doses.

In November, Merck reported interim results from a phase IB study. At that point, the investigators had collected data on 85 of 132 patients enrolled in the single-arm study. A total of 43 patients (51%) showed an objective anti-tumor response, with 8 patients (9%) showing a complete response at or after an assessment performed at 12 weeks. The investigators also reported that 11 of 27 patients (41%) who had been previously treated with ipilimumab monotherapy for late-stage melanoma showed an objective antitumor response.

In general, MK-3475 was well-tolerated, with the most common adverse events including fatigue, rash, diarrhea, nausea, cough, joint pain, fever, and itching. Seven grade 3/4 events were reported as potentially immune-related.

The FDA initiated breakthrough designation earlier this year. This designation can be assigned to drugs that are designed to treat a life-threatening condition and demonstrate a substantial improvement over existing therapies. Drugs that receive the designation can receive an expedited review process, since the designation allows for more meetings between the FDA and the manufacturer during the development process, requires fewer patients for clinical trials, and reduces the amount of time required for these trials. Merck can still submit lambrolizumab for fast-track designation, accelerated approval, and priority review.

“We are pleased that the FDA has designated lambrolizumab a breakthrough therapy for patients with advanced melanoma,” said Gary Gilliland, MD, PhD, senior vice president and Oncology franchise head at Merck Research Laboratories, in a statement. “The FDA’s decision to place lambrolizumab in a category that may enable expedited development and review is an important milestone for Merck as we advance ongoing programs in multiple cancer indications.”