Researchers report some of the most encouraging results yet for treating lung cancer with the latest immune-based treatments, most of which have been approved to treat other types of tumors.
In three papers presented at the American Association for Cancer Research annual meeting, and published simultaneously in the New England Journal of Medicine, lung cancer experts found innovative ways to weaken lung tumors to improve people’s chances of surviving the disease.
“There is definitely a high unmet need,” says Patrick Forde, assistant professor of oncology and associate member of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, of the lack of effective treatments for lung cancer. Currently more than half of people who are treated even at early stages of the disease can expect the cancer to return, and chemotherapy typically leads to only a 5% improvement in people’s chances of living five years — but an up to 70% chance of being exposed to serious toxicities.
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The studies involve a group of immune-based cancer drugs called checkpoint inhibitors, which are designed to rip away the molecular cloak behind which cancer cells hide from the immune system. The medications target a protein called PD-1, its related PD-L1, or CTLA-4, which protect the body’s cells from being killed by immune cells; because tumors are normal cells growing out of control, they take advantage of this molecular security blanket to avoid getting detected by immune cells. A series of checkpoint inhibitor drugs, first approved in 2011 initially for treating melanoma, expose the tumor cells to the immune system. Based on their success in treating skin cancers, scientists are now studying this group of drugs in a number of other cancers, including tumors in the lung.
In one study, called CheckMate-227, researchers tested whether a combination of two of these checkpoint inhibitor drugs could keep tumors from growing better than the standard treatment of chemotherapy in people with advanced non small cell lung cancer (NSCLC). Nearly 300 people were randomly assigned to receive either the combination of the immune-based drugs or the traditional chemotherapy treatment. After nearly a year, the lung cancer in people taking the immunotherapy was 42% less likely to have progressed than among people getting chemotherapy.
What’s more, say the study’s authors, doctors may also figure out which people are most likely to respond to the two-drug combination of nivolumab (Opdivo) and ipilimumab (Yervoy) and which are not. In the study, he and his colleagues found that people whose tumors had more mutations enjoyed the longest time period during which their cancers did not progress.
Currently, lung cancer treatments rely heavily on chemotherapy, but doctors are shifting toward a more customized and precise way of treating each person’s disease in order to improve their chances of survival. For example, newer targeted therapy drugs home in on specific genetic mutations that are responsible for driving a person’s cancer. Doctors can also determine if a person’s lung cancer is genetically vulnerable to the checkpoint inhibitor drugs tested in the current study. Putting together everything that doctors currently know about lung tumors, “more than half of people with lung cancer can avoid chemotherapy and get more precision-based treatments,” says Dr. Matthew Hellmann of the Memorial Sloan Kettering Cancer Center (MSKCC), lead author of the study. In addition, “a year after treatment, three times more people on immunotherapy were doing well compared to those who just got chemotherapy.”
The results could play a role in changing standard treatments for people diagnosed with advanced NSCLC, by making a strong case for starting people immediately on the immunotherapy combination rather than giving them chemotherapy first, as many doctors currently do. While nivolumab is approved for treating metastatic NSCLC, for example, that indication calls for using it either together with or after chemotherapy. This combination of nivolumab and ipilimumab showed that the paired drugs could be more effective when begun as the first treatment, instead of chemotherapy.
There may also be other ways to improve outcomes for people with advanced NSCLC. In another study, researchers found that combining standard chemotherapy with another immune-based checkpoint inhibitor, pembrolizumab (Keytruda), helped them live nearly four months longer on average than people treated with just chemotherapy. People getting the combination of immunotherapy and chemotherapy were 51% less likely to die after 10.5 months than people receiving chemotherapy alone. “The magnitude of benefit was unexpected and great to see,” says Dr. Leena Gandhi, associate professor of medicine at NYU Langone Medical Center and co-author of the study. Pembrolizumab is already approved for treating about 25% to 30% of people with advanced NSCLC who have a certain genetic profile that makes their cancer vulnerable to the drug, but this latest study expands that population to many more people who may benefit from the immunotherapy if the medication is combined with chemotherapy.
The results are even more encouraging for people with early stage lung cancer. In a third, small study of 21 people diagnosed with early stage disease, researchers led by a team at Johns Hopkins and MSKCC found that giving people two doses of nivolumab before surgery to remove lung tumors shrunk those tumors drastically and lowered chances of relapse, thanks to its ability to jump start the immune system to fight the cancer. When the scientists analyzed the tumors they had cut out, they found that in about half of the people treated with nivolumab, the growths showed significant destruction by immune cells, meaning that nivolumab had unmasked the tumors as foreign and allowed the immune system’s killer cells to attack them. And when the scientists studied the blood of the people receiving the immunotherapy, they discovered a close match between the types of immune cells in the blood and certain targets on the tumor cells, suggesting that nivolumab had released the immune system to pump out the appropriate cells it needed to tackle the cancer.
“We expected to see some response, but I don’t think we expected to see a 45% significant response,” says Forde. “To give you some idea of how significant that is, with chemotherapy we normally see the same degree of response around 20% of the time.”
Forde says that the strong response seen in people at the beginning of the disease could suggest that immunotherapies might be useful in re-training the immune system to fight cancer for long periods of time — possibly even a lifetime. “The Holy Grail is to have a relatively non-toxic therapy that could potentially use the body’s own immune system to prevent recurrence,” he says. “And while our study is only with 21 patients, the early indications from this study are very positive.”
Taken together, the results could fundamentally change the way lung cancer is treated, significantly improving people’s ability to both hold off lung cancer for longer periods of time, as well as live longer with the disease.