Emerging Immunotherapies and Combinations for NSCLC
Insights From: Roy S. Herbst, MD, PhD, Yale School of Medicine; Corey J. Langer, MD, University of Pennsylvania; Vassiliki A. Papadimitrakopoulou, MD, University of Texas MD Anderson Cancer Center
Roy S. Herbst, MD, PhD: Besides the CTLA-4 inhibitors, tremelimumab and ipilimumab, which are already in combination, I think I’d keep an eye on things such as TIM-3 and LAG-3, which are 2 other checkpoint inhibitors that are involved. I think those are in more advanced trials right now. Agents that are agonists for T cells such as 4-1BB or CD137 are looking quite exciting. There’s a whole host of what we call “bifunctional antibodies,” which might bind tumor cells and also bring in immune infiltrate by binding CD3, for example. Some of those are in clinical trial. There’s an enzyme known as IDO, which is involved in immune regulations, and there are several inhibitors of IDO. It’s been shown that blocking that might activate the immune response in a more profound way. So, those are just several of the agents that are in trial right now, and there are other agents that might stimulate immune infiltration as well.
Vassiliki A. Papadimitrakopoulou, MD: In the setting of frontline therapy, chemotherapy combinations of checkpoint inhibitors with chemotherapy are being investigated actively. The IMpower studies are a series of clinical trials combining platinum-based chemotherapy with atezolizumab versus the standard of care chemotherapy. These studies have not been reported yet. They were designed on the basis of a very encouraging objective response rate in smaller phase I and phase II studies that reported a couple of years ago.
Corey J. Langer, MD: There are a number of clinical trials that are comparing immune-oncology combinations to standard chemotherapy in the front-line setting. CheckMate 227 is an example that investigated combining nivolumab with ipilimumab versus standard chemotherapy. That trial has not yet been reported, so we’ve not seen any of the results, but the early phase I and phase II data certainly look promising, with response rates that appear to be considerably higher than in the nivolumab-alone arm. The big question, however, is, considering the nature of the patients going on these trials. Will we see a preferential benefit for those with higher levels of PD-L1 expression? The early phase I data did suggest that. I worry that these broader trials that take all comers, independent of PD-L1 level, may ultimately dilute that benefit. We really have to look at 3 separate groups: 50% or higher, or 1% to 49%, and those with that expression, and I am not convinced that CheckMate 227 has actually captured those very specific data. It would be of tremendous interest to delve into the data once they’re presented and see if there is a differential benefit based on PD-L1 level.
A separate but very similar trial, MYSTIC, is looking at a similar PD-L1 and CTLA-4 combination—in this case, durvalumab and tremelimumab in combination versus standard of care, front-line chemotherapy. Again, there are phase I and phase II data to suggest that the combination can generate response rates certainly higher than PD-1 inhibition alone with acceptable levels of toxicity, but the proof is in the pudding. We need to see the phase III data and, frankly, in this setting, we need to see a survival advantage, as we’ve seen in KEYNOTE-024 for single-agent pembrolizumab compared to chemotherapy alone.