Mark Socinski, MD: Maybe it’s changing an extensive-stage disease. We do see on all these immunotherapy curves there’s a better tail on the curve and who knows what’s going there. In limited-stage disease, this is on our list of potentially curable diseases with aggressive chemo/radiotherapy. This is a situation where I routinely use cisplatin/etoposide. There’s not much to say there from a medical oncology point of view. I’m a big fan of early intense radiotherapy, and I want Kristin to tell us what is early aggressive radiotherapy in this disease.
Kristin Higgins, MD: Right now for radiation, we give 45 Gy bid [twice a day] with either the first or second cycle of platinum/etoposide. This was established as a standard of care by the Turrisi trial that was published in 1999, which confirmed what the CONVERT trial (that was published recently over the last 5 years) [showed]—the excellent contemporary radiation trial randomized patients to 45 bid or 66-Gy daily radiation with the hypothesis that the daily radiation to 66 Gy would be better. That did not end up being the case. There was no difference in overall survival between the 2 arms. Right now, people give either 45 Gy bid or 60 to 66 Gy daily. However, we did see an interesting trial presented at ASCO [American Society of Clinical Oncology], a small phase 2 Norwegian trial that was about 175 patients. They randomized patients to that standard 45 Gy bid compared with a dose-escalated bid radiation treatment course of 60 Gy twice daily. Their primary end point was 2-year overall survival and they did show significant survival difference: 73% versus 46%. This is a small phase 2 trial; we haven’t seen very much detail in regard to radiation technique. We don’t know much when it comes to local control, there wasn’t a difference in response rates between the arms. There’s also no difference in high-grade toxicity, which is puzzling. You would expect that with the dose-escalated radiation regimen you would get higher rates of esophagitis. I’m not sure what to make of that. I will say if you look at the control arm, it underperformed with median survival of just about 23 months. [In] the CONVERT trial, the 45-Gy bid median survival was about 30 months. I look forward to seeing this in publication so we can learn more details. I don’t think it’s practice-changing yet. It’s definitely interesting and I wouldn’t draw too many conclusions just until it’s tested in a larger phase 3 setting.
Mark Socinski, MD: It’s funny, I’ve always been a huge fan of the Turrisi trial, doing 45 Gy bid. It gets it done in 1 cycle and if you can start at day 1, by the time they get to cycle 2, they’re almost done with the radiation. They tend not to get their esophagitis until after the radiation is done so it all works out fairly well. How often is 45 Gy bid given?
Kristin Higgins, MD: About 10% of patients get bid treatment. Logistically, it’s challenging. It’s difficult to schedule. Patients many times don’t like to come twice a day. In many radiation departments, it’s not in their routine to schedule somebody to come twice a day. For those reasons, for better or worse, it’s just not utilized as often as it probably should be. Even if it were positive in a large phase 3 trial, I still don’t know if it would replace 66 Gy given daily, which also gives great results.
Mark Socinski, MD: What are your views on PCI [prophylactic cranial irradiation] in a limited-stage setting?
Kristin Higgins, MD: Right now, PCI is still standard of care in limited stage. It has shown to produce a survival benefit in meta-analyses; however, patients with limited-stage small-cell [lung cancer] are included in the SWOG MAVERICK trial, so we will be testing MRI surveillance in limited stage and I look forward to those results. It may be that perhaps we don’t need to do PCI if they’re getting q3 month MRIs. We don’t know that answer yet and I would hate to pull back on PCI in limited stage right now if the survival benefit in a patient population has the potential to be cured.
Mark Socinski, MD: We spent the majority of our first half of this thing talking about how immunotherapy has changed the standard of care in extensive-stage disease. Let’s get Steve and Roy’s opinion on limited-stage disease.
Stephen Liu, MD: I think that will be a big impact in the United States. There’s plenty of rationale to combine immunotherapy on the cusp of radiation. We learned in non–small cell from the PACIFIC study that there’s a potential synergy between them and that’s where we saw an improvement, not just in PFS [progression-free survival] but in overall survival, we now accept checkpoint inhibitors after thoracic radiation. Years ago early on, we had some concerns about the possible risk of pneumonitis. We didn’t know if it would be higher using immunotherapy after thoracic radiation but now, we’re very comfortable with that—the safety of that approach clearly established. Based on the rationale for potential synergy, once we start introducing checkpoint inhibitors in the limited-stage setting, hopefully we’ll see more cures. Our goal in limited-stage small cell with chemo and radiation is to cure patients, but we know that for the majority of patients, we don’t achieve that goal. Hopefully, use of checkpoint inhibitors will allow us to do that, and there are a couple of very important studies.
One of those studies is chaired by Dr Higgins and that’s using atezolizumab. Dr Steven Lin at MD Anderson did a small phase 2 [study] looking at concurrent thoracic radiation in non–small cell [lung cancer] with atezo [atezolizumab]—so radiation of the chest and atezo at the same time just to be sure there weren’t any worrisome signals in terms of pneumonitis. The rate of grade 3 pneumonitis was quite low, about 3%. Immunotherapy can [cause] modulation [in] the microenvironment and facilitate the efficacy or radiation and vice versa. This study is looking at atezolizumab with chemoradiation followed by atezolizumab maintenance afterward. Kristin, correct me, I think it’s NRG LU005.
Kristin Higgins, MD: Yes, that’s correct.
Stephen Liu, MD: That’s currently enrolling, so we’re trying to send patients over to that study.
Kristin Higgins, MD: Yes, we have just about 100 patients on so far.
Mark Socinski, MD: Roy, what about immuno combos in this setting? What do we know about the ADRIATIC trial?
Roy S. Herbst, MD, PhD: The ADRIATIC trial is looking at chemoradiation followed by durvalumab, and that’s certainly an approach. We’ve always been taught to use these drugs after and then to add tremelimumab. There's less enthusiasm for that right now given the results of that arm of the CASPIAN trial. These are curable patients; you want to watch out for the toxicity. The trial is ongoing, so it’s another setting. Perhaps in this setting, you can deliver the tremelimumab better, maybe it has a different effect after getting radiation but we’re not that optimistic given what we’ve already seen with CASPIAN trial.
Mark Socinski, MD: Yes, but certainly the concept building on the PACIFIC trial in non–small cell makes sense for the monotherapy arm.
Roy S. Herbst, MD, PhD: Yes, you can argue for that the effect of immunotherapy in a tumor that’s received chemotherapy and radiation therapy. You can almost imagine it would be nice to go study, but I think you’re warming up the whole microenvironment and making it ready for immunotherapy. As Stephen said, the toxicity of this is always a concern, but it looks like it’s quite manageable.
Mark Socinski, MD: Are there any parting thoughts to our audience in the general field of small cell? What’s the message you want? I’ll start with Kristin as our lone radiation oncologist.
Kristin Higgins, MD: I’m excited that we have new therapies for patients with small-cell lung cancer. Immunotherapy has shown small but consistent survival benefits for our extensive-stage disease, and I’m excited about the prospects of moving that into limited-stage disease and curing more patients with small-cell [lung cancer].
Stephen Liu, MD: Although there are encouraging combinations looking at different immunomodulators, TIGIT for example, I think the only path forward to get those hazard ratios we’re used to in non–small cell [lung cancer] is with some type of reliable biomarker. We’ve done a lot of work looking at sequencing, looking at PD-L1, TMB [tumor mutational burden], there are just no obvious answers there. The greatest lead has to do with those transcriptional factor subsets looking at ASCL1, narrow D1, PUT3, YAP1, maybe as a predictor for I-O [immune-oncology]. Without a biomarker, it’s only going to be incremental gains.
Roy S. Herbst, MD, PhD: We’re making progress. We’ve built on platinum, but I’d say we haven't made it all the way. I agree with the others that we need biomarkers, but as long as you’re having some activity, biomarkers become very viable because you can hopefully build on what we’re seeing. I think there’s so much more enthusiasm in the study of small cell than ever before. There are meetings on small cell alone. You recall Mark, the targeted therapies meeting we have every year, we always put small cell as the last session on Saturday. This year, we opened up with it. More investigators, more new ideas, and patients with this disease are benefitting from that. That’s a very positive thing.
Mark Socinski, MD: Thank you all. It’s been great. It’s been a great discussion. Hopefully, this will be helpful to our audience, and thanks for joining me today for this discussion on perspectives in small cell.
Transcript Edited for Clarity