Dr. Heather Wakelee:
Welcome to The ASCO Post Roundtable Series on New Directions in Nonmetastatic Non–Small Cell Lung Cancer. I'm Dr. Heather Wakelee, Professor of Medicine and Chief of the Division of Oncology at Stanford University and Deputy Director of the Stanford Cancer Institute. Joining me today are two world experts on early-stage non–small cell lung cancer, and I will allow them to introduce themselves.
Dr. Marina Garassino:
Hello, I'm happy to be here. My name is Marina Chiara Garassino. I am a Professor of Medicine at the University of Chicago and I am the Director of the Thoracic Program there.
Dr. Tina Cascone:
Hello, everyone. Thank you, Heather, for having me today. I'm Tina Cascone, Associate Professor in the Department of Thoracic, Head and Neck Medical Oncology, and Director of the Translational Research Program here at MD Anderson in Houston, Texas.
Dr. Wakelee:
Great. Thank you Marina and Tina for joining me. Today we will be discussing the treatment of resectable nonmetastatic non–small cell lung cancer with three patient cases. Our final installment will focus on EGFR-mutated early-stage non–small cell lung cancer. Let's jump into our case.
Ms. CL is a 48-year-old woman, no past medical history other than two normal pregnancies. She was in a minor car accident, and for that, as part of the evaluation, has a chest x-ray, where, surprisingly, a 3 cm mass is seen in the right lower lobe. What would be the next steps in her workup? Do you want to kick us off, Tina?
Dr. Cascone:
Sure, sure. Thank you, Heather. Here we're really starting our workup from scratch. Many times, I think, in academic or community centers, we see some of this workup already started by our wonderful primary care physician doctors or navigators, so I always want to appreciate the work that they do. But I think in this case we need a diagnosis. We have a mass, so I think it's important to obtain a biopsy, and many times, as I mentioned, we have a CT chest to adrenal already done. But as part of the biopsy workup for the diagnosis, we also want to get, in parallel, the staging workup. A PET-CT is something that is absolutely critical to evaluate the mediastinum and, of course, occult metastatic disease that will definitely trigger a different workup in terms of biopsy of potential distant disease.
Here we have a 3-cm, so it's something that it's always important to discuss if a patient is completely asymptomatic from a neurological standpoint. A brain MRI, in many centers, is not mandated. I personally, if I'm on the fence, usually less than 3 cm, I perhaps can skip it, but especially if I'm in the resectable potential setting, I would tend to have an MRI of the brain as well. And, of course, once we have all of this multidisciplinary discussion based on the results is paramount.
Dr. Wakelee:
Anything you would add, Marina?
Dr. Garassino:
No, we do exactly the same. I always do the brain MRI.
Dr. Cascone:
Thank you, Marina. That's so reassuring.
Dr. Wakelee:
The patient does have a biopsy and unfortunately it confirms an adenocarcinoma. PD-L1 results come back the next day and they're 85%. PET scan confirms uptake in the mass, but also in a level 7 lymph node. Brain MRI is negative. There's a multidisciplinary tumor board and there's discussion of starting chemotherapy plus immune checkpoint inhibitor immediately or going straight to surgery, given that there's relatively limited extent of disease, though it does appear to be in a level 7 node. From this standpoint, what additional results would be helpful prior to start of treatment? There is lots of discussion, heated discussion happening in tumor board over this one. Marina?
Dr. Garassino:
Yeah, clearly here there is the temptation to go immediately and do chemoimmunotherapy, and this is important because this could result in a big mistake. Sometimes we can see that PD-L1 is high just for a constitutive activation coming from driver mutation. So this is a young patient with no comorbidities. I don't know if she was a smoker or not, but I guess not. And so, in particular in the never-smokers, it's mandatory to stop any decision before we have the results of the NGS, because you can treat in a patient in a way for which then you can't come back. So, in particular for never-smokers, maybe for a squamous it can be an exception, but for the other patients, the adenocarcinoma just stop, wait for the NGS, pray your pathologist to be quicker as possible, but don't decide any treatment.
Dr. Wakelee:
I think the NGS testing can take a little bit of time and we know that the liquid biopsies are not always as sensitive when it's early stage, so it can be tricky. But there are faster ways to get at least EGFR and ALK where we have data about alternatives to the immune checkpoint inhibitor therapies. We've all seen, especially with ALK, there are a lot of patients with high PD-L1 who have ALK-positive lung cancer and checkpoint inhibitors just don't work. So such an important case, an important emphasis that you just made.
This patient's tumor was tested. PCR testing comes back within few days and did reveal an EGFR L858R. She's taken to surgery, so the camp from tumor board arguing for immediate surgery won, in this case, where a 3.2-cm mass is revealed and that only involved lymph node was that level 7 node. Would you consider now adjuvant immune checkpoint inhibitors since her PD-L1 is 85%? Would you give 3 years of osimertinib? Would you consider giving a longer course of osimertinib? Would you do something else? Throwing this one at you, Tina.
Dr. Cascone:
Yeah, sure. Heather, for sure. I would not consider to give this patient an adjuvant immune checkpoint inhibitor despite the PD-L1 85%, as Marina nicely summarized and you underscored as well. We have a level 7, positive subcarinal station, we're in a stage III setting, I would administer adjuvant chemotherapy for this patient followed by osimertinib. And then to your question, 3 years based on the ADAURA trial with benefit, of course, in the DFS and OS. To your question of if I will give it 3 years vs a longer course, I think we've seen the Kaplan-Meier curves on the overall survival post 3 years, so to me it's an important conversation with the patient based on toxicity, based on logistics, based on patient goals. If all of those are channeled toward the direction of continuing therapy for more than 3 years, I would do so.
Dr. Garassino:
I totally agree. I think that here maybe for the audience there can be the temptation to start osimertinib first and maybe go to the resection because it is a stage III and then continue again with the osimertinib later. I just want to remind that there are no neoadjuvant trials that show the benefit in terms of overall survival. There are a lot of trials in progress, but interestingly, while with immune checkpoint inhibitors, we see complete pathological responses, there are zero pathological responses with osimertinib.
We are in a different situation. So in this case, as Tina nicely said, we should go with the adjuvant. That can be part, again, of the discussion with the patient. But if the adjuvant or if the benefit is not so high, it is a possibility to increase maybe more, again, the survival of these patients, and she's a young patient without any comorbidities. 3 years of osimertinib or more, now I say something that maybe is not showed, but if the patient is tolerated quite well at the treatment, maybe I would continue also beyond 3 years.
Dr. Wakelee:
Yeah, I think this is an area where we have a lot of controversy. Getting back to your comment about the prior to surgery osimertinib, a group from UCSF, Jackie Aredo, presented at ASCO 2023 showing that the major pathological response rates were lower than we would've anticipated and there weren't those past CRs. So we kind of questioned that a little bit more.
We certainly have ADAURA, where we now not only have the disease-free but also that overall survival benefit. And as you've both alluded to, we have this question where, if they gave it for 3 years, when we look at the curves that continue beyond 3, there definitely does seem to be a rate of recurrence in the patients after that 3 years when the osimertinib is stopped vs the plateau that was already reached for those who didn't get osimertinib. But many more of those had already recurred, of course, so there's a huge gap between those curves. How is that going to impact survival and how are we going to know without longer term? And so, just so many questions still there about what's going to be the right strategy.
As I reflect on my patients from prior to the ADAURA era, I recently had a couple of patients who presented with brain metastases that year 4 who had done well and with no evidence of any recurrence, we'd even gotten some brain MRIs early on which had never shown anything. And so that really sparked that different feeling of like, "Oh, how do we know how long to continue the osimertinib?" I don't think there's any question that for this patient. Upfront surgery and then adjuvant osimertinib was the right answer. And I agree with you about the chemotherapy in patients with stage III, but if this patient was 75 and frail and was getting a little bit deaf and their kidneys weren't working so well, I think that's a harder discussion. But we still have lots of questions.
And now we have, of course, the ALINA trial with alectinib for patients who are ALK-positive, where, so far, we've only seen disease-free survival data, and that trial was vs chemotherapy with a lot of stage III, which I think many of us are a little bit uncomfortable about. I am wondering if either of you have comments about that. We're veering away from this particular case, but it's such a linked and connected question.
Dr. Garassino:
Yeah, I think that, again, the discussion with the patients is crucial for the chemo. I try to continue the chemo in particular in the ALK-positive patients because pemetrexed is a very good ALK inhibitor, so we can maybe maximize the benefit of the adjuvant part. So I would suggest to continue, but there are some patients that at just the word chemo, they say no. I think we should respect also what the patients want. And I think that it is also important to ask the patients to be compliant with the treatments, because sometimes when I see them in the clinic and you ask, "How many pills did you take?" Sometimes they are just taking 5 days so they can feel just a bit better. These drugs are very potent, but they have side effects and the patients must be on board on the long time that they have to receive the treatment.
Dr. Cascone:
Agree 100% with what Marina summarized. I don't need to add.
Dr. Wakelee:
Great. I also want to come back to a really important point that was alluded to, which is that if we don't know the mutation status of the tumor for the patient and they get started on an immune checkpoint inhibitor, we have to remember that that elevates the toxicity profile for osimertinib with a pretty high rate of pneumonitis in that setting of concurrent or even for 3 months and maybe even longer, you've altered that toxicity profile of the osimertinib. We've also seen that with alectinib with liver function test abnormalities. And so I think it's just really important to emphasize to the audience that in a patient who really has a high chance or any chance of having a driver mutation where you're going to be thinking about a better strategy involving an EGFR inhibitor or ALK inhibitor, that you don't want to just leap into the checkpoint inhibitor because you could actually cause harm. It's not just that you're not helping them, you actually are potentially causing harm because you're increasing that toxicity profile. Just another important point. All right.
Well some key takeaways from this, especially in patients with that high pretest probability, really critical to know the molecular results. Though the full NGS can be very helpful, what we really, really need to know are EGFR and ALK. And so trying to work with your teams to figure out ways to get those resulted faster, even if it's outside of the classic full NGS. Prior to start of any immune checkpoint inhibitor, adjuvant osimertinib is absolutely the standard of care for EGFR mutation–positive early-stage non–small cell lung cancer, but chemotherapy still plays a role, especially in stage III in the adjuvant setting. Adjuvant alectinib has a proven disease-free survival benefit vs chemotherapy for ALK-positive early-stage resected non–small cell lung cancer, but we still have some questions to answer about what's the optimal strategy for either of those.
With that, that brings us to the end of this case. Please see the other segments for further discussion about the latest data in non-metastatic non–small cell lung cancer or visit ascopost.com. I'd like to thank my colleagues Marina Garassino and Tina Cascone very much.
