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 colleagues; from the Anderson Cancer Center, Dr. Tina Cascone.
Dr. Tina Cascone:
Hi, Stephen. Thank you for having me.
Dr. Stephen Liu:
Thanks, Tina, for joining us, and from the Johns Hopkins University, Dr. Susan Scott.
Dr. Susan Scott:
Hi, Stephen. Thanks for having me.
Dr. Stephen Liu:
Great to have you, Susan.
Today we will be discussing the treatment and management of EGFR-mutant non–small cell lung cancer with three patient case studies. Our second installment will focus on the treatment of resectable EGFR-mutant non–small cell lung cancer.
This case, Mr. TG, is a 70-year-old man who presented to his primary care physician for evaluation of a persistent cough. Medical history relevant for hypertension, sleep apnea, and a prior cholecystectomy. This patient is married, works in an office, no history of smoking. Medications include valsartan and hydrochlorothiazide, and a chest x-ray performed by the primary care doctor shows a right upper lobe ground glass infiltrate. So this patient is treated with antibiotics, symptoms persist, and ultimately gets a CT scan. That CT scan showed a suspicious right upper lobe lung nodule.
A PET scan was performed that showed a hypermetabolic right upper lobe nodule and mild uptake in a right peritracheal lymph node. Bronchoscopy and EBUS were performed that revealed lung adenocarcinoma in the right upper lobe and that R4 lymph node. And so this patient with what appears to be a resectable stage IIIA adenocarcinoma of the lung was offered neoadjuvant cisplatin, pemetrexed, and pembrolizumab based on the FDA approved KEYNOTE-671 perioperative trial.
But he's seeking a second opinion, and so, Tina, this patient arrives in your office, is very excited about the prospects of immunotherapy, has read the lay press about the wonders and the transformative benefit we see. What do you recommend at this stage?
Dr. Tina Cascone:
So this happens very often. There is a major excitement in the community, in the patient community just for the reasons that you have mentioned. But I would take a moment of pause here and discuss with the patient how important is to obtain the molecular profiling on the tumor to really understand at a minimum what's the status of EGFR and ALK alterations because we do have standard-of-care options for patients that have potentially resectable disease. So I would definitely obtain molecular testing. And I would be very adamant about discussing this case in the multidisciplinary tumor board to have the opinion of our surgeons and radiation oncologist. This is a stage III, appears to be single station, but it's paramount to define the resectability status and the mutational status before we disposition the patient to surgery. And we'll also get an MRI of the brain if that has not been done.
Dr. Stephen Liu:
So we order molecular testing on this sample as you recommend, and lo and behold, it reveals an EGFR L858R mutation. Susan, how does this change things?
Dr. Susan Scott:
At this point, I would definitely not recommend neoadjuvant chemoimmunotherapy with an actionable EGFR mutation. I would recommend the patient go straight to enroll in a clinical trial or go straight to surgery and then talk about chemotherapy and osimertinib after. Agreeing with Tina, that's assuming the patient is surgically resectable, especially with those N2 disease. It always requires a multidisciplinary discussion.
Dr. Stephen Liu:
An important point, I didn't mean to gloss over that. We certainly want to discuss this with our surgical colleagues to make sure that surgery is appropriate, that it is resectable, and that's not really a decision that oncologists should make in a vacuum. This case is resectable. We have a IIIA. Tina, would you ever consider neoadjuvant chemotherapy alone?
Dr. Tina Cascone:
I would. I actually would. I think that we know historically, and again this is an extrapolation from meta-analysis and historical data, but we know that the overall survival benefit of 5 years for a platinum-based chemotherapy in the adjuvant setting or in the neoadjuvant setting is overall very similar, approximately 5% to 5.4%. So I really appreciate the opportunity for our patients to receive platinum-based chemotherapy if possible upfront. I tend to find them more fit prior to surgery to receive full four cycles if possible of platinum-based chemotherapy. And I really hope that the chemotherapy can have, right, some ability to treat micrometastatic disease early on in the development of the disease. And so I do tend, if possible, to administer the four cycle before and then start the osimertinib, in this case, post-surgery.
Dr. Stephen Liu:
But again, just as Susan mentioned, no immunotherapy in your plan here, right?
Dr. Tina Cascone:
Absolutely no.
Dr. Stephen Liu:
So because the EGFR status changed our plan so dramatically because we went from all on board for the immunotherapy to really staying away from immunotherapy, Susan, what do you do if the biopsy does not have enough tissue? If our bronchoscopist performed a fine-needle aspirate enough to tell us adenocarcinoma, enough to stage, but not enough to do our molecular testing, what do we do then?
Dr. Susan Scott:
That's a great question, and this actually comes up quite frequently in the clinic. So I often consider a repeat biopsy, particularly in patients who've never smoked because I want to make sure we get it right the first time. But if that's not feasible or not kind of in line with the patient's goals, I think the neoadjuvant chemotherapy is a reasonable option here. It's helpful to know everything upfront. The other option would be the upfront surgery, but I don't usually offer immunotherapy because I could always give that in the adjuvant setting to a patient without knowing their molecular status, particularly if they have never smoked.
Dr. Stephen Liu:
But imagine the patient that really is worried this cancer is there. Tina, I imagine that sometimes the patients are very anxious to begin therapy and maybe threatened with driving across town to another oncologist. And so if you tell them, "We need another biopsy," and they say, "You've waited 3 weeks to get these results, we need to move on this. We need treatment today." What do you tell that patient?
Dr. Tina Cascone:
Yeah, this again happens. It's another scenario that happens quite often and it's quite understandable, right? There is a lot of emotions that go with initiating therapy and we have to be very respectful of these emotions and again, embrace them in how we develop that treatment plan. So oftentimes I agree with Susan, I tend to re-biopsy if possible because that information is paramount to give the patient the right treatment. And I tend to explain that to them really with the data that might completely change the treatment of the disease and the outcome of the disease if we don't have the right treatment in place. At times, I do collect, I should say probably more often than at times, a liquid biopsy. This is a stage III with a 4R node, so perhaps the chances to detect a driver mutation due to shedding would be a little bit higher than what we have in a stage I. So I would be hopeful that without repeating a tissue biopsy, I could gather that information with a liquid biopsy. If they're squamous, that's a completely different setting. They're heavy smoker or squamous, that changes really my inclination to repeat a tissue biopsy and perhaps be content with a liquid biopsy.
In many situations, to answer the second part of your question, when there is really a desire to start treatment or there are symptoms that really need to be treated, I do start chemotherapy only in the neoadjuvant setting as I'm waiting for the molecular profiling to come back. I find that that strategy brings patient a lot of peace in that compromise.
Dr. Stephen Liu:
I agree, that's a clever strategy to use, chemotherapy alone. Because if you find there's no driver, we can add immunotherapy for the next three cycles and if not, we haven't burned any bridges and can just move forward with chemotherapy alone.
This particular patient received neoadjuvant cisplatin and pemetrexed alone for four cycles and then underwent a left upper lobe lobectomy. The pathology did show some treatment affect but largely viable tumor about 3.5-cm with persistent R4 adenopathy. And so Susan, what treatment do we recommend now? We're seeing the patient after surgical resection, we've completed neoadjuvant chemotherapy. What's our next move?
Dr. Susan Scott:
So I would recommend osimertinib at this point. I wouldn't give more chemotherapy. The patient's already received four cycles in the preoperative setting, and so that part of their perioperative treatment's complete. And then I would start them on osimertinib. I would typically re-scan and include a repeat MRI of the brain before initiating osimertinib because it's usually been a few months planning from the chemo and the surgery. And without seeing a major response in the surgical specimen, if they haven't had that preoperatively, then I would repeat that as a new baseline before starting osimertinib.
Dr. Stephen Liu:
And so the use of adjuvant osimertinib here based on the phase III ADAURA trial where 3 years of osimertinib daily improved disease-free survival and that did translate to an improvement in overall survival. And again, this is for EGFR-mutant specifically activating sensitizing mutations in exon 19 and exon 21. Tina, any role at all for neoadjuvant-targeted therapy?
Dr. Tina Cascone:
That's a wonderful question, Stephen, and I think we're all trepidating to see really the data that we hope will come out soon from the new ADAURA trial. We have seen neoadjuvant osimertinib alone in small scale phase II studies, but I think the new ADAURA trial that is really using the osimertinib alone, the chemotherapy plus osimertinib or the osimertinib alone in a randomized fashion prior to surgery will really give us the answer on whether do we need to implement the osimertinib with chemotherapy in the neoadjuvant setting. I'm very hopeful that the data will be compelling enough to the point that we can bring the osimertinib even earlier into the neoadjuvant space for our patients.
Dr. Stephen Liu:
Susan, you mentioned the use of adjuvant osimertinib here based on the ADAURA trial. What is your approach to the duration of osimertinib? Assuming it's well-tolerated, your scans all look good, how long are you giving treatment?
Dr. Susan Scott:
So I'm giving treatment for 3 years and stopping. However, in a patient like this with N2 disease, I'm very concerned about their risk of relapse. So I'm hopeful that more testing will come, MRD testing, more data to guide us here in risk stratification of how to take these patients off. When they come off of osimertinib, I watch them like a hawk. I scan their brain and their chest, abdomen, and pelvis every 3 months for the first year to make sure that if any recurrences occur, then we catch them as early as possible.
Dr. Stephen Liu:
Tina, a similar approach to duration?
Dr. Tina Cascone:
Overall similar. I have to say, if I can, I tend to continue if there is a very good tolerance and excellent performance status, if the patients are on board with continuation on therapy without really affecting their quality of life. If we look at the curves of DFS, really we see the initial drop after the 30, 36 months. This is something that I try to keep in mind as I tailor that decision to the patient treatment. If I can, I tend to continue, and if not, I really try to monitor as thoroughly as possible.
Dr. Stephen Liu:
I do think that all of us want the same thing. We're using empiric approaches to duration, but we would like it to be more informed and hopefully we'll have those accurate MRD assays that will tell us who needs more treatment and who doesn't and can safely stop.
I think our key clinical takeaways here, whenever possible, neoadjuvant chemoimmunotherapy should be offered for non-squamous non–small cell lung cancer only after EGFR and ALK status are known. If we see EGFR and ALK alterations, we really want to consider alternate strategies in EGFR-mutant non–small cell lung cancer. Neoadjuvant immunotherapy really should be avoided. Adjuvant osimertinib should then be considered after resection for EGFR-mutant non–small cell lung cancer, and then hopefully it continues to evolve and hopefully we'll develop new strategies in the near future.
This brings us to the end of the 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.
