Dr. Suresh Ramalingam:
Hello. Welcome to Optimizing the Care Continuum for EGFR-Mutant Non–Small Cell Lung Cancer, an ASCO Post roundtable. I'm Dr. Suresh Ramalingam, Professor of Hematology and Oncology, and Executive Director of Emory Winship Cancer Institute. Today, I'm joined by two esteemed guests, Dr. Zosia Piotrowska and Dr. Helena Yu, and I'll call upon them to introduce themselves. First, Dr. Piotrowska.
Dr. Zosia Piotrowska:
Hi, everyone. I'm Zosia Piotrowska, a thoracic medical oncologist at Mass General Brigham Cancer Institute here in Boston. Nice to be here.
Dr. Helena Yu:
Hi, everyone. I'm Helena Yu. I'm also a thoracic medical oncologist at Memorial Sloan Kettering in New York.
Dr. Suresh Ramalingam:
Thank you, Helena and Zosia. It's great to have you both. Our case will focus on the management of acquired resistance after first-line osimertinib-based therapy in EGFR-mutated non–small cell lung cancer.
So let me introduce the patient. This is a patient who is a 64-year-old male who actually was diagnosed with stage I lung cancer in 2019. This was an incidental pickup that was made when the patient went for an unrelated medical issue, and thankfully, this was picked up and he ended up having a right upper lobectomy in 2019. And the clinical stage was T1c N1. He had a hilar lymph node positive, and that was the reason for the N1 status.
At that time, the patient had molecular testing done and we knew that he had an EGFR exon 21 mutation. This was before the days of ADAURA, so this patient was treated with four cycles of adjuvant cisplatin and pemetrexed.
And since then, he has been on regular follow-up, and everything looked very good, no problems, until in 2024 when he was about to hit the 5-year milestone from his surgery. Unfortunately, he presented with progressive dyspnea, and on evaluation, he had a large right-sided pleural effusion. We did a therapeutic thoracentesis, and that revealed malignant cells on cytology, and this resulted in subsequent workup. He had a pleural biopsy that confirmed that he had recurrent lung adenocarcinoma. It showed the same EGFR L858R mutation that he had.
We did a PET scan as you can see from the images. He had pleural disease in the right hemithorax and he did not have any extra thoracic disease. So we started him on osimertinib plus chemotherapy for recurrent disease, and even though he responded initially, he progressed within 11 months, and the progression was once again in the pleural space. And at this time, we did ctDNA analysis in his peripheral blood and it showed the same L858R mutation. There was no other molecular abnormality detected.
His performance status is still good, and obviously, the question now is what's the next line therapy for this patient? So let me first start with Helena Yu as to how you approach a situation like this.
Dr. Helena Yu:
Yeah, I think there's a lot of interesting points to this case. Of course, this patient got chemotherapy twice. I think initially after perioperatively or postoperatively after his resection, and then of course, received the FLAURA2 regimen. I think the first thing to distinguish is was the patient on chemotherapy plus osimertinib when he progressed or was this many months later when perhaps he was on just osimertinib and had a chemo-free interval? And because his progression-free survival was short, 11 months as you mentioned, and he was presumably still on the pemetrexed maintenance therapy.
So I think in that setting, I wouldn't think about one of our standard second-line therapy regimens, which would be potentially retrial of chemotherapy, maybe with continuation of osimertinib or adding in amivantamab, the EGFR-MET bispecific antibody based on the MARIPOSA-2 regimen.
You did mention that he got a liquid biopsy that did not show any acquired alterations. We know that acquired alterations after first-line osimertinib are more infrequent, but we do see them in about 20% of cases. I think in this case, especially with the more quick or rapid progression on the regimen, I would think that I would first want to get a tumor tissue biopsy if possible. He has that effusion that we can see on imaging, so I think one thing for both symptomatic and maybe diagnostic benefit would be to get a thoracentesis and see if we can get some next generation sequencing on that biopsy, so that would probably be my first step.
Dr. Suresh Ramalingam:
Zosia, how do you approach this situation?
Dr. Zosia Piotrowska:
Yeah, I agree. I think this case highlights several important points and I fully agree that I think repeating the molecular testing would be important, particularly given the relatively short duration of response to the FLAURA2 regimen. I think this is much shorter than what we typically would see with the FLAURA2 regimen, where in that study, we saw median progression free survival exceeding 2 years. So 11 months feels quite short, and it raises your antennae to think about whether there might be an underlying resistance mechanism that might be driving this.
Liquid biopsies are helpful when they're positive, but I think we have to keep in mind that they're potentially not as informative as doing tissue- or cytology-based analysis to more directly analyze, and specifically things that I would be looking for would be, one, the possibility of a histologic transformation, so a transformation to a small cell carcinoma, which can sometimes occur even to a squamous cell carcinoma from an adenocarcinoma, and that of course is not something that we can detect on liquid biopsy.
We know that there are certain molecular features, which this patient doesn't seem to have, that can increase risks. So for example, co-mutations in p53 and RB1 together with an EGFR mutation significantly increase the risk of histologic transformation, but keep in mind that even if you see those co-mutations on a liquid biopsy, it doesn't necessarily tell you whether that transformation has or has not occurred. So I think doing a thoracentesis, sending that pleural fluid cell block to look at both histology and repeat the NGS testing. I'd also be curious if this patient could have med amplification, which is today really one of the most targetable findings that we can find at the time of TKI resistance.
We know that patients with high-level MET amplification can benefit from the combination of an EGFR and MET inhibitor. We've seen that across a number of studies using drugs like savolitinib and tepotinib and others, and so for a patient who had a MET amplification, we might think about either enrollment on the clinical trial if available, or sometimes, even off-label use of a MET inhibitor, although that's not yet an approved regimen, so keep that in mind.
But I think looking for those is always important and helps us really explore any potential targeted options that we may have, even if at the end of the day, it's likely that we'll repeat that testing and we won't find a targetable resistance mechanism, in which case, then we have to go down our pathway of non-targeted treatment options for a patient like this.
Dr. Suresh Ramalingam:
So we attempted to get that information, the pleural fluid. We actually ended up with the pleural catheter to manage his pleural fluid. Our thoracic surgeon did not want to go in again into the chest and, in the setting of recurrent pleural effusion, create some potential down the road problems. So we did not have the option of biopsy, but certainly, the pleural fluid did not give us any additional information, so this is all you have.
He was getting pemetrexed, but he was beginning to get tired of it. The fatigue was increasing and he was no longer enthusiastic about going on another chemotherapy-based regimen.
Dr. Helena Yu:
I think that that is what we see. I think with pemetrexed, we can see that progressive kidney dysfunction, edema, and just fatigue that wears on people over time. This would be someone that, again, I wouldn't do a repeat of carboplatin and pemetrexed anyways, obviously because he had just progressed while still actively on pemetrexed.
I guess the most likely thing that I would probably recommend, but would have to talk through with him because it is in some ways chemotherapy, would be some of our antibody-drug conjugate options. As we know, those are I call them hybrid medications, where they are part chemotherapy, obviously part targeted therapy with the antibody.
You didn't mention, I don't know if the patient could have gotten MET or HER2 IHC testing. That would open doors potentially for MET-directed or HER2-directed ADCs, but in light of those not being done or possibly done or negative, we do have a new option for patients with EGFR-mutant lung cancer after progression on osimertinib and chemotherapy. That would be datopotamab deruxtecan, the TROP2-directed ADC. And so that would probably be something, as long as he was willing to tolerate the toxicities of an ADC that does have some of the standard chemotherapy toxicities like cytopenia, fatigue, nausea, also some unique toxicities with the TROP2 target of mucositis, eye toxicity like keratitis. But in terms of what would give him potentially the most benefit or likelihood of benefit, that would be what I'd recommend as next line therapy.
Dr. Suresh Ramalingam:
It's interesting you mentioned that, because as it turned out, the time he developed this acquired resistance was just a few weeks after the approval of datopotamab, and that's a conversation I had and we started him on datopotamab, and he got the 6-mg dose with cycle 1. He had some mucositis issues, and then for cycle 2, we dose reduced, and he's now received 7 cycles. He's had a good clinical response and is tolerating it very well, so he continues to go on suggesting the utility of some of the more recently approved options in the second-line setting.
So Zosia, let me ask you this question. Would you consider continuing the osimertinib for this patient along with whatever salvage therapy option you use?
Dr. Zosia Piotrowska:
I think that it really depends on what that salvage therapy is going to be. I think we have historically really thought that continuing TKI's for some patients can be beneficial. I would say mostly, we think about that as most important for patients who've had brain metastases at initial diagnosis where those brain metastases remain controlled but they have systemic progression. In those patients, we've sometimes seen that if you stop the TKI, their brain, they can develop CNS progression that you can prevent by continuing the TKI.
And so for those patients, as Helena alluded to earlier, I think particularly when combining with cytotoxic chemotherapy, we will often continue the TKI and add, whether that be platinum pemetrexed or later-line chemotherapy agents. We have less data for combining newer drugs like datopotamab with osimertinib. We do have a little bit of data from the ORCHARD trial where osimertinib and datopotamab were combined, and we saw, I would say overall, that the toxicity profile was similar, but it's still relatively small studies.
And so I personally, for a patient starting on datopotamab who doesn't have a specific reason, like the CNS situation I just described, I would be wary of combining and the potential additive toxicities of the TKIs. But I think this is a question that's coming up a lot in practice and I think it will continue to come up. It really speaks to the importance, I think, of doing these studies and looking at the safety of new drugs and new combinations together with TKIs and trying to generate as much data as we can. Because I think all things being equal, if possible, we like to have the opportunity or the option to continue TKI therapy, but I think for your patient, I'd probably feel comfortable with datopotamab and be very happy to have that as an option. Because prior to the approval of datopotamab, really, all we would have for a patient like this in terms of approved therapy would be single-agent chemotherapy, which we know has a lot of toxicities, but really pretty modest efficacy.
Dr. Suresh Ramalingam:
Great. So as we wrap up, let me ask this last question, ask you to chime in quickly for this, which is we all work in academic settings. There are clinical trials. When we get a rebiopsy, we can potentially steer the patient towards an option that's more likely to theoretically work on a clinical trial. What do you recommend for an oncologist who perhaps does not have all of this ability to get a biopsy? What are situations where you would say you should get a biopsy in this clinical situation for a patient who's developed acquired resistance? Helena?
Dr. Helena Yu:
Yeah, I think that Zosia brought up this point earlier. I think exactly a case like this where the benefit was lower or shorter than expected. I think if there's a very significant uptick in the disease where the progression is multi-site and you feel like something or the tempo has changed of the cancer, those are cases that I am worried about histologic transformation, so I would consider that.
But I would counter that by saying that at an academic center, because we do biopsies very frequently, I also have many cases where I've been surprised with the histologic transformation where it may be it was just one site that increased, but with biopsy, I do see mixed histology where there's a mix of adeno and small cell. So I'd say liquid biopsy on everyone, and if there is a area of disease that's easily accessible and safe for the patient and liquid biopsy is unrevealing, I would try to recommend tumor tissue biopsy and all.
Dr. Suresh Ramalingam:
Great. Zosia, anything to add to that?
Dr. Zosia Piotrowska:
Yeah. As I mentioned earlier, I think also keeping an eye on the co-mutations, so patients with P53 and RB1 co-mutations, if you see those, even at the time of initial diagnosis, those patients have a much higher risk of transformation. And for those patients, I would say, Helena, I've had the same experience too where I've sometimes been surprised. I didn't really clinically suspect small cell, and yet that's what the pathology came back at, or a mix of both adenocarcinoma and small cell histology. And so I think for patients with those co-mutations in particular, I think tissue biopsies can be really important, because sometimes you can identify something that will really impact you choose your chemotherapy regimen for that next line of therapy.
Dr. Suresh Ramalingam:
Great. So this has been a great discussion. Let me summarize this for our audience. I think the treatment options in the setting of acquired resistance to EGFR tyrosine kinase inhibition can broadly be either mechanism-based or mechanism-agnostic approaches. The conversion to small cell histology as a potential acquired resistance mechanism is something we need to keep in mind. A new agent like datopotamab deruxtecan has response rates of nearly 40% in this patient population and adds to the ability to extend patients' quality of life through this novel option.
This brings us to the end of this case. Please see the other segments for further discussion about the latest research in lung cancer or visit ASCOpost.com. Thank you for joining us.
