Unmet Needs: Sequencing After Immunotherapy in 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
Vassiliki A. Papadimitrakopoulou, MD: One of the most important questions for patients refractory to immunotherapy is, how are we going to sequence therapies beyond chemotherapy? And that remains one of the highest unmet needs in the setting of non–small cell lung cancer.
Corey J. Langer, MD: The therapeutic landscape, again, has been altered by the initiation and elevation of checkpoint inhibitors in the frontline setting. For the patient with a 50% or higher expression level who gets pembrolizumab and then, ultimately, has disease progression, we can initiate standard frontline chemotherapy. That person, particularly since they have nonsquamous non–small cell disease, will most likely get a combination of carboplatin and pemetrexed, with or without bevacizumab. Then, if they have further disease progression, we still have an opening for taxanes or docetaxel, plus ramucirumab.
In the group that I am starting to treat with the triplet combination, independent of the PD-L1 level, it’s going to be a lot more problematic, because we’ll have already given both the checkpoint inhibitor and chemotherapy upfront. I anticipate, however, that there will be a fairly large cohort that will have been on maintenance therapy with pemetrexed and pembrolizumab, probably together, and may have disease progression at a year or 18 months. So, the standard approach in that group has not really been established. These individuals are still potentially sensitive to carboplatin. They’ve been off carboplatin for 6, 8, or 10 months. They’ve never seen a taxane, and they’ve never had exposure to an anti-angiogenic inhibitor. I can easily envision putting those individuals on a platinum again with a taxane, either weekly paclitaxel or weekly nab-paclitaxel combined with bevacizumab. If disease progression occurs quickly on the pemetrexed/carboplatin/pembrolizumab combination, then I’d imagine I’d be using docetaxel and ramucirumab. Again, the therapeutic approach, or therapeutic standards, will be turned around a bit by the arrival of these agents in the frontline setting.
Giving immunotherapy sequentially, I think, is going to be very problematic. I doubt we will see much activity for a switch from a PD-1 inhibitor to a PD-L1 inhibitor in the face of progression on the original agent. I do have a certain basic comfort level in equipoise for looking at new immune-oncology combinations in that group. If an individual has already received chemotherapy and they’ve had disease progression, and then they’ve gone on to a second-line PD-1 or PD-L1 inhibitor, at least it had some benefit for some period. And maybe they’ve been on it for 6 months or 8 months and then had disease progression. In that case, I could easily see assigning that patient to a different PD-1 or PD-L1 inhibitor, in combination with another agent, and there are a number of examples in that regard. Certainly, CTLA4 inhibitors are being looked at in this setting. Immune-oncology inhibitors are being looked at, and some of the results—at least some of the preliminary early results—look quite exciting. I would not do a one-for-one switch, though, from a PD-1 to a PD-L1 inhibitor.