Transcript:Everett Vokes, MD: Another item is maintenance therapy. Of course, in non—small cell lung cancer, first-line, particularly for adenocarcinomas, we give pemetrexed. That is well established. Another item has been, should a PD-1 inhibitor be given after chemotherapy? You already mentioned, Naiyer, this issue that when pembrolizumab is given first, at least if you then wait until progression, chemotherapy is not an effective rescue agent. Well, it can be effective, but the opposite of starting with chemotherapy is inferior. But in those cases, you’re actually waiting for progression to occur. Whereas in the classic maintenance context, you would not do that. You would simply go from one modality to the next. And so, for PD-1 or PD-L1 inhibitors, what experience do we have of starting with chemotherapy and then going to maintenance therapy? Do you see it as a valid approach?

Naiyer Rizvi, MD: I don’t think we have any experience in doing that—to give chemotherapy first and then transition to PD-1 as a maintenance therapy. I think those questions are being addressed. Certainly, for KEYNOTE-021g, patients received chemotherapy for 4 cycles and then they continued pembrolizumab as maintenance. But there wasn’t the option to continue pemetrexed as maintenance, as well, which most of the patients actually did. I tend not to do that. You want the T cells and the immune system to be activated. If you’re giving them steroid premedications with every pemetrexed, and you’re suppressing their marrow, then perhaps there could be some negative effects. So, when I think of maintenance therapy, I think of it as pembrolizumab alone rather than pembrolizumab and pemetrexed.

Fred Hirsch, MD, PhD: Can I make a comment, Everett? These days, we see a lot of combination therapies out in clinical trials. You were asking the question on maintenance immunotherapy after chemotherapy for patients, I guess, who respond to chemotherapy? I would like to ask the panelists if they agree with me that there is a huge lack of scientific knowledge around what it means for the immune system when you give chemotherapy? The rationale for giving immunotherapy after chemotherapy should be based on some scientific knowledge about what the chemotherapy does for the immune system. As far as I know, there is very little knowledge about the biology behind it, at this stage. I hope that the current clinical trials will include the translation of the research to give that knowledge so we can have more rational combinations and the sequencing of therapies in the future. Do you agree with that?

Suresh Ramalingam, MD: I agree with you, Fred, in that we have only scratched the surface in terms of our knowledge about what factors drive responsiveness to immunotherapy. How does radiation therapy play into it? How does chemotherapy play into it? Our bone marrow transplant colleagues have, for a long time, used chemotherapy to address some of the immune issues—for example, to suppress myelodysplastic syndromes to clear the marrow and so forth. So, I think at this point, proceeding in a step-wise manner is important. We don’t want to assume that what’s good with chemotherapy is good with immunotherapy. These concepts have to be studied in a well-designed randomized clinical trial, and then be adapted to practice.

Everett Vokes, MD: We have a trial that may come a little bit close to this. Before the pembrolizumab data were out, we randomized patients to either 4 cycles of chemotherapy followed by a PD-1 inhibitor (not waiting for progression) or the other way around—starting with pembrolizumab but then stopping after 4 cycles (or 3 months) to give 4 cycles of chemotherapy and then go back on pembrolizumab unless there was, initially, progression. It’s a little bit complicated on that arm, but the intent was to address the sequencing issue in that trial. What really was needed was a third arm, where the 2 are given together. Unfortunately, that was not included, so that ultimate comparison will not be there.

Transcript Edited for Clarity