Discussant Dr. Jedd Wolchok of Memorial Sloan Kettering Cancer Center, New York, said people working in immunotherapy feel like they have been riding a wave over the past few years and have just washed up on a beach, wondering where to go from here. “I think combination therapies have really announced themselves as being the next step forward,” he said. Early studies with checkpoint inhibitors produced some strong and durable remissions, but for the most part, in only a minority of patients.
So investigators started to try checkpoint inhibitors with nonredundant targets, as Dr. Antonia’s study did. Nivolumab + ipilimumab has been tried in melanoma, but grade 3/4 toxicity was more prevalent than in this SCLC trial. Dr. Wolchok suggested maybe SCLC patients are more immunosuppressed and therefore do not react to the combination treatment as strongly. The toxicity was lower even than that seen in non-SCLC, “so even in diseases that occur at the same organ site, there is a different biology in the microenvironment that is leading to different tolerability, different degree of immune suppression,” he said.
He congratulated the Checkmate 032 investigators and sponsors for testing different doses and schedules “because this is not one-size-fits-all.” But he said more patients have to be studied. And remaining questions concern the nature of the response, that is, is the response deeper with the combination therapy, and balanced against the additional toxicity?
He noted that not all patients in Dr. Antonia’s study had fine needle aspirates, so their tumors could not be evaluated for PD-L1 expression. So it is still not entirely clear if a subset of patients could benefit the most, such as ones with higher expression.