Dr. Stephen Liu:
Welcome to The ASCO Post Roundtable Series on EGFR-Mutant Non–Small Cell Lung Cancer: Treatment Considerations for Early-Stage Disease. I'm Dr. Stephen Liu from Georgetown University. Joining me today are two of my colleagues from MD Anderson Cancer Center, Dr. Tina Cascone.
Dr. Tina Cascone:
Hi Stephen. Thank you for having me.
Dr. Stephen Liu:
And from Johns Hopkins University, Dr. Susan Scott.
Dr. Susan Scott:
Hi, good to be here. Thanks.
Dr. Stephen Liu:
Today we'll be discussing the treatment and management of EGFR-mutant non–small cell lung cancer with three patient case studies. Our first installment will focus on the management of resected EGFR-mutant non–small cell lung cancer. Jump right into our case.
Mr. FM is a 73-year-old man who was incidentally found to have a left upper lobe lung nodule on CT, something that will continue to happen as we do CT scans more and more frequently. This particular patient had no relevant medical history and no history of smoking. Eventually got a PET scan that showed only uptake in that left upper lobe of the lung, and MRI of the brain that showed no metastases. In this case because this was a spiculated suspicious lesion, they opted to bypass the biopsy and go straight to surgical resection. And pause here, Tina, is this something that you are in favor of? Do you often send patients to surgery without a biopsy?
Dr. Tina Cascone:
Yes, Stephen, this is definitely something that occurs that we are accustomed to see. I have to tell you, there is a very solid multidisciplinary clinic type of effort here. In these situations, very often it will happen that on the same day, we will have in the multidisciplinary clinic, the surgeon, the medical oncologist, and the radiation oncologist, to see the patient at the same time. To make real-time treatment dispositions.
In this situation it would be a live discussion with the surgeons and deciding with the patient, whether we want to perhaps do more work up with a biopsy and so forth, or disposition the patient to surgery directly.
Dr. Stephen Liu:
There are complex cases and it's all about minimizing a risk and maximizing outcomes. In this particular case, the patient went directly to surgery, had a video-assisted thoracoscopic surgery, a left upper lobe lobectomy and mediastinal lymph node dissection. Now the patient sees you after surgery and the pathology showed a 2.5-cm left upper lobe adenocarcinoma and a regional hilar lymph node. That L10 lymph node was positive. Not enlarged, not avid on PET, but pathologically confirmed as node-positive lung cancer.
The final stage T1, cN1, M0 stage 2A, non–small cell lung cancer. And Susan, they're now seeing you in the clinic. They've recovered from their surgery. What additional studies should be performed to assess the disease state here?
Dr. Susan Scott:
First I'd want to further characterize what type of lung cancer they have in terms of the biomarker status. So, NGS sequencing, particularly for EGFR and ALK, which have indications postoperatively. I also usually look for PD-L1 status for patients that don't have those indications and I would, if he hadn't had it before, get a brain MRI as well.
Dr. Stephen Liu:
I liked how you said that. That's part of the diagnostic evaluation. Really, we think of the molecular testing not just as an added feature, not some optional component, but really part of a diagnosis. It tells us about the biology, the prognosis, but increasingly, it informs our treatment and now it does so at every stage. In this case the PD-L1 expression was 0%, but the next generation sequencing did reveal a mutation in EGFR. That mutation in EGFR exon 21, L858R mutation, an activating sensitizing mutation. We see the tissue profiling panel here.
And so Tina, this patient now seeing you, has a PD-L1–negative, EGFR-mutant, resected node-positive, adenocarcinoma of the lung. And so, what would your treatment recommendation be for this patient?
Dr. Tina Cascone:
Yes, well, first of all I'll discuss with patient this results in the context of the ADAURA study. With the opportunity to have adjuvant osimertinib as a standard of care. But I am very much in favor of administering chemotherapy, platinum-based chemotherapy in presence of node-positive disease, prior to the administration of osimertinib.
We know that with the osimertinib in the ADAURA trial, approximately 60% or so patients received chemotherapy and the benefit from osimertinib was seen regardless of adjuvant chemotherapy. But let's not forget that that was an exploratory endpoint and the trial was not only powered to look at the role of adjuvant chemotherapy.
Based on historical data in presence of node-positive disease, I would recommend four cycles of platinum-based chemotherapy. Of course, based on comorbidities, I would decide cisplatin vs carboplatin. If it's an adenocarcinoma or nonsquamous, I would choose pemetrexed. And then after the completion of up to four cycles, I will trying to restage the disease and initiate the osimertinib with an echocardiogram as well at baseline.
Dr. Stephen Liu:
All right. We're thinking four cycles of adjuvant platinum-based chemotherapy. You mentioned cisplatin or carboplatin. Is your preference there, cisplatin?
Dr. Tina Cascone:
I have to tell you, Stephen, that prior to the chemoimmunotherapy adjuvant and neoadjuvant era, I was very firm on the cisplatin, in absence of comorbidities. But I have to say, I've become a little bit more flexible on considering the carboplatin because the reality is that the patients do tend to have a better compliance with the carboplatin. We're able to put the four cycles in a much more expedited manner. The toxicities tend to be better. I decide to go with the cisplatin if I have a very robust performance status, no comorbidities, but I have a very low threshold to choose the carboplatin, if I have to.
Dr. Stephen Liu:
Susan, what's your recommendation here? Resected EGFR-mutant lung cancer, PD-L1 0%. What are you recommending for this patient?
Dr. Susan Scott:
I agree with Tina. I'd recommend four cycles of chemo followed by osimertinib. I think the relapse rate, even with stage II EGFR-mutated lung cancer is very high. We saw that in the ADAURA study in the placebo group. In more than 60% of those patients, their disease relapse in the first 5 years. And so, though stage IIA feels like a group that could be cured by surgery, they're still very high risk. I always offer the osimertinib to my patients. But I agree fully that the data still supports that doing that after chemotherapy.
Dr. Stephen Liu:
You both referenced the ADAURA Trial, a randomized phase III study that really has shaped our practice in this setting. In this global randomized phase III trial, patients with resected EGFR-mutated non–small cell lung cancer, could receive chemotherapy and then were randomized to receive 3 years of osimertinib, at 80 mg daily vs not. The benefit with osimertinib was pretty profound. We saw DFS hazard ratio of 0.17, we've not yet reached the median and we did learn in an update that translated to a survival benefit. Now that benefit there is pretty substantial and those Kaplan-Meier curves are pretty spread apart.
Let me just really push on that one point. With the profound benefit, Tina, that we're seeing with osimertinib here, is chemotherapy really essential? You're meeting with the patient, and they say, "I'm totally on board with targeted therapy. Do we really need the chemotherapy?" Chemotherapy can be a toxic treatment, it invokes a lot of emotion. How essential is the chemotherapy here?
Dr. Tina Cascone:
I think it's a very fair point, Stephen, and I definitely embrace these discussions with the patient to tailor that decision, right? Specifically to the status, the clinical status and the wishes of the patient. I have to tell you again that I feel that if we look historically at the data, we still know that even for stage II patients, platinum-based chemotherapy, four cycles after resection, does improve survival. In the meta-analysis 5.4% across other studies, I'm sorry, that have looked into that question, 5% to 8%.
I feel that in presence of node-positive disease—despite the ADAURA trial did demonstrate a benefit, regardless the administration of chemotherapy—I feel that if there are no contraindication, the administration of chemotherapy will give the patient an additional layer of potential treatment to minimize any risk of relapse. You're absolutely correct, toxicity are non-negligible, and that's something that we have to keep in mind as we make these decisions. It's always a patient-based decision in each specific context.
Dr. Stephen Liu:
Susan, how strongly do you feel about the chemotherapy? If this is a patient that really is hesitant about it, is it something that you strongly encourage?
Dr. Susan Scott:
I give them the straight data. I say, "This has the potential to save the life of 1 in 20 patients. And if that's you, and that feels like something that you want to go through with, then we should do it. And if those odds don't speak to you and after talking about the risks of chemotherapy, then we bypass it."
I think I present it fairly and I would recommend it to my loved ones or if I was in that situation. But I do have a lot of patients that decline it after talking to me about it. I think they clearly hear from me more benefit from the osimertinib, but, that goal of the chemo is a potential elimination of micrometastatic disease and a cure, and I'm not sure that we're seeing that with the osimertinib. And so, though there is an overall survival benefit, I still believe that the greatest benefit is from the two together.
Dr. Stephen Liu:
That's an important point that, we do see an improvement in overall survival, we don't necessarily know if that translates to cure. Cure is a charged word and a little hard to define. The question is, is the benefit from osimertinib a durable one? And does that persist after stopping the treatment with chemotherapy? We do think that there really is some long-term benefit and history tells us that, but is of a magnitude less, at least in the short term, than targeted therapy. I think my approach is very similar and in this particular case, we did administer cisplatin and pemetrexed to this patient.
I also have found myself softening though to the platinum. And I think when we hold on to cisplatin in the curable setting, I think a lot of it is dogma. And really we focused on differences between cisplatin and carboplatin I think, because we didn't have a whole lot else to talk about. But realistically, I do think that the benefit is probably incremental. And what you certainly don't want, is you don't want the chemotherapy to get in the way of the osimertinib. And the last thing I would want to see is someone get so sick from cisplatin and have nephrotoxicity, that now it may not be safe to give other treatments. Susan, what's your stance on platinum here? What do you reach for first?
Dr. Susan Scott:
I agree completely. I would say I use carboplatin 75% of the time, if not more. I look for an excuse not to give cisplatin. I think it's probably more toxicity than it's worth. And I think, coming into thoracic oncology in the age where we had all these options, I agree with you. I see this as old news.
Dr. Stephen Liu:
This patient though did receive cisplatin and pemetrexed, completed treatment, we did a CT scan, no disease, recovered from chemotherapy, and so we got a fresh slate. And then as planned, we did begin osimertinib. The third-generation EGFR inhibitor, 80 mg daily. Now we're on treatment, labs look good, tolerating the treatment well. Tina, what's your approach to monitoring here?
Dr. Tina Cascone:
Yes. For the imaging with CT scan, is what I preferred and not PET scan. I'm glad you asked that question because that's something that comes in the patient discussions very much, they seem to be at times very adamant about wanting to have that PET scan. To look not only at the anatomical response but at the metabolic response. And so, I tend to really get a CT, chest and abdomen, with contrast, if I can.
And at the beginning I tend to do this every 8 weeks, and then switching to every 3 months, so 12 weeks. And then as far as the MRI of the brain, that's another very delicate imaging that we discuss with the patients. They have an MRI baseline as you told us from this case.
And then usually, I'll do—the ADAURA Trial did a mandate MRI brains in the follow-up throughout the osimertinib. I find myself very often ordering an MRI of the brain, even despite absence of symptoms, perhaps every 6 months to once a year. Just to make sure that there is no occult disease that I might miss in absence of symptoms. And this is usually really my journey in terms of imaging workup with the patients during the osimertinib phase.
Dr. Stephen Liu:
Susan, what's your imaging strategy there in terms of radiographic surveillance while on osimertinib?
Dr. Susan Scott:
Very similar. I get a CT scan only, unless a patient can't get contrast then sometimes I alternate between PET and CTs without contrast. Usually every 3 to 4 months. Because patients are disease-free after; I get a scan after chemo, but I feel more comfortable widening that interval a little bit more right up front, because I know there's nothing to watch.
I actually worry after the first year or two about, keeping those scans more regularly when I think patients are more likely to start recurring. I offer a once-yearly brain MRI and the more high-risk patients are or the higher stage they are, the more I really lean into that. Because our local therapies for brain metastases have increased so much over the past several years. And I often, if a patient has a solitary brain met, will refer them for local therapy and try to keep them on the osimertinib or other targeted therapies. I want to identify that disease as early as possible before it becomes symptomatic. That's usually my thought pattern. And of course if patients have symptoms, I change it up.
Dr. Stephen Liu:
I think we learned from these studies that CNS is a sign of failure from these drugs at times, and so it's important to monitor. I agree with that completely. What about MRD assays, Susan? We see some of these commercial assays, where we can use blood tests to look for minimal residual disease. Any role in lung cancer?
Dr. Susan Scott:
In this setting, I use a commercially available MRD assay only to escalate therapy. I have the same discussion with patients, I say, "This is the data for osimertinib and this is my recommendation that you take this for 3 years." And if a patient hears that and says, "No thank you," then I say, "Okay. I understand." We can do an MRD test and see if it's positive, then I'll very strongly recommend that you start the osimertinib. If it's negative, then I wouldn't change.
I would not though, I don't think we have enough data on the sensitivity of these assays for me, to decline giving adjuvant osimertinib to a patient based on that study. I really don't use it in that setting, and so, I don't use it very often.
The other time I might consider using it in the future is, for patients who've come off therapy or who are getting ready to come off therapy. I'm hopeful that that will become part of our practice in terms of making decisions on when to stop and maybe even upfront deescalation, but we're not quite there yet.
Dr. Stephen Liu:
That's our hope to get there. Tina, your stance on MRD assays?
Dr. Tina Cascone:
I have to say it's a very similar approach, Stephen. We use commercial assays. Those are institutional, but commercial. And really I found myself getting into the routine testing when they want to stop osimertinib at 3 years. And so, in that case, I tend to use that to help me to detect reoccurrence of the disease. Also based on the MRD tumor-informed data that we have from the ADAURA rital, that have been presented last year, where we know that there is less MRD positivity in osimertinib-treated individuals, and that correlates really with a longer DFS status.
And if patients don't want to get on this osimertinib to start with, which is very rare, then again, that's also a strategy that I can help myself with to decide when definitely is necessary to start.
Dr. Stephen Liu:
I think our key clinical takeaways here, molecular testing really should be performed for patients with resected stage II or III non–small cell lung cancer. That adjuvant osimertinib is our standard of care for patients with non–small cell lung cancer, harboring an EGFR exon 19 deletion or L858R mutation. The duration of osimertinib therapy, 3 years. But ongoing studies will seek to better define the optimal course and the optimal monitoring after surgery isn't really clear, but monitoring for CNS recurrence really does need to be a consideration.
This brings us to the end of this case. Please see the other segments for further discussion about the latest research in EGFR-mutant non–small cell lung cancer or visit ascopost.com.
