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 and joining me today are two of my expert colleagues from MD Anderson Cancer Center, Dr. Tina Cascone.
Dr. Tina Cascone:
Hello, Stephen. Thank you for having me today.
Dr. Stephen Liu:
Thank you for joining us. And from Johns Hopkins University, Dr. Susan Scott.
Dr. Susan Scott:
Hi, Stephen. It's great to be here.
Dr. Stephen Liu:
It's great to have you. Today we will be discussing the treatment and management of EGFR-mutant non–small cell lung cancer with three patient case studies. Our final installment will focus on the management of unresectable EGFR-mutant non–small cell lung cancer.
This case, Mrs. J.U., is a 66-year-old woman who is found to have a right upper lobe lung mass on a screening CT scan. She had a history of smoking. She smoked one pack per day for 37 years but managed to quit 6 years ago, meeting the criteria for screening. That screening CT scan did show a right upper lobe lung mass. A PET scan was performed that showed FDG uptake in that right upper lobe mass, but also bulky mediastinal lymphadenopathy and a bronchoscopy did confirm adenocarcinoma in the right upper lobe as well as R4, 7, and L4 contralateral mediastinal adenopathy. With biopsy-confirmed N3 adenopathy, the multidisciplinary team determined that this was unresectable stage III non–small cell lung cancer.
Tina, let me stop here. Do you agree with generally an approach that excludes surgery for N3 adenopathy?
Dr. Tina Cascone:
I do tend to agree so, Stephen. I think we have seen across all the trials that really have tested neoadjuvant approaches and adjuvant approaches for multistation N2 disease, including the opportunity to perform pneumonectomy, but really the N3 disease tells us that this is a different type of disease that is slightly more advanced than what could be controlled with surgery. And so I tend to really make a call to my radiation oncology colleagues and have mind-setting in favor of a definitive chemoradiation approach for this type of patients.
Dr. Stephen Liu:
That is a decision that we do not make on our own. We involve our radiation oncologists and certainly our surgeons to comment on resectability. Susan, we have here what was determined to be an unresectable stage III non–small cell lung cancer. Is there any other information you need to put together the optimal treatment plan?
Dr. Susan Scott:
Yes, so we need, I think, a brain MRI for this patient, but also kind of further definition of the cancer. So molecular status and PD-L1 would be ... PD-L1's less actionable in this setting, but certainly EGFR will be important.
Dr. Stephen Liu:
And so in this case, those tests were ordered, but patient did proceed with definitive concurrent chemoradiation. Patient received weekly carboplatin and paclitaxel, and there were initial plans for durvalumab consolidation after completing therapy based on the phase III PACIFIC regimen. And so the patient starts concurrent chemoradiation, weekly carboplatin and paclitaxel. But a couple of weeks into treatment, those test results come back and it does in fact reveal an EGFR exon 19 deletion. Susan, does this change our initial plan of chemoradiation and durvalumab?
Dr. Susan Scott:
Yes, it changes the plan for the consolidation treatment. So I often have this in my practice where we go ahead and start chemoradiation without having the full molecular diagnosis because it doesn't change our upfront practice as long as it's in process, though I have been burned a few times on that where it's QNS, or quality not sufficient, and then I don't have anything to biopsy at the end. But oftentimes the liquid biopsy can be helpful in these patients that are more advanced. And so in any case, no, I do not use durvalumab after this. I put patients on osimertinib indefinitely based on the LAURA study.
Dr. Stephen Liu:
So this is a really important point that you bring up, Susan, that if that initial biopsy, which might've been a fine-needle aspirate, is enough to make the diagnosis in the stage, but not enough for testing, Tina, would you ever recommend going back and doing a repeat biopsy before we embark on chemoradiation?
Dr. Tina Cascone:
Absolutely so, Stephen. I think this is a very important step not to take lightly for this position in the patient to the best option. Let's remember that we are in definitive chemoradiation setting, so still we are in the potentially curable setting. Things are very different as a non-N3 type of disease, but even in the N3 disease, I think we want to maximize the chances of a very improved progression-free survival with the right treatment. And if we have an EGFR mutation, definitely as Susan mentioned, the osimertinib is the best consolidation therapy to give them.
If we don't have that information, I will not want to put the patient on durvalumab and then knowing later about the EGFR positivity because of the potential toxicity that we might also induce to the patient if we have to switch therapy. So absolutely this is a repeat biopsy that I would strongly encourage.
Dr. Stephen Liu:
Now, this particular patient had discussed her case with friends and family and after hearing about osimertinib therapy, as appealing as it was, this patient's still very interested in immunotherapy. Susan, what role does durvalumab potentially play in this setting?
Dr. Susan Scott:
None, Stephen. I would very strongly argue against. I would not offer immunotherapy and no, none.
Dr. Stephen Liu:
And we're basing our recommendation on the phase III LAURA trial. In this study, patients who had completed concurrent definitive chemoradiation were randomized to receive osimertinib or not, and the use of osimertinib in the consolidation setting here did significantly improve progression-free survival with a median PFS of 39.1 months vs 5.6 months, hazard ratio of 0.16. When we look at these Kaplan-Meier curves, immediate separation, they widen over time; a profound benefit with osimertinib.
Two important points here. One, osimertinib given indefinitely, so a very long course of therapy. And two, that control arm with a median PFS of 5.6 months is pretty poor. Tina, you mentioned this is potentially a curative setting, but that control arm didn't look like we were very successful with our historic standard. Do you agree?
Dr. Tina Cascone:
I absolutely agree, and that tells us how the biology of the disease in the N3 setting is quite poor. And so I absolutely agree with the fact that in the context of a more aggressive disease, despite still being locally advanced, the durvalumab has no role as Susan effectively mentioned. And based on the separation of the curves that as you mentioned, it's quite dramatic, quite robust, and has a ratio of 0.16, it's absolutely non-negligible. So osimertinib is what I would recommend.
Dr. Stephen Liu:
So can we talk a little bit about the delivery here? We're familiar with osimertinib. This was approved in the frontline setting based on the FLAURA trial for stage IV, and it's been our standard of care since 2018, a well-tolerated drug, but can you comment on tolerability in this setting, Susan, after chemoradiation. Has your experience been very similar to stage IV or is it a little different?
Dr. Susan Scott:
It's actually quite a bit different. I've seen more toxicity in the earlier stages. I'm not sure if the patients are more robust or they've been through major surgery or chemoradiation. I've also seen, and was seen in LAURA, a few cases of pneumonitis on the osimertinib. I think the rate of grade 2 pneumonitis was about 40% in the osimertinib arm and only 20% in the patients that only had the radiation. So there's definitely a synergistic effect between the radiation and the osimertinib that can be quite profound and I don't think we have a lot of data yet on reintroduction of osimertinib. I think in the earlier stages you might kind of drop it because it was adjuvant and you were going to plan for the 3 years. But in the LAURA paradigm, when you're planning indefinite therapy, I think everybody's going to think very seriously about reintroducing that osimertinib at some point with these expected recurrences. And that is something that I've been challenged with in the last year.
Dr. Stephen Liu:
I agree with the tolerability part. I think that part of it also perhaps in a stage IV setting, patients come in often symptomatic, you give them a drug with a response, they're going to feel better. But in this setting after surgery, after chemoradiation, the cancer has been addressed, and if someone is not symptomatic from their cancer, you can't make them feel better, only worse. Maybe part of the reason why those toxicities are a little more noticeable. With the LAURA trial, we're talking about a long course of therapy, chemoradiation is one of the tougher treatments I think a thoracic oncologist would deliver. Tina, what's your approach to when you start osimertinib? Are you looking at the calendar and picking out days or is it sort of based on how the patient's doing?
Dr. Tina Cascone:
Yeah, it's a compromise, Stephen. I really tend to give them usually a 3, 4 weeks break after the chemoradiation phase. They're pretty beaten. I mean, as you mentioned, it's a pretty tough treatment. And again, the cancer has been addressed, as you nicely said. So I do tend to give them the time, and I also tend to do a very early look CT scan to make sure that there is no progression of the disease. I explain to them very well that this is an early look and really will take some time to really get the magnitude of the benefit of the radiation at 3, 4 months with a PET later on. But this is really an initial scan as a new baseline. And then usually between the 4 and 6 weeks if they're ready, tend to start the osimertinib.
Dr. Stephen Liu:
Susan, what's your approach to surveillance? Patients are on osimertinib, they're doing well, feeling well. What's your radiographic surveillance plan here?
Dr. Susan Scott:
I scan patients every 3 months for the first year. And I continue generally at that interval given how high risk they are, and I offer an annual brain MRI.
Dr. Stephen Liu:
Tina, is your approach similar?
Dr. Tina Cascone:
Yes, very similar. I have annual MRIs and I tend to do perhaps a first scan 8 weeks after I've started because that overlaps pretty much with the 3 months after the completion of chemoradiation. So that will be a PET usually, and then I tend to do a CT every 3 months, but that's pretty much my take.
Dr. Stephen Liu:
Important point about the duration with LAURA, osimertinib was given until progression or intolerance. Susan, is this really lifelong treatment or is there some test we can do to stop therapy? What are you telling your patients?
Dr. Susan Scott:
I am preparing them for lifelong treatment based on that placebo arm and the design of the trial and the approval, and just, I kind of expect that 90% of them are advanced and have disease remaining after chemoradiation, and I treat them as such. I hope again that we will in the future be able to identify patients that can take a break from osimertinib or can come off completely and are in that small group of patients that are definitively treated with locally advanced disease. But for now, especially if they're tolerating it well, then everybody stays on indefinitely.
Dr. Stephen Liu:
Tina, similar approach, and if so, how do your patients react to being told they need to be on this medicine forever?
Dr. Tina Cascone:
Very similar approach. I really appreciate the phrasing of educating them and preparing them to a lifelong type of administration of therapy. I think it's important, Stephen, to take the time to understand really what matter the most to our patients as we have those discussions. Because quality of life is so critical, whether this is a stage III or a stage IV or a stage I disease, and I think for our patients, it's critical to be able to be functional and continue to go on with their life, what makes them really fulfilled every day without having those functions impacted.
So many times we come to an agreement that perhaps after a certain amount of time, this has become impossible to tolerate as a treatment, and because there is no quite evidence of the disease, we stop the treatment with the understanding that the disease might come back and the monitoring is to be very, very robust. And that happens, and it's a common decision. It's a mutual decision that we make, an informed decision that we make with our patients that is tailored to their specific scenario.
Dr. Stephen Liu:
I think those are important points. When we look back at this case of unresectable EGFR-mutant non–small cell lung cancer, I think the key clinical takeaways, one, molecular testing essential for the optimal management of unresectable stage III non–small cell lung cancer. And if we are not going to get results, we may need to repeat biopsy. Key here is that that biopsy probably needs to be done early before the chemoradiation, and so we need to do that testing at an early stage as well. That concurrent chemoradiation remains our standard for patients with unresectable stage III, non–small cell lung cancer. And after completion of chemoradiation, osimertinib consolidation therapy improves PFS for patients with EGFR-mutant non–small cell lung cancer.
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.
