Dr. Suresh Ramalingam:
Hello. Welcome to Optimizing the Care Continuum for EGFR-Mutant Non-Small Cell Lung Cancer, an ASCO Post Roundtable. I'm Dr. Suresh Ramalingam, Professor of Hematology and Medical Oncology and Executive Director of Emory Winship Cancer Institute.
Today I'm joined by two esteemed guests, Dr. Zosia Piotrowska and Dr. Helena Yu. I'm going to first invite Dr. Piotrowska to introduce herself and then Dr. Yu. Zosia?
Dr. Zosia Piotrowska:
Hi, everyone. I'm Zosia Piotrowska, thoracic medical oncologist at Mass General Brigham Cancer Institute here in Boston. Great to be here.
Dr. Helena Yu:
Hi, everyone. I'm Helena Yu. I'm also a thoracic medical oncologist at Memorial Sloan Kettering in New York.
Dr. Suresh Ramalingam:
Thank you both for joining us today. Let me start with a case, we're going to talk about a situation with regards to perioperative management of non–small cell lung cancer with EGFR mutation.
This is a patient who is 59 years old and this patient had presented with nonspecific chest pain. And at that time she had imaging of her chest and it showed a four-centimeter lesion in the right upper lobe of the lung.
This was subjected to a biopsy, it showed a adenocarcinoma. A further workup with a PET scan did not show any evidence of mediastinal lymph nodes, no evidence of distant metastases. The MRI of the brain did not show any brain metastases, and the patient has no comorbid conditions, in excellent health, performance status is 0. The patient had molecular testing done and it showed that her tumor harbored an EGFR exon 21 mutation.
So let's invite first Helena to talk about how do you manage this patient in your institution?
Dr. Helena Yu:
Yeah, this is a great case that does, I think, highlight the need for multidisciplinary discussion. We do this routinely for patients. We have a tumor board where we discuss cases, and I think that the sort of finding of note for her is that the tumor, although solitary and without lymphadenopathy, it's four centimeters. Four centimeters at our institution is right at the cutoff where larger tumors and of course node-positive disease we would consider neoadjuvant treatment for patients.
And so I think this would be something I would discuss with the surgeon after he or she saw them. But with that four-centimeter tumor or anything larger than that, I would be thinking about neoadjuvant therapy.
And in this patient that has an EGFR exon 21 mutation, it would be platinum-based chemotherapy. I think she's fit and young, so I would think about cisplatin pemetrexed for her adenocarcinoma histology.
And then the one question I'd have is we know from data that we would give the osimertinib postoperatively based on the ADAURA study, but one question I'm posing back to you two is would this be a patient where you would also think about neoadjuvant osimertinib or would you give chemotherapy prior to surgery and then reserve the osimertinib for the adjuvant setting?
Dr. Suresh Ramalingam:
Helena, that's great. You're bringing up the NeoADAURA trial. So Zosia, perhaps you can briefly discuss the NeoADAURA data with our audience and then tell us what your approach is.
Dr. Zosia Piotrowska:
Yes. Absolutely. I think we've all moved sort of broadly speaking in non–small cell lung cancer to more and more strongly considering neoadjuvant therapy for our patients. And of course we've seen a big push to use neoadjuvant chemoimmunotherapy for many of our patients or perioperative chemoimmunotherapy.
And I think one important point to make before we talk about the NeoADAURA study is just really the critical importance of EGFR testing in a patient like this. I think we can discuss sort of the pros and cons of chemotherapy or chemo plus TKI, but we can definitely all agree that giving a patient like this neoadjuvant chemoimmunotherapy without knowing that they have an EGFR mutation would potentially hinder your ability to give them TKI in the adjuvant setting, which is a big problem. We know that there's survival benefit to using adjuvant osimertinib.
And so I think the first point is just for patients like this, how critically important molecular testing it is in finding those EGFR mutations and really getting those results back before you initiate any neoadjuvant therapy.
I agree. I think for a patient like this with a larger tumor, we would certainly be thinking about and talking to our surgeons about whether to consider neoadjuvant therapy and thinking about the NeoADAURA trial, which was a study that looked at sort of different neoadjuvant approaches for patients with resectable, the non–small cell lung cancers with known EGFR mutations.
There were three arms in that study. One was chemotherapy alone, platinum/pemetrexed, one was chemotherapy with osimertinib, and then a osimertinib alone arm, each of these given for three cycles or about 2 months prior to the time of surgery.
The primary endpoint of that study was major pathologic response, and we did see that the rates of major pathologic response were higher with TKI and with chemotherapy and osimertinib than they were with chemotherapy alone.
To me it was a little bit surprising that the results were actually quite similar in the chemo plus TKI arm as they were with osimertinib alone. I would've thought there would've been more of an additive benefit to the combination.
I think the other take-home from the study was that the rates of pathologic complete response, which we've sort of held as our North Star in the chemoimmunotherapy neoadjuvant studies, were quite low, it's really single digits across these different arms.
And so I think it speaks to the fact that the biologic impact of TKI-based therapy is different than immunotherapy. And I think what we don't know is what that will mean in the long term. We wish we were seeing more pathologic CRs, but we're certainly happy to see higher rates of major pathologic response for these patients and I think we still consider these to have benefits.
And so for a patient like this, coming back to our patient here, I agree, it would be a discussion with the surgeon. This is sort of right on the cusp, a 4-centimeter tumor in otherwise very well patient. We assume that if they went straight to surgery they would need chemotherapy in the adjuvant setting and then would get adjuvant osimertinib.
And so for me I think I would, if I was to consider a neoadjuvant approach, I would talk about the combination of chemotherapy with osimertinib. Again, acknowledging that the NeoADAURA approaches are not yet approved, so we'd have to get insurance approval for it, and I think that's always an important discussion point with the patient. But if it was available, I do think it would be appealing for a patient like this.
Dr. Suresh Ramalingam:
Thank you. So at our institution we've sort of for the present approaching this as whether a patient has N2-positive disease or not with EGFR mutation.
If they have N2-positive disease, we all know that upfront surgery is not helpful for those patients regardless of their mutation status. So in that situation where we were previously just giving chemo alone, I have shifted to using chemo plus osimertinib as neoadjuvant therapy and then taking them to surgery.
If they have node-negative disease, we have taken them to or first have the surgical resection, then do the four cycles of platinum-based chemo if they are fit candidates for that and then continue on to osimertinib for the ADAURA program.
And that has served us well. I think the key is going to be from the NeoADAURA trial whether we see a difference in event-free survival, and ultimately, overall survival between the three different approaches.
Helena, one of the things that I want to pick your brain on here is the MRD status and how that might guide. Right now if you use osimertinib in the adjuvant setting, there are two questions you deal with. One is at 3 years do you stop it or not? And do you use MRD status to make those decisions? Where are we as a field in that area?
Dr. Helena Yu:
That is a great question and one that I do, now having had patients on the ADAURA regimen and getting to that 3-year mark, there's a lot of different sort of opinions or decisions that are made.
I think that the MRD assays are very intriguing. I don't use them yet in my clinical practice, but I know there are ongoing studies looking to see whether detection of MRD at different time points post-surgery can help dictate sort of length of whether or not certain therapies are needed and certainly the length of therapies.
I'm interested to hear what you two do in your practice, but for me, I don't use the MRD assays currently. I think that when we get to the 3-year mark, there's a couple things that I consider. How well was the patient tolerating the osimertinib? I think although it is generally a well-tolerated agent, 3 years of any therapy can be significant. And so for people who had a relatively tough time getting through those 3 years, I do feel very comfortable with stopping.
I think the question really is for those higher-stage patients like a stage III patient with N2-positive nodes, and that's because of the LAURA data which you've presented in the past where if after concurrent chemo radiation for a locally advanced stage III disease patient, the adjuvant osimertinib is given indefinitely until progression.
And so for those higher-risk stage III patients, I have a discussion with my patients and maybe are a little bit more inclined to continue the TKI. Obviously insurance approval is an issue there too because of course ADAURA really was 3 years of osimertinib. But would like to hear your thoughts about stage III and also if you use MRD assays in your clinical practice.
Dr. Suresh Ramalingam:
Absolutely. So I would say I have been intrigued as well by the MRD and we've seen that patients who have MRD-positive disease, the recurrence is almost invariably going to happen, whereas in the MRD-negative patients, you still see recurrences.
So whether MRD is positive or negative, at least based on these early-generation technologies, it's hard to make a treatment decision. It's very interesting to know that if a patient is MRD-negative, perhaps that can provide some reassurance to the patient, but that still doesn't take the cloud of recurrence away.
So I'm not using it in my practice at this point. Certainly very eager to learn from ongoing clinical trials as to how to integrate this exciting platform in decision-making.
With regards to the 3-year issue, I completely agree with you. I think I look at what's at risk of recurrence. And if the patient has higher-stage disease, I tend to believe that continuation of osimertinib might be beneficial than stopping it at 3. Zosia, your thoughts?
Dr. Zosia Piotrowska:
Agree on both fronts. I will say I think this is a very well-informed group of patients. I've had many patients now who've come asking about MRD assays, and so this comes up in practice quite a bit. But I agree, I think in the future I hope it will be informative and we will have data to sort of guide clinical decision-making around an MRD test, but right now what I tell patients is whether positive or negative, we don't really know yet what to do with that result.
If someone has a positive MRD test but their disease is stable, I think it's hard to know exactly what to do with that in clinical practice. And so I'm not routinely using it. I hope that we will in the future. I think it has a tremendous potential, but we're not quite there yet.
And I fully agree with both of you about the 3 years. I think it's probably not enough for some patients, but we don't quite know yet which ones sort of stage and baseline risk factors.
What I will say is in patients where we choose to stop after 3 years, I watch those patients quite closely in the period of time after they've stopped TKIs, including CT scans and periodic brain MRI surveillance as well. We have seen with some of the post-TKI data from the ADAURA study that sometimes we can see CNS recurrences in those patients. And so I think considering sort of careful monitoring for both symptoms and even surveillance brain imaging after stopping TKI therapy can help you potentially pick up cases of recurrence early such that you can reintroduce the TKI and hopefully get patients on the right track.
Dr. Suresh Ramalingam:
Great. So I'll ask one final question before we wrap up, which is a situation that I see in my clinic where patients would ask me, "Okay, you said there is a large randomized trial that showed that using adjuvant osimertinib is helpful. Do I still need my chemotherapy after surgery?" So Helena, what do you tell that patient?
Dr. Helena Yu:
Yeah, I tell them the short answer, yes. I think chemotherapy and TKIs work differently, and we do know from many randomized clinical trials that there is a small but real survival benefit with chemotherapy. And so unless there are issues with the patient being able to tolerate platinum-based chemotherapy, I do really encourage them to do both, because I think there's additive benefit, and again, these patients are relatively young and have fewer comorbidities, and so I want them to receive the maximum benefit possible.
Dr. Suresh Ramalingam:
Right. Zosia?
Dr. Zosia Piotrowska:
I agree. I think these decisions have to be made independently, but I offer both, I recommend both. I have had some patients who are older or perhaps borderline for chemotherapy where we have collectively sort of made the decision that we're going to forego chemotherapy, given the modest benefit and especially given the fact that patients can benefit from a TKI.
But I think for young fit patients, there is a survival benefit to both of these and we want to give these patients the best chance that we can. We know that, unfortunately, despite all of these advances, recurrences still can happen with non–small cell lung cancer, and so we really want to use all the tools that we have to give our patients the best chance.
Dr. Suresh Ramalingam:
I couldn't have said it any better, use all the tools in our toolkit to give the patients the best chance.
So with that, let's summarize this discussion. Thank you both for joining. I think it's fair to say that we now have good evidence that adjuvant therapy with osimertinib improves overall survival for patients with resected EGFR mutant non-small cell lung cancer.
I think the role of neoadjuvant osimertinib is evolving with early results from the NeoADAURA showing potential benefit. And use of MRD status is, at this point, not helpful to determine treatment decisions.
This brings us to the end of this case. Please see the other segments for further discussion about the latest research in lung cancer or visit ascopost.com. Thank you so much.
