For NSCLC, neoadjuvant, adjuvant, or both?



This transcript has been edited for clarity.

Dr. West: Here at ASCO 2023 [American Society of Clinical Oncology] in Chicago, we’ve seen some blockbuster presentations in thoracic oncology. Many of these have brought up some important questions about the clinical implications that we need to discuss further.

At ASCO, as well as in the couple or 3 months preceding ASCO, we’ve gotten more and more data on perioperative approaches. Of course, over the past couple of years, we’ve had some new options of postoperative immunotherapy for a year, say, after chemotherapy or possibly after chemotherapy.

We have also had very influential data, such as the CheckMate 816 trial that gave three cycles of chemotherapy with nivolumab vs. chemotherapy alone to patients with stage IB to IIIA disease, but largely, nearly two thirds, with IIIA disease. That showed a very clear improvement in the pathologic complete response (pCR) rate with nivolumab added to chemotherapy and also a highly significant improvement in event-free survival and a strong trend toward improved overall survival. This is FDA approved and has been increasingly adopted, I would say, maybe with some variability by geography and center, but really a good amount of enthusiasm.

Now, we have a bunch of trials that give chemotherapy with immunotherapy. We’ve got the AEGEAN trial with durvalumab. We have Neotorch with chemotherapy and toripalimab. At ASCO 2023, we had a highly prominent presentation of KEYNOTE-671, giving four cycles of chemotherapy with pembrolizumab vs. chemotherapy and placebo.

Then there’s the built-in postoperative component of a year of immunotherapy as well, in all these trials. The data for KEYNOTE-671 look quite good. Of course, the other trials also were significant. I would say the comparator now is not nothing or chemotherapy alone anymore; it’s really against what is the best current standard of care.

The real question is, if we were happy to do chemoimmunotherapy neoadjuvant with chemotherapy/nivolumab, do we want or need to add the year of immunotherapy? It certainly adds some cost, it adds some risk for toxicity, and it adds a year of a patient coming into the clinic and getting IV infusions all this time to get a treatment that the patient has already had for four cycles in most of these trials.

If your cancer is resistant, is there going to be an incremental benefit to giving more of it? What are your thoughts about the risk and benefit? Going to a patient in your own clinic, how are you going to counsel your patients? Will anything change after the presentation of all these data and how you approach preoperatively?

Dr. Rotow: I agree. In some sense, it’s an embarrassment of riches, right?

Dr. West: Yes.

Dr. Rotow: We have so many positive studies looking at perioperative immunotherapy for our patients. They all show improved outcomes, but of course, they all compare with the old control arm of chemotherapy alone in some form, and this is no longer a useful control in this space. The open question is, do you use neoadjuvant, do you use adjuvant, or do you use both?

My high-level takeaway from these data is that the neoadjuvant component appears to be important. I think the overall trend, comparing across studies, of course, is that outcomes seem to be better with the neoadjuvant component. You also get the advantage of potential downstaging and potential greater ease of surgical resection. We know they have lower morbidity resection and shorter surgeries. You can comment on that. You also get your pathologic response data.

Dr. West: You get the feedback.

Dr. Rotow: Exactly.

Dr. West: The deliverability is also a big issue. You know you can much more reliably deliver your intended treatment by doing neoadjuvant followed by surgery.

Dr. Rotow: Exactly.

Dr. West: We know there’s major drop-off if patients have surgery, and in the recovery room they hear you got it all, and then they need to come back and maybe get chemotherapy and immunotherapy for a year. They’d ask, “What for? I can’t see anything.”

Dr. Rotow: Exactly. I think there are many advantages to that neoadjuvant component. I think all or many of us now have integrated this into our routine practice. Now the question is, do you need the adjuvant element or not on top? That is challenging because no trial has compared adjuvant to nonadjuvant. I think we all advocate for the need for this trial to answer this in a more randomized, prospective fashion. Of course, that doesn’t help our clinic practice tomorrow when we see a patient.

Dr. West: Or for the next 4 years.

Dr. Rotow: Or for the next 4 years – exactly. There’s going to be the open question of who really needs this? In some sense, we may be guided by the path response during the surgery itself. I think there may be those who claim that if you have a pCR, do you really need additional therapy? We don’t know the answer, but it’s tempting to say we know the outcomes in event-free survival are extremely good with a pCR.

Dr. West: Which is only 20% or 25% of patients, so it’s not most.

Dr. Rotow: It’s not most, but it’s better than the 2% or so with chemotherapy alone. That’s real progress, and it’s nice to have that readout. For that 80% without a pCR, what to do? I suspect there will be variation from provider to provider and from patient to patient, depending on tolerability to prior therapy, the patient’s wishes around the goals of care, and the patient’s risk for autoimmune toxicities.

Maybe there’s a patient with underlying autoimmune disease who’s gotten their neoadjuvant therapy and done well. You don’t want to risk that ongoing risk of exposure. Perhaps a patient with no risk factors who desires very aggressive treatment might be interested in more treatment.

In KEYNOTE-671, I was interested in the PD-L1 subgroups. These did trend the way you expect, with better responses in PD-L1 high, but there were also good outcomes and benefit to immunotherapy with the perioperative strategy in PD-L1–negative patients.

Dr. West: That didn’t really exclude anybody.

Dr. Rotow: It didn’t exclude anybody. In CheckMate 816, everyone benefited, but the benefit was less with those PD-L1–negative patients.

Dr. West: True.

Dr. Rotow: Absent further data to guide me or any prospective data here comparing these strategies, I might lean toward a longer course of immunotherapy in that population in hopes of triggering a response. I suspect that there will be variation from clinician to clinician in that space.

Dr. West: This is a setting where I feel like I have equipoise. I really feel that the incremental benefit is pretty small.

Dr. Rotow: Small. I agree.

Dr. West: It’s, frankly, somewhat dubious. On the other hand, you’re in a situation where if you know that three of four patients will experience a relapse and less-than-amazing outcomes, it’s hard to leave something that’s FDA approved and studied and a well-sanctioned option on the table if this patient may have relapse later.

In the end, I feel like I’d like to offer this and discuss it with all my patients. I think it’s a great place for shared decision-making because if a patient hears about that and decides they’re not interested, I’ll be fine with that. I think that’s a very sensible approach, but I don’t want to make it unilaterally. Other patients may say they want every opportunity, and if it comes back, at least I’ll know I did everything we could.

Dr. Rotow: Exactly. I agree with your statement about equipoise. I truly think that this is present here in the situation, and that there’s room for discussion in both directions with patients.

Now, one caveat I’d like to add to all these data is that the data should not apply to patients with some of our classic nonsmoking-associated driver mutations. This is another piece to the neoadjuvant data that I think is worth commenting on – the need to get appropriate testing before initiation of therapy and the pitfalls of starting this kind of treatment without knowing full biomarker testing. I think that’s something we have to watch for in our clinical practice as well.

Dr. West: Perhaps especially if we’re talking about doing a year of postoperative and someone has an ALK rearrangement or an EGFR mutation and we didn’t know it. That is a group where we’re worried about a rapid transition and potentially prohibitive, even life-threatening, toxicities from not planning in advance for this. This is something you don’t want to give concurrently or one right on top of the other. You don’t want to give immunotherapy and then transition right to targeted therapy. It’s dangerous.

Dr. Rotow: Exactly. The stakes were already high with neoadjuvant alone, but at least you had that gap of the presurgical period, surgical recovery, and then initiation of adjuvant therapy, if needed, or at relapse. With a postoperative long adjuvant period, those stakes are elevated because the immunotherapy exposure continues, so it’s something to be mindful of.

Dr. West: We have a general sense that many, but not all, of the targets that we’re talking about are associated with low benefit from immunotherapy. It’s not that well studied. I think this is another place for individualized discussion of the pros and cons. They were included in the trial, but they probably benefit less.

Dr. Rotow: Exactly. I think with the best established, EGFR and ALK probably are not benefiting much. They were actually included in the trial. Many of the neoadjuvant studies do not allow them to enroll if they’re known. On the other end of that spectrum, I think KRAS is just fine to treat with immunotherapy.

Dr. West: Sure.

Dr. Rotow: It’s an actionable driver. It’s not a traditional nonsmoking-associated driver, and those do just fine.

Dr. West: The studies show that these patients benefit just as much, at least, as the other patients.

Dr. Rotow: Exactly. I would never withhold this form of therapy for a KRAS driver mutation. The others, I think, are still in a gray zone. Depending on the patient demographics and tobacco use, I may elicit more or less caution in that space.

Dr. West: Well, I think we’re going to have much to still tease apart, with room for judgment here without a strong sense of the data telling us exactly what to do.

Dr. Rotow: Exactly.

Dr. West: There’s a large amount of excitement and interest in these new data, but there are still many open questions. I hope we continue to mull it over as we get more data and more insight to shape our plans.

Dr. West is an associate professor at City of Hope Comprehensive Cancer Center in Duarte, Calif., and vice president of network strategy at AccessHope in Los Angeles. Dr. Rotow is the clinical director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute in Boston. Dr. West reported conflicts of interest with Ariad/Takeda, Bristol Myers Squibb, Boehringer Ingelheim, Spectrum, AstraZeneca, Celgene, Genentech/Roche, Pfizer, Merck, and Eli Lilly. Dr. Rotow reported conflicts of interest with Genentech, AstraZeneca,Guardant, and Janssen.

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