Clinical Cases in Lung Cancer - Episode 12

Case 2: Treatment After Progression of EGFR+ NSCLC

Mark Socinski, MD: I think to Tim’s point, sometimes the molecular testing can take 2, 3 weeks, and the patient has time to see the radiation oncologist, have an opinion, and in this case SRS was done while she was awaiting molecular studies. I don’t think that that’s necessarily a bad thing, and Tim made all of the great points with regard to that. She was started on 80 mg of osimertinib daily, and she had a good partial response. Now unfortunately, 20 months later—remember the median PFS was about 18.9 months, so she’s spot on in terms of when we think she might develop some issues—she has some new liver lesions, she has a new brain lesion; she still retains an ECOG performance status of 1. What do you do now, Ed? You’ve got a lady who’s kind of wearing out her welcome on osimertinib, she’s got new disease in the brain and liver. Do you repeat testing?

Edward Kim, MD: Whenever there is progression on an existing therapy, we like to rebiopsy if possible. If there’s new or existing disease and it’s growing, that’s the first step. Liquid biopsy is also an option that we do, that’s less invasive. As was reported out of Massachusetts General Hospital years ago by Jeff Engelman and others, transformation to small cell that can occur in patients. We always try to get tissue first, because that can be up to 14%, 15%. Then that’s where we get artistic, right, Mark? If somebody has done really well, then we start dabbling, if there can be something added. I know some people are tempted to even add a VEGF sometimes, depending on the type of progression that occurs. I don’t think that’s something we characterize very well in the metastatic setting, is that there are different types of progression. Some make us very nervous and some make us less nervous. I’ve followed a patient who has progressed on a TKI for 3-plus years, and she was still hiking in the mountains and stuff. We don’t quite understand it, and there are different scenarios, but the academic answer would be that you could consider something like IMpower150 because it did include these patients who had an EGFR mutation or ALK translocation and gave them the 4-drug regimen with the chemotherapy, carboplatin/paclitaxel, and then gave them the VEGF plus the I/O. I think that’s the academic answer. I can’t say that I’ve done it that often, but it is out there.

Mark Socinski, MD: Yes, I also retest. Obviously, you have to be aware of histologic transformation. It’s a different clinical situation typically with rapid progression, you should be suspicious of histologic transformation to small cell. In the typical slow-progressing sorts of patients, which also is fairly common, I do test, but I often don’t feel good about testing because I don’t know that it’s informative most of the time. We got so used to retesting when we used the first-generation drugs because everyone was excited about finding T790M. That was a great story because we had osimertinib. Now that we use osimertinib first line, at least my understanding of the resistance mechanism is they’re all over the map with regard to things, and this C797S resistance mutation is not like T790M was, you know, 60% of the patients, it’s more like 8% to 10% of the patients, and I still don’t quite know what to do with that outside of a clinical trial.

You mentioned IMpower150, obviously a trial near and dear to my heart. One of the things that I struggle with is physicians who treat with the KEYNOTE-189 regimen, and these patients were excluded. It seems kind of intellectually dishonest to me. At least the scant amount of data we have, either with monotherapy or with chemoimmunotherapy, does not suggest that this population gets a great benefit from immunotherapy. Your comments on that, Ed?

Edward Kim, MD: Yes, I feel the same way, Mark. I’m not a big fan of doing KEYNOTE-189. I think if you don’t go with a VEGF-type regimen afterward, then it’s a chemotherapy-based regimen. You hope and pray that you find something on the repeat biomarker testing, but that’s generally the route that we will go as well.

Mark Socinski, MD: Let me ask Tim. I guess you could make the argument that this lady has oligoprogression, she has a couple of lesions in her liver and a single lesion in her brain. Back in the old days, we got some traction when patients were on erlotinib/gefitinib, and they didn’t want to go to chemotherapy. If they had 1 or 2 spots that were progressing, we’d typically zap them or resect them or something like this. What are your thoughts in a patient like this? Would you ever offer the patient focal radiotherapy? She seems to have a limited number of sites.

Tim Kruser, MD: It’s a great question. Of course, as you said earlier, there’s not a lot of room to wait in the brain. Normally we’re going to offer radiosurgery to a patient like this. I think the question more so is, is there value to trying to ablate other extracranial sites of progressive disease? There are some emerging data in that. Interestingly, at ASCO last year there was this SINDAS study out of China looking at up-front SBRT [stereotactic body radiation therapy] for molecularly driven EGFR patients, and it showed a survival benefit. Now, this was not the oligoprogression, this was up front, but it does speak to some value to debulking patients with a relatively modest volume of metastatic molecular-driven tumors. I think it’s an area that we’ll know more about in the coming years. I do think it’s entirely reasonable for oligoprogressive disease to keep them on the drug that seems to be working at most foci and add radiation in or surgical resection. I’m sure Dr Stiles has experience with doing some focal surgeries on these types of patients as well.

Mark Socinski, MD: Alright, this has been a great discussion. I think we’re going to end case 2 and then transition to case 3.

Transcript edited for clarity.