Varied Timing of IO Therapy in Patients With Stage III NSCLC

Mark Socinski, MD: I want to ask Dr Stiles, at least prior to the PACIFIC data, it was fairly frequently that I would see patients in which they would have stage III disease. The surgeon they saw wasn’t wild about operating on them at that time, but then they would say let’s give them some chemotherapy, let’s give them some radiation and see what happens, which to me, is a treacherous strategy. My training was deciding if surgery is going to be part of the treatment up front, and if it’s not, then it’s probably not likely to be part of the treatment out back. I wanted to get your thoughts on has this changed that at all? Do you find yourself reassessing patients if they have great responses either to chemoradiation or to immunotherapy?

Brendon Stiles, MD: It’s a great question. I do think it’s a pretty treacherous area though. I tend to agree with you, and I know that all of us surgeons for the most part do. I think these are decisions that should be made up front with the multidisciplinary tumor board and the radiation oncologists, and try to decide a priori. They can be challenging decisions, without a doubt. I think we know that chemoradiation from the group trial 1601 has a relatively low complete pathologic response [CPR] rate, less than 20%, even if you push it to a higher dose in the RTOG studies, 0229 and 0839, although there was a great rate for mediastinal nodal downstaging, the CPR at surgery was still relatively low, around 25%. That’s with the caveat that there may be ongoing cell kill, and it may get higher as they get farther out.

Also, if you look at the PACIFIC data and you look at the failures, 85% of progression was in the chest, either in the lung or in the lymph nodes. Some of that may have been new lesions in the lung, but clearly there are issues or times when locoregional control could be better. It’s a challenging place for surgeons to get good locoregional control as well though, so again, to me, it often comes to that idea of trying to decide up front. Most of us don’t believe that you can take any of these drugs and make a patient who’s unresectable, resectable. I think that’s a fallacy. Sometimes with immunotherapy it can be even more challenging.

Mark Socinski, MD: That’s a great perspective. One of the other issues I wanted to address to all of you is, obviously, the PACIFIC strategy was a consolidation strategy. I’ll pick on Kristin first. Is there a rationale for concurrent use? Then I’ll ask Stephen and Roy to chime in on, should it be part of induction treatment prior to radiation? Kristin your thoughts on moving it up earlier?

Kristin Higgins, MD: I do think there's great preclinical data demonstrating radiation and immunotherapy synergy, and there are a multitude of trials that are testing concurrent immunotherapy now in the stage III unresectable setting. We did see some interesting data at ASCO [the American Society of Clinical Oncology annual meeting]. Salma Jabbour, MD, presented some preliminary results from KEYNOTE-799, which is a trial of concurrent immunotherapy. It’s a nonrandomized phase 2 trial where there were 2 cohorts of patients. The first cohort got concurrent radiation, 60 gray, with carbo-Taxol [carboplatin, paclitaxel] and pembro [pembrolizumab]. The second cohort got CIS/PEM [cisplatin/pemetrexed], 60 gray, and [pembrolizumab]. The primary end point of this trial was overall response rates and grade 3 or higher pneumonitis.

Not unexpectedly, the response rates were very good. A little better in cohort A, 67%. The high-grade pneumonitis rates were also manageable, between 5% and 8% for both cohorts. The follow-up isn't long enough to give any survival or progression-free survival data on this trial, but nonetheless, I think it is encouraging that perhaps concurrent immunotherapy could be a strategy in the future.

Mark Socinski, MD: Stephen, the role of induction?

Stephen Liu, MD: We’re still trying to work out how immunotherapy and radiation work best together in a patient with lung cancer. They're not additive; we’re not looking for additive benefits. We’re looking for synergistic benefits and the effect that radiation has on the microenvironment, and the effect that chemotherapy has on the microenvironment, and the effect that the immunotherapy and radiation work together. Do we need to give them together or in sequence? Helen Ross, MD, at ASCO presented an update on one of the Alliance Foundation studies, AFT-16. It’s an early look at about 64 patients, and in that study they received PD-L1 inhibitor atezolizumab first, by itself. They did an early look to make sure patients weren't progressing. They completed 4 cycles, so 12 weeks of just PD-L1 inhibitor, an induction immunotherapy approach, then followed by chemoradiation at that point.

Then they looked at disease control rate, and it was high, but these different strategies, what's going to determine which is the best way to go, is which approach leads to more long-term survival, which approach leads to more cure. Right now, we have disease control rate, we have early responses, we have landmark PFS [progression-free survival] rates, but we don’t have what that 3-, 5-year tail will be, and I think that’s going to help guide us more so.

We also saw in the Alliance trial there was a little bit of toxicity. While it was relatively well tolerated, we did see some grade 3 toxicity, 1 episode of colitis, 1 episode of Guillain-Barre syndrome. If we’re looking at strategies that maybe jeopardize the definitive or curative treatment, be it surgery or radiation, that’s something we have to look very closely at.

Mark Socinski, MD: Roy, your thoughts there and then your thoughts on the immuno [immunotherapy] combos, like CTLA-4, added to this scenario?

Roy S. Herbst, MD, PhD: My first thought is you would want to move immunotherapy as early as possible because the tail in the curve is clearly there for some patients, and you’re getting it to them earlier and it can only be better. That said, we can’t forget that before recently our curative therapy in lung cancer was chemoradiation in patients who were unresectable. You want to make sure we don’t compromise giving those full doses of chemotherapy and radiation. If immunotherapy can be given concurrently and there are not toxicity issues, and full doses of those drugs can be given, yes, I’d say go ahead and do it, and give the immunotherapy more time to work.

As far as immune combos, that’s again, if you don’t see activity in the metastatic setting, I’m hard pressed to want to bring it forward with the added toxicities of a combo to the early stage curative setting. Certainly, it can be tried, and neoadjuvant approaches are good ones, we’ll talk about that in a bit because that gives you the ability to biologically look at what's happening and understand primary resistance, but I’m not that enthusiastic.

Transcript Edited for Clarity