Dr. Melissa Johnson:
Welcome to The ASCO Post Roundtable Series on Optimizing Outcomes for Patients with Locally Advanced and Metastatic Non–Small Cell Lung Cancer. I'm Dr. Melissa Johnson, Chair of the Executive Thoracic Committee for SCRI, Director of the Lung Cancer Research Program, and a founding member of SCRI Oncology Partners. Joining me today are two of my colleagues. Dr. Velcheti?
Dr. Vamsidhar Velcheti:
Thank you, Dr. Johnson. I'm Vamsidhar Velcheti. I'm a Professor of Medicine at NYU School of Medicine and the Director for the Lung Cancer Program at NYU.
Dr. Helena Yu:
Hey, everyone. I'm Helena Yu. I am an Associate Professor of Medicine at Memorial Sloan Kettering Cancer Center in New York, New York. Happy to be here.
Dr. Johnson:
Today we will be discussing the treatment and management of non–small cell lung cancer with three patient case studies. Our final installment will focus on neoadjuvant therapy for the management of EGFR-positive lung adenocarcinoma. Case 3.
LG is a 75-year-old female, minimal smoker. During prep for colonoscopy, she was found to have an electrolyte abnormality and was admitted to the hospital. Scans incidentally showed a right upper lobe speculated mass, 3.3 by 2.8 cm with right hilar lymphadenopathy, 1.3 by 1.1 cm. Bronchoscopy with biopsies of both the hilar lymphadenopathy and the right upper lobe mass confirmed a diagnosis of adenocarcinoma consistent with lung primary. The hilar lymph nodes were also tested. One of five was positive for adenocarcinoma, and it was actually a 4R lymph node, so N2. NGS was performed first with a plasma-based test that showed PALB2, her PD-L1 level was negative, and tissue NGS showed an EGFR L861Q, with a low tumor mutation burden of 5.4. This case was brought to our tumor board. There's lots to unpack here, but the first question is, what neoadjuvant therapy should we give? Dr. Yu, maybe I'll start with you.
Dr. Yu:
Sure. I think a lot of tricky nuances to this case. Obviously a stage III lung cancer where we want to give some sort of neoadjuvant therapy before consideration of surgery. I think one key point is to do mutation testing in all patients preoperatively, but in particular for these people like never-smokers, where we really have a high pre-test probability of finding a driver mutation.
And so we find one, EGFR L861Q. This is an atypical EGFR mutation. It's a couple percent of all EGFR mutations. Actually, if we follow the label strictly, the approved drug for this in the metastatic setting is afatinib, but many of us in the metastatic setting would use osimertinib for these atypical mutations as well. And so, I think, for me, with a positive N2 lymph node, I know I want to give her chemotherapy, and in this setting, I actually would forego the immunotherapy and do the chemotherapy alone. There are some cases where I've even tried to throw the kitchen sink at someone and also give osimertinib if very high risk, but I think what would be standard would be platinum doublet chemotherapy.
Dr. Johnson:
In fact, that's what you told me to do at the time, and that's what I did. I gave three cycles of carboplatin and pemetrexed to this patient, and then we re-imaged. Unfortunately, at the time of resection, there had been no shrinkage. We went to the operating room, the cancer was resected. It was actually bigger than we thought, ypT3N1. There was no treatment effect. So, we think we got it all. But now what? What would be your recommendation, Dr. Velcheti, to do next?
Dr. Velcheti:
Yeah, this is a tricky one. ADAURA trial doesn't really apply here. It's atypical EGFR mutation. In the adjuvant space, a platinum is really poorly tolerated to begin with, and I think given that the related benefit here probably would be lower, I probably would not give adjuvant TKI here in this setting. The question about adjuvant IO, given that she's a never-smoker or EGFR mutation, I really would be hesitant to give adjuvant IO. So it's a really difficult situation here. I think she is at risk for recurrence given that she had absolutely no response at the time of surgery. But we don't have great options either.
Dr. Yu:
Yeah, I'll counter that. Again, these stage III patients, we know that they have a very high likelihood of recurrence, and so really thinking about, what else can we do to sort of decrease that risk of recurrence? And so, without positive margins, I wouldn't do radiation in this space, but she would be someone that I would at least discuss with adjuvant osimertinib. I think that we know that patients with L861Q respond to EGFR-TKI's, including osimertinib. That response might be slightly attenuated compared to the standard sensitizing exon 19 deletions or L858R. But when you see that nice disease-free survival reduction with this, if patient was willing and if we were able to get reimbursement, this would be someone that I would model adjuvant treatment on ADAURA and consider the osimertinib. Gray space, for sure.
Dr. Johnson:
This is a space where, absolutely, we're making it up as we go along. Actually, we were all so taken aback by her lack of response that I decided to push our tumor board towards a more definitive approach with chemo-RT, and so she reluctantly underwent 6 weeks of definitive chemo radiation with weekly carbotaxol. She did really well and came through with flying colors, although she did have some trouble swallowing for a time, needed Roxanol and Carafate and all the things that we do to decrease the risk of odynophagia.
She came to me recently having completed all of her therapy and said, "Am I done? Am I done now?" And so this is where we had the conundrum of post–chemo-radiation durvalumab vs osimertinib vs afatinib. As my colleagues have said, durvalumab does give us all a little pause because of the EGFR mutation, because she was a minimal smoker and the TMB being low, there's just no reason to think that the durvalumab would be able to harness the immune system. I was a little concerned about afatinib because of tolerance, and any maintenance therapy that we give has to be well tolerated. So I also chose osimertinib.
Maybe I'll ask both my colleagues, going back to the beginning of the case before any treatment at all, when this patient was treatment-naive, would it change things if she had had a classic EGFR mutation, Dr. Yu? If she had an exon 19 deletion or an L858R EGFR mutation? Would that have changed your choice for carbo-pemetrexed neoadjuvant therapy?
Dr. Yu:
I think it wouldn't have changed my choice on chemotherapy neoadjuvantly, because we do have the data there that can downsize people and get them to a successful resection. But the question would be, would I add something to that? I think there was provocative data by the Stanford group at ASCO last year that osimertinib alone actually was not good for a short period of induction. Osimertinib was not helpful in kind of getting major pathologic response in patients. So that, again, feeds to the fact that I would want the chemo.
But just having had a different case in that it was a classical mutation, it was an adenosquamous, it was much bigger, it had bulky N2 disease, in that setting where I wasn't sure how well she was going to respond to chemotherapy, that's someone that I did add osimertinib to neoadjuvantly. Not a lot of data there. And then other cases, if I've done four cycles of upfront chemo and after two I've seen pretty minimal response and I've known EGFR status, I have added it in a little bit early, just wanting to get as much shrinkage prior to resection, but I fully appreciate that those are not strongly data-driven, but hopefully we'll have that data soon.
Dr. Johnson:
Yeah. Dr. Velcheti, any other thoughts or trials that you're looking forward to that will help us understand this neoadjuvant EGFR space a little bit better?
Dr. Velcheti:
Yeah, I think the neoadjuvant space, especially for EGFR, is a little complex because, obviously, lack of data, but also the challenges that come along with radiation in this setting. If you give chemo-radiation, you are a little worried about giving adjuvant osimertinib following radiation. So I have been, again, without much data here, but if somebody has a locally advanced lung adenocarcinoma with a classic EGFR mutation, I probably would do a chemo plus osi and could consider, if there's an adequate cytoreduction, they may potentially even be candidates for surgical resection or maybe consolidation radiation with a break from TKI. It's possible. I think I would prefer surgical consolidation if we can achieve that.
Dr. Johnson:
I think those are really good points that I have struggled myself with trying to add a TKI after chemo-radiation. Chemo-radiation is one of the most difficult therapies that we prescribe, right? Because patients have to be coming daily for 6 or 7 weeks, everybody gets inflamed, whether they have a history of bronchospasm and smoking or whether, like this lady, they are minimal smokers. So to find a way to bring the chemo and the TKI upfront followed by the ablative treatment or the surgery is a really creative idea that I like a lot.
Let's summarize the key clinical takeaways for this case 3, an uncommon EGFR mutation. Remember that common EGFR mutations, exon 19 deletions and exon 21 L858R mutations, encompass the vast majority and only 10% are going to be these uncommon mutations like the L861Q that we talked about today. For these patients, osimertinib is an acceptable choice for all EGFR mutations in the metastatic setting, but it is only approved for common EGFR mutations in the adjuvant setting. By contrast, neoadjuvant use of osimertinib in patients with EGFR mutations, common or non, is not yet approved, is a provocative idea, and we are still trying to figure out the best way to sequence therapies for these patients to bring about the most optimal outcome.
This brings us to the end of case 3. Please see the other segments for further discussion about the latest research in non–small cell lung cancer or visit ascopost.com.
