Despite the promise of molecular profiling, approximately 80% of patients with lung cancer lack a defined genotypic mutation, and become resistant when treated with a tyrosine kinase inhibitor. According to data presented at the 16th Annual International Lung Cancer Congress, however, lung cancer remains a highly mutated disease, suggesting great potential for immunotherapy.
“If you look at lung cancers and the number of mutations per megabase of DNA, they’re right up here,” said Roy S. Herbst, MD, PhD, Chief of Medical Oncology and Associate Director for Translational Research, Yale Cancer Center, New Haven, CT. “Lung and bladder and small cell and non–small-cell lung cancers alike are highly mutated, so you’d think that the immune system could recognize some of the neoantigens.”
Specificity, memory, and adaptability are the key attributes of the immune system that make it such a promising weapon of defense, he explained. Cancer cells develop many mutations that can make them appear foreign to the immune system. The problem, however, is that these cells can also exploit immune checkpoints—turning off these molecules to stop the immune response—and evade detection.
“The job of cancer immunotherapies is to relieve this block and make the tumor visible to the immune system again…,” Dr Herbst added. “And if we can prime the immune system the right way to recognize cancer, this immunity should have durability.”
Smokers Respond Better to Immunotherapy
Although immunotherapy has been used successfully in the treatment of certain lung cancers, it is not for every patient. For example, most patients with squamous-cell carcinoma were smokers and have a higher number of mutations. Nivolumab has been used effectively in the second-line setting in these patients, with improvements seen in survival. In non–squamous-cell carcinoma, however, the benefits are less pronounced.
“We have therapies that are working, but using biomarkers will help us find patients who are going to benefit more, so they can get these drugs early on,” said Dr Herbst. “If the patient isn’t benefitting, he or she can receive combination therapies and other approaches.”
“Those who are smokers, who have more mutations, tend to do a little better with these therapies,” he added. “Although, what is the right endpoint? Is it response or survival? We still need to figure that out.”
The trick, Dr Herbst elaborated, is to identify patients who will be alive at 1 or 2 years and determine who they are at the beginning of treatment.
Although the survival benefit of these therapies has been great in certain populations, Dr Herbst cautioned that these agents are not a “free ride.” In diseases of the endocrine gland, such as hypothyroidism, these therapies often carry irreversible side effects, even when patients are treated with steroids.
“If it says ‘itis’ on it, you can get it,” he said. “I would think these toxicities are more manageable than cytotoxic chemotherapy, but they can still be pretty serious. Physicians have to look for them.”
Much of immunotherapy research is centered on acceptable toxicity—determining ways to produce better responses and activity early on by combining the right drugs. The ultimate aim is to increase the number of patients with long-term survival.
Dr Herbst and his team at Yale have been very focused on rebiopsies at multiple points throughout the patient’s treatment.
“When you look at a rebiopsy, you see distorted immune cells and fragments of tumor cells, but you really don’t see any viable tumors,” he said. “That’s very reassuring, but we want to do more and determine the molecular characteristics of an inactive immune response.”
Challenges notwithstanding, the results of immunotherapy have been extraordinary, Dr Herbst concluded. “I believe that science will drive the day with these agents.”