The study is the longest follow-up of a type of immunotherapy called checkpoint inhibitors in melanoma, and marks a climactic moment in a dramatic success story that has unfolded over the past five years. The first checkpoint inhibitor for advanced melanoma — Yervoy (ipilimumab) was approved by the U.S. Food and Drug Aministration (FDA) in 2011. Several checkpoint inhibitors are on the market. Checkpoint inhibitors block a specific protein on cancer cells, allowing the immune system’s disease-fighting T cells to see and kill cancer. The medications have proved to be especially effective for melanoma, a dangerous form of skin cancer that, only 10 years ago, was typically fatal when the cancer spread to other parts of the body. The study represents long-term phase 3 (a stage of testing bent on finding optimal safety and effectiveness) clinical trial data from CheckMate 067, which looked at the impact of the drugs Opdivo (nivolumab) and Yervoy alone or combined in patients with advanced melanoma. The drugs were previously shown to help many patients with advanced melanoma. Data published in July 2015 in the New England Journal of Medicine from the trial showed that Opdivo alone or Opdivo combined with Yervoy produced better progression-free survival rates compared with Yervoy alone. That study led the FDA, in 2016, to approve the combination for advanced melanoma. The new study confirms the long-term benefit for many patients, says James Larkin, PhD, the lead author of the study and a medical oncologist with the Royal Marsden NHS Foundation Trust in London, UK. “The durable benefit from these drugs is one of the key questions,” he says. “Five years later, more than half of people on combination therapy are still alive, and the shape of the curve is now quite flat — suggesting that if patients get to five years, I think there’s a pretty good chance they’ll get to 10 years.” The drug combination appears to be particularly effective in patients with a type of gene variant known as BRAF mutant or BRAF v600, the study shows. In BRAF mutant patients, those treated with both drugs experienced a five-year survival rate of 60 percent compared with 46 percent in the Opdivo group and 30 percent in the Yervoy group. Patients with higher levels of the PD-L1 protein also experienced higher survival rates with the drug combination compared with patients with lower PD-L1 levels. RELATED: The Difference Between Chemical and Mineral Sunscreen
A Deadly Disease Now Treatable
Melanoma is the most serious type of skin cancer. About 96,000 Americans are diagnosed with the disease each year, according to the American Cancer Society (ACS), and about 7,200 die of melanoma each year. According to the ACS, the current five-year survival rate for metastatic melanoma is 23 percent. But that figure is based on diagnoses made between 2008 and 2014 and may not reflect current developments in treatment, such as the immunotherapy drugs. A decade ago, says Larkin, “we didn’t really have any kind of effective drug treatment (for metastatic melanoma). Average life expectancy was six to eight months. We’ve seen a remarkable transformation in a relatively short period of time.”
Study Sets a New Standard for Treating Metastatic Melanoma
CheckMate 067 includes data from 945 people with stage 3 or stage 4 melanoma who were randomly assigned to take either Opdivo alone, Yervoy alone, or both. Researchers analyzed data according to the stage of metastasis and some molecular markers, such as PD-L1 status and the BRAF gene mutation. PD-L1 and BRAF status reveal the possible molecular mechanisms involved in the disease process and can help predict the effectiveness of a particular treatment. The study showed a long-term impact in preventing death for the combination of Opdivo and Yervoy. The overall five-year survival rate was 52 percent in the patients receiving the combination compared with 44 percent for patients receiving Opdivo and 26 percent for patients receiving Yervoy. Overall, 112 of the 151 patients who received Opdivo plus Yervoy were alive and treatment-free five years following treatment. The authors noted that the drug combination is currently the only treatment for metastatic melanoma for which the median survival rate has not been reached at the five-year mark. The study has established practice standards — has changed what is considered standard optimal treatment — for this group of melanoma patients, says Keith T. Flaherty, MD, the director of developmental therapeutics at the Massachusetts General Hospital Cancer Center and a professor of medicine at Harvard Medical School in Boston. Dr. Flaherty serves on the board of directors of the American Association for Cancer Research and is the editor in chief of the AACR’s journal, Clinical Cancer Research. “You have this group who are holding steady at five years and counting,” he says. “This is truly the best evidence we have. Every practitioner looks at this data as the source of information. We’ve come to appreciate the value of looking at five-year data for all of these [checkpoint inhibitor] therapies.” The study also shows that the treatment response lasts in some patients even when they have to stop the therapy early because of serious side effects. “It turns out that for the people who stop treatment because of side effects in the combination arm, the outcomes are the same as in people who did not stop therapy early,” Larkin says. “This is really important to patients. Immunotherapy can work durably even after the treatment has been stopped.”
A More Fine-Grained Look at Side Effects
The study also provides updated information on the safety of combining Opdivo and Yervoy. After five years, 96 percent of patients receiving both drugs experienced treatment-related adverse events compared with 87 percent in patients on Opdivo and 86 percent taking Yervoy. Severe side effects were more common in patients taking Opdivo or the combination compared with Yervoy alone. “You can see that PD-L1 mono-therapy [Opdivo alone] is far better than ipilimumab and far safer. That is reinforced in this data,” Flaherty says. “And then you have data that shows you’re risking a lot more in the way of toxicity by combining these two drugs. But if you look at this five-year data, you can say: Here is what we think we’re getting in terms of efficacy.” There is no way to predict which patients may suffer severe side effects, Flaherty says. About half the patients taking the combination therapy have severe side effects. “Almost everyone had some side effects. But we don’t know who is going to run into trouble,” he says. “We know it’s likely to happen in the first few weeks to first few months.” The study also does not clarify which treatment should be recommended — Opdivo and Yervoy combined or Opdivo alone, Larkin says. “Clearly the side effects are greater for the combination than with [Opdivo] alone,” he says. “Most of the markers of efficacy are better for the combination. In my view, it’s necessary for physicians to sit down with patients and their families and talk about the benefits of the treatment and the risks of the treatment. I don’t think there is a one-size-fits-all. I think it has to be individualized.” RELATED: People Who Are Obese Respond Better to Some Cancer Immunotherapy Drugs
