'Aspirationally Resectable'? Neoadjuvant Tx Evolves in NSCLC

H. Jack West, MD; Julia Rotow, MD


September 18, 2023

This transcript has been edited for clarity.

H. Jack West, MD: I'm Dr Jack West, a thoracic medical oncologist at the City of Hope Comprehensive Cancer Center in the Los Angeles area.

Julia Rotow, MD: I'm Dr Julia Rotow. I'm a thoracic medical oncologist at the Dana-Farber Cancer Institute in Boston, Massachusetts.

West: We're here at ASCO 2023 in Chicago, where we've been seeing some real blockbuster presentations in thoracic oncology. Many of these have brought up some important questions about the clinical implications that we need to discuss further.

The topic of neoadjuvant chemoimmunotherapy has been very hot at ASCO 2023, with some new data presented and some preceding this meeting in various presentations. Momentum has really shifted largely toward chemoimmunotherapy, with open questions about whether something should follow that.

One of the other questions or challenges about neoadjuvant is that there is the potential to significantly shrink cancers. Many of the patients who have been eligible for various studies have been part of broader, more liberal criteria than many of the other preoperative or postoperative trials where we've largely limited it to at least low-volume stage IIIA disease and not IIIB.

Now, many of these trials include large numbers of patients with stage IIIA disease, perhaps with multistation N2 disease, potentially bulky, and increasingly stage IIIB, although some of these studies use the older, 7th-edition AJCC criteria and others the 8th, so it's a little bit like comparing apples and oranges.

One of the take-home questions, if not clear messages, is that these patients in the upper register of what we would consider maybe resectable are now increasingly being considered, if not strongly favored, to go on neoadjuvant approaches with chemoimmunotherapy. Potentially, some of these are not de novo upfront great resection candidates, but something we might consider as "aspirationally resectable," like if they have a good response — they're not great now but maybe they'll be better. That would be great.

I have some concerns about this. We've seen in many of these trials, over and over, that the rate of resection is about 80%, which is not terrible but not as high as we'd like. These patients who deviate from that plan are probably not well served compared with just starting on chemoradiation followed by durvalumab, per the PACIFIC trial, which gave us much better results than we used to see. It's not a terrible consolation prize.

Then, a subset of the patients who undergo resection have an R1 or R2 resection with microscopic or grossly visible residual disease. These are not people well served by the surgery decision. My general question and concern is whether we are being a little too broad here, particularly if this rolls out into the broader community setting with people doing surgery who are not dedicated thoracic surgeons and may not be as discriminating about which IIIB disease is a possible candidate or not.

Frankly, many of our quality measures, at least in the US, suggest that a number of these people are not meeting the mark for stage I and II resections, let alone stage IIIA or IIIB. I'm concerned that they're not going to be well served.

You're at a center of excellence, but you see people from all over New England, if not the country or the world. What are your thoughts about the implications of this in terms of what we consider to be resectable disease now?

Rotow: I agree. It speaks to the challenge we've had for a long time of defining what it means to be resectable in stage III lung cancer, which varies from surgeon to surgeon and from center to center. The important point is that in all of these studies, patients were defined to be resectable up front. It was upfront resectability, like you said — not "aspirational resectability."

There's a real risk in extending these trial data to the borderline-resectable patients who really weren't the topic of study here in these trials. Remember that we have chemoradiation as an alternative strategy for those patients who are truly unresectable, where we are not going to achieve a definitive resection up front. This is an excellent option with the ability to do consolidation durvalumab as per the PACIFIC regimen, for example.

This gives us the opportunity to have good outcomes for these patients, even without necessarily undergoing a surgical resection. It's very tempting to extend these data to the borderline resectable or the unresectable, hoping to convert. That's really, right now, I think, an overextension of the data.

Trials are, as always, needed in this space to understand whether we can use this, which is a highly effective preoperative systemic therapy strategy to try to convert these patients. But it really should be studied again in a prospective manner.

West: And not just that. I think the issue is, where is it being studied? One of the first studies that looked at this was NADIM, a single-arm, multi-institution trial out of Spain. This was a group of institutions that are really dedicated to this and have been doing it for years.

How generalizable is that to the patterns in the US or the rest of the world, where people may not have that experience and expertise in knowing what they don't know, judging who is a strong resection candidate, and [end up] doing a "peek and shriek," so to speak? That doesn't help a patient if you go down this road and then have to backtrack and start anew.

Rotow: I agree. We don't want the situation of patients getting neoadjuvant chemoimmunotherapy and then trying to go on to definitive chemoradiation. There's a toxicity profile that's not fully understood there yet. There are studies ongoing looking at IO being added into the chemoradiation regimen.

West: You'd like for it to be deliberate and prospective.

Rotow: I'd like it to be deliberate and prospective — exactly. We definitely want to avoid the surgical resection that is not a full resection because now the patient has the morbidity, mortality, and recovery of surgery, delaying definitive therapy without the benefit from that strategy. These are the situations you want to avoid.

Again, it's the resectable upfront patients who can get that chemoimmunotherapy and move forward. Otherwise, chemoradiation still plays a very important role in our treatment here for stage III.

West: I think the take-home message is that there is some fluidity here, but we should not be irrationally exuberant about applying this to populations where it should be very judiciously considered. To our patients, surgery is not the only way to be cured. There are other paths that can serve them potentially better.

Julia, thanks so much for taking the time.

There's a large amount of excitement and much 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.

Rotow: I agree. It's exciting to see these personalized therapies happening, and now in early-stage patients.

H. Jack West, MD, is an associate professor at City of Hope Comprehensive Cancer Center in Duarte, California, and vice president of network strategy at AccessHope in Los Angeles. West serves as web editor for JAMA Oncology, edits and writes several sections on lung cancer for UpToDate, and leads a wide range of continuing medical education and other educational programs.

Julia Rotow, MD, is the clinical director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute in Boston, Massachusetts. Her research interests include the development of targeted therapies and immunotherapies for the treatment of oncogene-driven lung cancer.

Follow Medscape on Facebook, X (formerly known as Twitter), Instagram, and YouTube


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.