Merck's lambrolizumab (MK-3475) monoclonal antibody received “Breakthrough Therapy” designation from the U.S. Food and Drug Administration in April for treating patients with advanced melanoma. The designation is one of many signs of progress in attacking cancer with agents designed for immune checkpoint blockade.
In April, Merck's lambrolizumab (MK-3475), a monoclonal antibody that inhibits the programmed death 1 (PD-1) receptor, received “Breakthrough Therapy” designation from the U.S. Food and Drug Administration (FDA) for treating patients with advanced melanoma.
The designation, which will help to expedite development and review of the drug by giving it special attention from the FDA, is a sign of progress in attacking cancer with immune checkpoint drugs. Such agents focus on releasing immune cells from the mechanisms that cancer cells use to suppress the anti-tumor immune response.
James Allison, PhD, now chair of the department of immunology at The University of Texas MD Anderson Cancer Center in Houston, pioneered this approach to immunotherapy at the University of California in Berkeley, after discovering in the mid-1990s that activated T cells express CTLA-4, a receptor that puts the brake on the immune response. The body normally uses this brake to prevent autoimmunity and overreaction; cancer cells exploit it to suppress the immune response, Allison explains.
Ipilimumab (Yervoy; Bristol-Myers Squibb), an anti-CTLA-4 antibody that gained FDA approval 2 years ago for advanced melanoma, releases the brake, allowing the immune system to kill cancer cells.
In addition to studying CTLA-4 inhibitors, researchers are working on PD-1 and PD-L1 inhibitors, with 4 agents that inhibit PD-1 and 3 agents that inhibit PD-L1 in early clinical trials. (PD-1, an inhibitory receptor expressed on activated lymphocytes, binds to PD-L1, which is selectively expressed on many solid tumors.)
A key feature of these new immune checkpoint blockade therapies is that when patients do respond, the responses may be more durable than with targeted therapies such as BRAF inhibitors, researchers say. Additionally, PD-1 antibodies may also work against other solid tumors that are not considered as immunogenic as melanoma.
In early interim results from a phase Ib study of 85 patients with inoperable and metastatic melanoma who were treated with lambrolizumab, 43 (51%) showed an objective antitumor response, and of those, 8 patients (9%) showed a complete response at or after the 12-week assessment. These results were presented in November 2012 at the 9th International Congress of the Society for Melanoma Research in Hollywood, CA.
In work reported in the New England Journal of Medicine in June 2012, Bristol-Myers Squibb's PD-1 inhibitor nivolumab (BMS-936558) was shown to elicit responses even in lung cancers—an apparent first for immunotherapy. Phase III clinical trials now have been launched for nivolumab in melanoma, renal cell carcinoma, and non–small cell lung cancer.
Overall, Allison believes, the PD-1 and CTLA-4 antibodies will prove complementary and synergistic. “In mice, the two together work better than either alone,” he notes.
Immune checkpoint blockade “is a game changer,” dividing cancer therapy into “before” and “after,” suggests Antoni Ribas, MD, PhD, professor of hematology and oncology at the David Geffen School of Medicine at the University of California in Los Angeles.
“We've never had anything like this, and it's just from phase I trials, not after years of figuring out dosing regimens,” says Ribas. He anticipates that researchers will report other significant results for immune checkpoint blockade drugs at the American Society of Clinical Oncology annual meeting in Chicago, IL, May 31–June 4.