Checkpoint Inhibitor Shows Promise in Smokers

Genentech made headlines in June by reporting that its PD-L1 inhibitor MPDL3280A shrank tumors by 30% or more in 22% of patients in a phase I trial who had non–small cell lung cancer (NSCLC) and had progressed on chemotherapy.

An update from this ongoing study suggests that patients in this population who have a history of smoking may achieve the greatest benefit from treatment.

Presented on September 29 at the European Cancer Congress in Amsterdam, the Netherlands, the new data show that among 53 patients, 26% of current or former smokers responded to the treatment, as opposed to only 10% of those who had never smoked.

“This was a real surprise to us,” says Jean-Charles Soria, MD, PhD, a professor at Institut Gustave Roussy in Paris, France, who presented the results. “Having a new compound that works better in smokers than nonsmokers is unheard of.”

PD-L1 puts a brake on the immune system by blocking T-cell activity, and cancer cells that express the surface protein also deter antitumor immunity. By binding PD-L1, MPDL3280A thwarts the cancer cell's ability to keep T cells at bay.

Among all patients in the study, higher PD-L1 expression levels correlated with better responses to the drug, but the data have not yet been analyzed to see if the correlation is stronger for smokers than for nonsmokers.

Soria hypothesizes that because smokers have a higher “mutational load” than nonsmokers, their tumors induce an especially robust T-cell response. “Cancer cells with more mutations also have more tumor-specific antigens,” he explains. Therefore, a drug that facilitates the cancer cell–killing effect of T cells may work better in patients whose T-cell response is strong.

However, although Soria says the data are the first to demonstrate a relationship between smoking and the efficacy of immunotherapy, other researchers say they're yet to be convinced.

Roy Herbst, MD, PhD, chief of medical oncology at the Yale Cancer Center in New Haven, CT, who presented the initial data on MPDL3280A at the American Society for Clinical Oncology annual meeting in June, says he welcomes a new drug that could work in NSCLC patients with a history of tobacco use. “But it's too soon to say conclusively that the drug works better in smokers,” he says. “Also, we still need to identify which specific mutations best amplify the immune response.”

Lecia Sequist, MD, an associate professor at Harvard Medical School in Boston, MA, describes the new evidence with MPDL3280A in smokers as a “very interesting preliminary result.”

“Looking at smoking status makes sense because general inflammation may be important for response to immunotherapy,” she adds. “However, the new data are certainly not definitive and we need to study this further in a prospective manner and within a larger group of patients.”