Integrating Perioperative Immunotherapy Strategies in NSCLC

Mark Socinski, MD: What are people’s thoughts about integrating immunotherapy? Let’s get away from the EGFR ADAURA population. The integration of preoperative immunotherapy strategies, either immunotherapy alone or combination chemotherapy and I-O—to me, that data look a little more optimistic. I’ll start with Roy and get your thoughts on the preoperative setting.

Roy S. Herbst, MD, PhD: Neoadjuvant therapy has a lot of promise. I would keep the chemotherapy in there for now unless you have a highly selected patient. But with chemoimmunotherapy neoadjuvantly, you can look at the tumor at the time of surgery, get a sense for what’s sensitive and what’s resistant, and design your therapy outback. It’s very promising—perhaps more surgery could be done. I’m very much in favor of these approaches. They’re tough to do, but if you have a good multimodality team and meet with tumor boards and review the cases, it is quite possible.

Mark Socinski, MD: Stephen, your thoughts?

Stephen Liu, MD: Whether you’re using immunotherapy alone or immunotherapy with chemotherapy, we are seeing major pathologic responses and the combinations of cytotoxic chemotherapy with checkpoint inhibitors show pretty impressive NPR [noncomplete pathologic response] rates and we’re seeing some pathologic CRs [complete responses]. What we don’t know is if that will translate to better long-term survival. Is that a surrogate for developing memory?

While chemotherapy will drive some of these initial responses up, are we going to sacrifice some formation of memory on the tail? That’s been a theoretic concern that we just don’t know the answer to. We’re seeing very exciting trials. Just for the biologic insight alone, the neoadjuvant has a window of opportunity. The trials really tell us a lot of what’s happening to that tumor and will help us hopefully unlock how to best use these drugs.

Mark Socinski, MD: Yes. Let me extend the number of modalities. For the most part, if you do induction treatment in the stage IIIA population, we use chemoradiotherapy. We just had a little audience about how great immunotherapy and radiotherapy may play together. Is there a role for preoperative chemoradiotherapy, Kristin, in the preoperative setting? What are your thoughts about that approach?

Kristin Higgins, MD: When it comes to neoadjuvant therapy, if you look at the trials, radiation doesn’t add a whole lot to neoadjuvant chemotherapy. I haven’t been a fan of adding radiation preoperatively. I think it’s institutionally specific in terms of what practice patterns are. I do think if you introduce radiation to chemoimmunotherapy neoadjuvantly, there is a high risk of toxicity, so it certainly would make your surgery more difficult.

There was a very small study presented at ASCO out of the Cleveland Clinic that looked at cisplatin-etoposide-radiation to 45 gray with pembrolizumab followed by resection, and the stopping rules for infeasibility were met. There were some high-grade toxicities, so that is not continuing. I would worry about excessive toxicity with introduction of radiation neoadjuvantly. I would favor more of the chemoimmunotherapy approach.

Mark Socinski, MD: Brendon, what are the surgical concerns? Do you have a sense? It doesn’t sound like the feasibility of tri-modality therapy with chemoradiation immunotherapy. At least the early read is that it’s probably not feasible.

In terms of the immuno-oncology alone versus chemotherapy–immuno-oncology—and then from the surgical point of view—once you’re in the operating room, are there any issues that you have found that are different in this population?

Brendon Stiles, MD: Yes, it’s become almost urban legend how hard some of these cases can be, and certainly some are. That’s particularly true if you’re waiting more on the salvage setting where you’re taking somebody who has had prolonged immunotherapy and trying to help them.

There have been great surgical perioperative results, both in the trial that was published in the New England Journal of Medicine from Johns Hopkins Sidney Kimmel Cancer Center and Memorial Sloan Kettering Cancer Center and also from the LCMC3, a large multi-institutional trial with really low rates of perioperative events and similar surgical complications that we would see in an induction setting. I’m not sure there’s anything uniquely different about these patients. Perhaps they’re a little harder to assess. If they’ve had a great nodal response, they can be challenging. Sometimes defining a nodal response is challenging. These are cases we can often do as we would normally and that often can be done minimally invasively. About two-thirds in our trial and the trial that I just mentioned from Columbia University and MDH, they had almost 50% of minimally invasive surgery in N2 patients and stage III patients. Surgeons just need to do what they would normally do and try to do it as safely as they can.

Transcript Edited for Clarity