Use of I/O Regimen in Relapsed/Refractory SCLC

Vivek Subbiah, MD: Thank you, Dr Chiang and Dr Ganti for sharing your perspectives on front-line management of small-cell lung cancer. Now that we’ve discussed frontline therapy, the next topic is the most challenging one in the clinic and for research, which is the relapse/refractory small-cell lung cancer. Dr Chiang, would you use an immunotherapy (I/O) regimen after progression chemo or chemo-I/O combination?

Anne Chiang, MD, PhD: I do have an investigator-initiated trial looking at IPI/NIVO (ipilimumab/nivolumab) for relapse disease with the idea of utilizing an anti–CTLA-4 and anti–PD-1 combination to salvage patients who progressed on ATEZO (atezolizumab). Obviously, the CASPIAN data with DURVA (durvalumab) and TREME (tremelimumab) was negative, but we’ve also seen in other instances that the DURVA/TREME combination may not be so active and mystic. I do think that IPI/NIVO has had a good track record in CheckMate-032 for small-cell, and this particular trial is really looking at biopsies and pretreatment to look at whether the ratio of CD8 to FOXP3 cells—the ratio of effector to T regulatory cells—can correlate with response, with the clinical question being can you use a combination to salvage progression on 1 single agent? I’ll comment in terms of looking at mechanisms of acquired resistance in non–small-cell. There are data in colorectal tumors that impaired antigen presentation, MHC (major histocompatibility complex), or beta-2 microglobulin defects that can be a mechanism. That’s something we’re interested in looking at because we know that, unfortunately, while we’re looking at the tail of the curve, the current data show that almost all these patients will progress and require second-line therapy if they have the performance status. There’s a possibility that we can salvage with combination I/O. Certainly, if we learn from the non–small-cell, if you use combination chemo-I/O upfront, then you usually go to a chemo regimen. I think we have some exciting new chemo options, at least one that we’ll talk about today, and then we may need to recycle some things so our patients who have good performance status can still continue with treatment.

Vivek Subbiah, MD:One more question I had for you is, would you think about re-challenging with platinum and etoposide combination for the second-line?

Anne Chiang, MD, PhD: For small-cell, we do have literature talking about platinum-sensitive disease, which is typically if you are strictly looking at 6 months, although a lot of trials look at recurrence within making it through the 3-month range. I do think that is an approach that we’ve used with pre-immunotherapy. We don’t know how it looks for patients on maintenance ATEZO or maintenance DURVA. I think we would probably add back the platinum if it’s been a long time, for example, 3 or 6 months, but this is a bit of a data-free zone because we didn’t have the IO when we were looking at the platinum-sensitivity before.

Vivek Subbiah, MD: Do you have any insights to share on second-line therapy for small-cell, Dr Ganti?

Apar Ganti, MD: I have a slightly different take than Dr Chiang about re-challenging with immunotherapy. If you look at CheckMate-032 in the relapse setting, the addition of ipilimumab and the nivolumab added the increased response rate but did not necessarily increase the duration of response of survival. In that setting, adding IPI in someone who’s progressing while on maintenance DURVA or ATEZO… I’m not sure that I would necessarily use that. I would use a different agent in that setting. As far as re-challenging with platinum/etoposide is concerned, I agree with Dr Chiang that if it is for more than 6 months, and sometimes even more than 3 months, since the last dose of these agents, I would tend to re-challenge with them. If someone is on maintenance immunotherapy when they progress, I would use their duration from the last chemotherapy cycle to decide whether or not to re-challenge with platinum/etoposide. If I decide to use platinum and etoposide, I would not necessarily continue with checkpoint inhibitor; I would use chemotherapy alone. Again, there is very little evidence one way or the other because, like Dr Chiang said, the data on re-challenging with platinum/etoposide was done in an era when we did not have immunotherapy, and those patients were not on any treatment when they relapsed and were re-challenged with platinum/etoposide.

Anne Chiang, MD, PhD: I just want to make sure that I had responded about IPI/NIVO. That’s within the context of a clinical trial. Off-trial, I would not give IPI to those patients. I would move on to chemotherapy, and I think that the classes of chemotherapy that are effective in relapse small-cell are… Topotecan was previously the only FDA-approved therapy. There are a lot of people who don’t like topotecan and don’t think it’s effective, but it is an option for the patient to go on an oral therapy and take a break from IV therapy. I think taxanes are very active for small-cell. Temozolomide is also a good option, especially if you are worried about progression or disease in the brain. There are approaches with maintenance strategies combining I/O with PARP inhibitors that are now available in clinical trials, so I think there are different options for these patients if they have the performance status. I will say, just anecdotally, I had a patient who came off of maintenance atezolizumab, went onto my IPI/NIVO trial, and then subsequently went on topotecan and had an extended response to topotecan, over 8 months. I don’t know what these checkpoint inhibitors are doing to sensitize the body to boost them when you have chemotherapy and cytotoxic chemotherapy subsequently. I think postprogression chemo added to or after immunotherapy is very interesting.

Transcript Edited for Clarity