Experimental Drug Improves Survival in Advanced Melanoma
An experimental drug that targets the immune system, ipilimumab, has helped patients with advanced cases of melanoma live longer than expected. The results are from the first large randomized clinical trial to show an improvement in survival for patients with advanced melanoma whose disease had progressed on other treatments.
Patients who received ipilimumab lived nearly 4 months longer than those who received an experimental therapeutic vaccine that has shown some activity against melanoma: median survival was 10.1 months for those who received ipilimumab versus 6.4 months for those who received the vaccine. The difference was both statistically significant and, given the lack of any effective treatment options for advanced melanoma, clinically meaningful for patients, researchers said earlier this month at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.
“We are finally getting some good news in this disease,” said lead investigator Dr. Steven O’Day of the Angeles Clinic and Research Institute in Los Angeles during the meeting’s plenary session. The study represents an important advance for patients and the development of immunotherapies in cancer, he added.
The 676-patient trial compared outcomes in three arms: ipilimumab alone, ipilimumab plus the experimental vaccine (which targets the antigen gp100 on melanoma cells), and the vaccine alone. To their surprise, the researchers found that adding the vaccine to ipilimumab did not help patients live longer. Indeed, the median overall survival in the ipilimumab group was slightly better than that in the combination group.
The study results, which appeared online June 6 in the New England Journal of Medicine (NEJM), will be submitted to the FDA for review. In the meantime, many patients may be interested in the experimental drug. Dr. O’Day said that ipilimumab would be available to patients at certain medical centers through a compassionate-use program. (ASCO and FDA just announced new online resources to make it easier for physicians to access the program, which makes experimental drugs available to seriously ill patients outside the context of a clinical trial.)
Also in the Journals: Combining Targeted Drugs and Immunotherapies for Melanoma
A preclinical study suggests that combining targeted therapy with a BRAF inhibitor like PLX4032 and immunotherapy such as ipilimumab or IL-2 may improve outcomes for some patients with melanoma. The study hypothesized that treating melanoma cells with a targeted agent might make the cells more vulnerable to immunotherapy, and the researchers demonstrated that this may occur through the upregulation of melanoma tumor antigens. The melanoma tumor antigens were increased up to 100-fold following treatment with targeted therapies, and this increase made tumors much more sensitive to immunotherapy.
“This study is preclinical, but it provides a rationale for combining targeted therapy with immunotherapy for treating patients with melanoma,” said lead investigator Dr. Jennifer Wargo of Massachusetts General Hospital. Further research is under way to confirm the results in patients, and clinical trials are being planned based on the study, she noted. The findings were published online today in Cancer Research.
Most patients with metastatic melanoma do not live a year after diagnosis, and the researchers noted encouraging evidence of some relatively long-term benefit. In the ipilimumab arms, the 1-year and 2-year survival rates were 46 percent and 24 percent, respectively. By comparison, 1-year survival rates in recent melanoma trials have ranged from 22 percent to 38 percent, the researchers reported.
“This is really an optimistic time for our patients with melanoma,” said Dr. Lynn Schuchter, who treats patients at the University of Pennsylvania and was not involved in the study. “This trial is a step forward.”
Although most side effects were manageable, Dr. O’Day cautioned that ipilimumab is a “powerful drug.” When the immune system is stimulated, it can attack healthy tissues, leading to complications such as rashes, colitis (inflammation of the colon), and even death. Patients need to be educated about potential side effects and should be monitored by an interdisciplinary team, the researchers said.
“Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment,” the researchers wrote in the NEJM. This is consistent with data from ongoing trials of ipilimumab and other immunotherapies, said Dr. James Gulley of NCI’s Center for Cancer Research, who has led multiple clinical studies of therapeutic vaccines for cancer. At the ASCO meeting, his group reported results from a phase I study of a different experimental vaccine combined with ipilimumab in patients with advanced prostate cancer.
“It’s been a great year for immunotherapy in cancer,” said Dr. Gulley, noting that the first therapeutic cancer vaccine, sipuleucel-T (Provenge), was recently approved for prostate cancer. With the positive results from the ipilimumab trial in melanoma and recent positive therapeutic vaccine studies, he expects growing interest in immunotherapeutic approaches for cancer from companies and academic researchers.
What’s new about ipilimumab is how it works. The drug stimulates the immune system to attack melanoma cells by removing a brake that prevents immune cells from attacking the body’s own tissues. The drug, which is an antibody, removes this check on the system by binding to a molecule on the surface of T cells called CTLA4.
In a discussion of the study at the plenary session, Dr. Vernon Sondak of the H. Lee Moffitt Cancer Center & Research Institute characterized the drug as “light at the end of melanoma’s long dark tunnel.” No improvements in survival for metastatic melanoma had been documented in 3 decades, he noted, and the last new drug for the disease, interleukin-2 (IL-2), was approved more than a decade ago.
But Dr. Sondak also cautioned that much remains to be learned about ipilimumab. Future studies will need to address how best to use the drug, whether alone or in combination with other therapies, and whether it should be a first- or second-line treatment, for instance.
In addition, markers are needed to identify which patients are likely to benefit from this and other immunotherapies. “That’s the million-dollar question—everyone is looking for markers,” said Dr. Gulley. His group is looking retrospectively for biomarkers associated with overall survival in patients who receive immunotherapies, but as yet there are no validated markers that can be used as response indicators for immunotherapy of cancer.
Some researchers have questioned the selection of gp100 for the study’s control group because the vaccine alone may not have much activity in the disease, said Dr. Claudio Dansky Ullmann of NCI’s Division of Cancer Treatment and Diagnosis, who was not involved in the study. But he added that there is not really an established or preferred standard treatment comparison in this setting.
Dr. Dansky Ullmann, who oversees melanoma trials for NCI Cooperative Groups, said that the Institute has an active portfolio of trials looking at ipilimumab alone or in combination with other immunotherapies that will likely expand to other combinations, such as with targeted agents. He pointed out that the dose of ipilimumab used in this study is now considered relatively low compared with what will be used in future studies, so there is certainly the potential for better outcomes.
Ipilimumab could potentially be combined with a molecularly targeted drug, such as a BRAF inhibitor like PLX4032. In early-phase clinical trials of patients with advanced melanoma, 70 percent of patients responded to that drug. But most responses last only about 6 to 8 months. By comparison, about 20 to 30 percent of patients respond to ipilimumab, but the responses seem to be more durable, according to Dr. O’Day.
Certainly, a few years ago it wasn’t possible to even consider combining melanoma therapies in this way. Dr. O’Day attributed the recent advances in treatment for melanoma to a much better understanding of the biology of the disease and its genetic pathways.
“And now the whole field of immunotherapies has broken wide open,” he added. “I think of it as going from darkness to light.”
—Edward R. Winstead