EGFR Exon 20 Insertion as a Therapeutic Target in Non-small Cell Lung Cancer - Episode 4

Current Treatments for EGFR Exon 20 Insertion+ NSCLC

Joel Neal, MD, PhD, and Alexander I Spira, MD, PhD, FACP, review current treatments for EGFR Exon 20 Insertion+ NSCLC, their preferred treatments, and current clinical trials.

Joel Neal, MD, PhD: Let’s go into treatment approaches. We covered a bit about how the patients have been treated historically, but I think it‘s worth going into our treatment approach in the first-line setting. Alex, what do you offer patients with newly diagnosed EGFR exon 20 insertion that you found before you started other treatment? That’s 1 of the keys—waiting 2 or 3 weeks for the mutation results for those patients with high-probability EGFR mutations. What’s your preferred therapy? Let’s say there’s a patient with a couple of tiny brain metastases, at 3 mm or so—not a large burden in the middle of the lungs, adenocarcinoma.

Alexander I. Spira, MD, PhD, FACP: I’m a carboplatin-pemetrexed person. I’m sure most of us are. I usually shy away from the I/O [immuno-oncology] agents. There aren’t a lot of data in this situation, obviously, but I expand on what’s known about the exon 19s and exon 21s and that immunotherapy really does not work that well in that population. I usually just treat with double chemotherapy. I’m sure some treat with triple therapy. Maybe you do, as I said, and you’re not going to be wrong in either situation.

For people with minimum brain metastases or very small metastases—2 or 3 mm—there’s enough penetration from pemetrexed that you can at least hold off on the radiation. But if anybody has a bigger 1, I usually just give them stereotactics, which is the standard of care for most people these days. I can’t tell you the last time I did a whole-brain scan on anybody except at the end-of-life stages. For me, it’s treating carboplatin-pemetrexed. On the second line—I guess selfishly—we’ve been very lucky because we have some of these exon 20 drugs in trial, as did you for 3 to 4 years. I haven’t had to give standard second-line therapy, which for me would be docetaxel, a drug we all hate to give for obvious reasons. How about you?

Joel Neal, MD, PhD: My first line approach—we do steer a little more toward the bevacizumab and the antiangiogenics when we can when treating these patients. They’re often young and relatively fit, so the bevacizumab probably increases the response rate slightly. They increase the progression-free survival certainly. We’ve seen a lot of data for EGFR exon 19 and L858R with the combination of TKIs [tyrosine kinase inhibitors] plus antiangiogenic therapies boosting that. John Heymach always says that the strongest predictor of response to antiangiogenic therapies—the only real predictor that we found despite 15 years of research—is the presence of EGFR mutations. These really do, biologically, behave similarly, and I try to give the bevacizumab when I can.

I don’t give immunotherapy. I don’t favor a 4-drug approach using pemetrexed because there’s no FDA approval for carboplatin, pemetrexed, bevacizumab, and any checkpoint inhibitor together with it. You could consider potentially the IMpower150 trial regimen, which is carboplatin, paclitaxel, bevacizumab, and atezolizumab, but the paclitaxel has a lot of negative adverse effects associated with it and of course less CNS [central nervous system] penetration than the pemetrexed does. Carboplatin-pemetrexed is viable for sure, and with bevacizumab, when I can do it, I do in the first line.

In the second line, it’s a debate between the immunotherapy, which is tempting, and may work in some patients—maybe a PD-L1 level would sway me some 1 way or the other. Or there are also docetaxel, docetaxel-ramucirumab, gemcitabine, and drugs like that. With the SRS [stereotactic radiosurgery] question, often times, I’ll refer patients just so other practitioners can keep an eye on patients together with me. Patients will say that the radiation oncologist and neurosurgeons will say, “How good is your drug?” They may say, “It might work, it might not.” The main reason I would tend to radiate patients was to make them eligible for second-line clinical trials, because sometimes patients have “untreated” brain metastases, and we’ve never radiated them in the past. They went away, but we would figure they’re going to grow back if we start something without good CNS coverage.

Alexander I. Spira, MD, PhD, FACP: That’s good point, and I would have done that myself in anticipating the second-line clinical study. Very much like you, I’m not an IMpower150 trial regimen fan. It dramatically affects the quality of life between neuropathy, in all patients. It’s just the general malaise of therapy. The bevacizumab story has been a long story, coming out of [The University of Texas] MD Anderson [Cancer Center] and John Heymach. We’ve heard, in just 1 of these stories, that you’re just waiting for that book to close. Either everybody is going to read it, or everybody isn’t going to read it. It’s still 1 of those things that people are very opinionated about.

Joel Neal, MD, PhD: Fortunately, we don’t have just those therapies. For the problems with CNS metastases and progression that we talked about at the beginning of the program, there are a few new emerging molecules; they are really exciting, in terms of directly treating EGFR exon 20 insertions. First, what was your experience? Did you ever try other TKIs—first-, second-, and third-generation TKIs—in the treatment of exon 20 insertion lung cancer and have any responses?

Alexander I. Spira, MD, PhD, FACP: I’ve never tried them myself. I’ve had some people referred for the clinical studies. We participated, as was the deal in the mobocertinib clinical study, and the afatinib clinical study. I’ve had people who’ve received those off-label. Most do not, notably because the physician didn’t realize that it was an EGFR mutation that did not tend to respond to those. They just saw an EGFR mutation and said, “Look, it didn’t work.” That’s probably more common than you’d think, but I’ll tell you from my anecdotal experiences that it’s usually 1 scan and then they move on. Although I think there are some data—maybe you want to talk about a higher-dose osimertinib because there are a little data there. There’s nothing earth shattering yet.

Joel Neal, MD, PhD: That’s right. My recollection is that we were excited, originally, about afatinib, because afatinib followed lorlatinib. Gefitinib was a second-generation drug that irreversibly bounced, so that was tested. As I recall, the progression-free survival was maybe 3 months, with a few patients having a transient response but not a lot of response. Despite afatinib’s approval in atypical mutations, it’s not that active in EGFR exon 20 insertion lung cancer. Regarding osimertinib, Zosia Piotrowska [from Massachusetts General Hospital] led an ECOG cooperative group study, and I believe 4 of 17 patients responded to 160 mg daily of osimertinib, a higher dose than normally would have been tested. Off-label, without any other treatment approaches, outside a clinical trial, it wasn’t a bad option. But it certainly didn’t have high enough response rates to say this is something we routinely recommend.

Alexander I. Spira, MD, PhD, FACP: That story came about with the advent of mobocertinib and some of the other drugs as well, so if it was out there a year or 2 before, it might have made a lot of headlines. I think it was overshadowed by some of the newer drugs.

This transcript has been edited for clarity.