Combining the immunotherapy drugs ipilimumab and nivolumab results in better outcomes in people whose tumors have a lot of mutations.
A treatment that combines two specific immunotherapy drugs has already had success in some people with advanced melanoma and kidney cancer. A phase III study has now shown that the same combination was also effective for people with lung cancer. The international research team that conducted the trial was led by Memorial Sloan Kettering medical oncologist Matthew Hellmann. The findings are being presented at the 2018 American Association for Cancer Research (AACR) annual meeting. They are being published online in the New England Journal of Medicine as well.
The clinical trial was called CheckMate -227. It looked at combining nivolumab (Opdivo®) and ipilimumab (Yervoy®) to treat people with advanced non-small cell lung cancer, the most common type of lung cancer. The analysis being presented focused on people with a molecular marker indicating that there were many mutations in their tumors. Previous studies from MSK have suggested that tumors with many mutations are likely to respond to immunotherapy. After a minimum follow-up of nearly a year, those whose tumors had many mutations who received the immunotherapy combination were 42% less likely to have their cancer progress compared with those in the control group, who got standard-of-care chemotherapy.
“This trial had two important findings,” says Dr. Hellmann, who is a member of the Parker Institute for Cancer Immunotherapy at MSK. “First, it showed us that the combination of these immunotherapies together control lung cancer better than chemotherapy. Second, it showed that molecular markers are effective in helping to predict which people will benefit from immunotherapy.
“The results of this study highlight the importance of molecular profiling to identify the best treatment options for each patient,” he adds. “We are already doing this type of testing routinely for people with lung cancer, for example, with MSK-IMPACT™.”
Leading the Way in Clinical Trials
Ipilimumab and nivolumab are both in the class of drugs called immune checkpoint inhibitors. These drugs help control cancer by taking the brakes off the immune system. This allows the white blood cells called T cells to attack tumors. MSK physician-scientist Jedd Wolchok led the clinical research that resulted in the approval of ipilimumab in 2011 by the US Food and Drug Administration for the treatment of advanced melanoma.
Dr. Wolchok also led the pivotal clinical trial that resulted in FDA approval for the combination of ipilimumab and nivolumab in melanoma in 2015. Because that combination has worked well for melanoma, researchers decided to evaluate it for other cancers as well, including non-small cell lung cancer. Nivolumab on its own is already approved for this type of lung cancer, as well as for a number of other cancers.Back to top
Importance of Mutational Burden
Despite the striking success of checkpoint inhibitors at stopping cancer growth and even eliminating tumors in some people, these drugs don’t work for everyone. Research at MSK has focused on why that’s the case and looked for ways to predict beforehand who is most likely to benefit.
One important discovery that’s been made in many types of cancer is that tumors with a greater number of mutations tend to respond better to checkpoint inhibitor drugs than those with fewer mutations. This characteristic is called a high tumor mutation burden (TMB). In a related study, published online April 12, 2018, in the journal Cancer Cell, Dr. Hellmann and colleagues at MSK and elsewhere focused on the role of TMB in people with non-small cell lung cancer who were treated with nivolumab plus ipilimumab. The goal of study was to examine was to link the molecular features of the tumors to the patients’ outcomes after treatment with nivolumab plus ipilimumab in a phase I trial called CheckMate-012.
Based on their analysis, the researchers found that a high TMB was a good way to predict the effectiveness of combination immunotherapy in people with non-small cell lung cancer. The findings were used to guide the testing that was later done in the CheckMate -227 trial. TMB is already part of the results obtained from the MSK-IMPACT test.
A New Treatment Option for Non-Small Cell Lung Cancer
In CheckMate -227, among people whose tumors had a high TMB, the response rate was much better for those who got immunotherapy rather than chemotherapy. After getting the combination, 45% had their tumors shrink compared with 27% of those who got chemotherapy. And responses were distinctly durable with immunotherapy, where 68% were still responding to the immunotherapy combination one year after treatment started compared with only one-quarter of those who got chemotherapy.
The researchers say that immunotherapy is an important addition to the roster of treatment options for people with advanced non-small cell lung cancer. “This drug combination shows that some people can be spared treatment with chemotherapy,” Dr. Hellmann says. “And if a person stops responding to immunotherapy, they can still be given chemotherapy for additional benefit.”Back to top