The U.S. Food and Drug Administration (FDA) announced today its approval of a new treatment for advanced melanoma, the deadliest and most difficult-to-treat form of skin cancer. The drug, a monoclonal antibody called ipilimumab, is the first treatment of any kind ever shown in a large, randomized phase III clinical study (study MDX010-20) to improve overall survival in patients with metastatic melanoma who no longer respond to standard therapy. It is also the first in an emerging class of therapies called "checkpoint blockade," which enhance the immune system's ability to attack cancer by interfering with immunological checkpoints that slow or stop immune cell activation and proliferation in the presence of tumors or chronic viral infection.
"The approval of ipilimumab to treat advanced metastatic melanoma is a game changer not only for the thousands of people fighting this disease, but also for the entire field of oncology," says Jill O'Donnell-Tormey, Ph.D., executive director of the Cancer Research Institute (CRI), a nonprofit organization that since 1953 has worked to advance the science of tumor immunology. "It represents a major leap forward in our understanding of the role the immune system can play in controlling cancer—an understanding made possible through decades of intensive laboratory and clinical research—and demonstrates how we can now apply this knowledge to develop new and powerful immune-based therapies that extend cancer patients' lives."
New data released earlier this week from another pivotal phase III clinical trial (study CA184-024) show the antibody also extends survival in patients with metastatic melanoma who have not received prior therapy. The study compared the effects of combining ipilimumab with chemotherapy (dacarbazine) versus chemotherapy alone. Although dacarbazine has been part of the standard of care for metastatic melanoma for more than 30 years, it has never been shown to increase overall survival in this patient population.
"Ipilimumab provides a way to overcome one of the most potent barriers to successful cancer immunotherapy—the ability of cancer to selectively suppress the response of immune cells to the cancer and shut down immune attack," says Lloyd J. Old, M.D., director of the CRI Scientific Advisory Council. "It inaugurates a new era of cancer therapy, one in which the principles and practices of immunology are integrated into standard and other novel approaches to cancer treatment."
The positive results from the two phase III studies of ipilimumab were made possible in part through the evolution of the clinical science, which is based on new models of academic-industry partnership to advance immunotherapy development. Over the course of several years, the CRI Cancer Immunotherapy Consortium (CIC), a group of 100 academic and industry partners in the cancer immunotherapy space, has worked with a broad and diverse network of immunologists, drug developers, and regulatory agency representatives to establish a new paradigm for clinical development and evaluation of cancer immunotherapies. The new paradigm offers a distinction from the conventional chemotherapy approach and represents the first defined development guidelines in this field.
"While chemotherapy treats the tumor directly, immunotherapy treats the immune system, which results in distinct clinical characteristics. This may be best addressed by a tailored development paradigm," says CIC Executive Committee member and a lead investigator in the ipilimumab clinical development program Jedd D. Wolchok, M.D., Ph.D., who is director of the Immunotherapy Clinical Trials Program at Memorial Sloan-Kettering Cancer Center in New York City.
The Consortium worked in partnership with other organizations across the field to gather knowledge and synthesize the new paradigm. Among the CIC's recommendations was to improve the use of clinical trial endpoints including overall survival—the length of time patients live after entering a clinical trial—in order to account for the unique biological characteristics in cancer patients receiving immunotherapy. Based on these new insights, Bristol-Myers Squibb changed the primary endpoint of the pivotal phase III study upon which the FDA based today's approval, to overall survival instead of response rate. The study met the revised endpoint successfully.
To date, several thousand cancer patients have received ipilimumab treatment in clinical trials for a variety of cancers, either as a monotherapy or in combination with other drugs.
"The integration of such combination approaches into the standard of care could radically change the practice of oncology. Low-dose chemotherapy, radiation, or targeted therapies given in combination with immune checkpoint blockade may prove to be an effective and efficient way to immunize the body against tumor cells," says CRI Scientific Advisory Council associate director James P. Allison, Ph.D., who identified the first immune checkpoint blockade with his discovery in 1995 that the cytotoxic T lymphocyte antigen-4 (CTLA-4) receptor inhibited T cell responses. He proposed that blocking CLTA-4 could enhance anti-tumor immune responses and conducted the first preclinical experiments showing that CTLA-4 blockade could lead to tumor rejection. Ipilimumab, which Dr. Allison later developed in partnership with Medarex and Bristol-Myers Squibb, binds to CTLA-4 and prevents it from inhibiting T cell activation.
Incorporating immunotherapies into the standard of care raises a number of challenges. Central among them is finding the right formulations of combination therapies and determining their optimal dose and schedule of administration. To address this, the CIC organized a three-day scientific colloquium earlier this month on the topic of schedule and dose of combination therapy, featuring presentations by more than thirty leaders in the field. The colloquium also hosted an interdisciplinary roundtable with representatives from the academic, industry, regulatory, nonprofit, and investment communities.
Several other drugs that are designed to modulate the anti-cancer immune response, such as anti-PD1 and anti-GITR, are showing promise in experimental studies in melanoma and other cancers, including colorectal, kidney, lung, prostate, and ovarian cancers and sarcoma. Many studies are now underway to learn whether such treatments may also synergistically enhance the effect not only standard cancer therapies but also investigational treatments like therapeutic cancer vaccines, tyrosine kinase inhibitors, anti-angiogenic drugs, and other targeted therapies.
Ipilimumab is the second active immunotherapy for cancer to be approved by the FDA, following the approval in April 2010 of sipuleucel-T (Provenge®) for advanced castrate-resistant prostate cancer. Approximately a dozen other active immunotherapies for cancer are in phase III clinical development.
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