EGFR Exon 20 Insertion as a Therapeutic Target in Non-small Cell Lung Cancer - Episode 7

Key Findings from the EXCLAIM Trial

Experts review the toxicity of mobocertinib and further discuss the key findings from the EXCLAIM Trial.

Alexander I. Spira, MD, PhD, FACP: We talked a lot about the EXCLAIM study, the published data from Cancer Discovery. Do you want to talk briefly about the toxicity of mobocertinib?

Joel Neal, MD, PhD: Mobocertinib, in our experience, has much of the same toxicity that we expect from other EGFR TKIs [tyrosine kinase inhibitors]. Predominantly, there was diarrhea, rash, anorexia, or reduced appetite. There weren’t many problems in terms of blood counts, but we can see some LFT [liver function test] abnormalities, some pancreatitis, and the occasional pneumonitis, which of course we all fear. I’d say that predominant dose-limiting effect seems to be the diarrhea. The closest drug it’s analogous to is afatinib, or 1 that I have less experience with, dacomitinib. Both drugs, second-generation TKIs, were effectively dosed a little higher and had a lot of EGFR inhibitory effects. Often, patients will need loperamide together with their dosing to maintain the dose as high as possible.

Alexander I. Spira, MD, PhD, FACP: It will be interesting to see. The ultimate question that people are going to be asking is with amivantamab and its approval: how do they differ from each other? Amivantamab is a monoclonal, and I’d describe it to people—I don’t know how you would, Joel—as very similar to cetuximab, with rash. That’s a big thing, the acne-like rash. There’s certainly less diarrhea in the paronychia. It’s a unique issue of an infusion-related reaction, so if you treat myeloma, it’s very similar to the way daratumumab works, which I guess isn’t surprising, considering it’s made by the same company. There are a lot of infusion-related reactions; you have to split the first dose. It’s given weekly for a month, and then biweekly, so it’s a little more challenging. Everybody is going to have a different opinion—assuming both get approved—in terms of which 1 they like.

One has the advantages of oral delivery. One has the advantages of IV [intravenous] delivery. It will be mostly anecdotal experiences. You said it best: how do you combine things? Do you give 1 before the other? We need to do a lot of work and consider what happens when the drug stops working? What are the resistance patterns? Which drug works in that scenario? Do you give mobocertinib to patients taking amivantamab? Do you give amivantamab to mobocertinib patients? Maybe it’s 1 of these other new drugs. Black Diamond has a completely novel approach, different from some of the other small molecule TKIs. I don’t know, but for me, that’s where things are going, and the ultimate question is what are the roles for this in the front line? Amivantamab is being studied this in the frontline therapy. Mobocertinib is also being studied. What are your thoughts on how these drugs are going to end up?

Joel Neal, MD, PhD: In the frontline setting, you have to say, “What’s our comparator?” As we talked about, the comparator is probably carboplatin-pemetrexed, with or without bevacizumab, with or without immunotherapy. But carboplatin-pemetrexed, even by itself, is a fair comparator. If you think about the numbers for EGFR-mutant lung cancer, carboplatin and pemetrexed—we probably see response rates in the 30s to 40s. Progression-free survival is in the 6- to 7-month range from carboplatin and pemetrexed. It’s hard to envision a head-to-head study being superior, but that doesn’t mean it’s not a better option because their toxicity profile is far different.

Additionally, 1 should be active after the other. There’s no reason to believe that chemotherapy would be ineffective after frontline TKIs or amivantamab. Another strategy would be combining this with chemotherapy. For that, I looked to the FLAURA2 study. Of course, FLAURA2 was the osimertinib vs first-generation EGFR TKI study, where osimertinib had longer progression-free survival and higher, more durable responses. In FLAURA2, it’s carboplatin, pemetrexed, plus osimertinib. We have a fair amount of experience using those 3 together. Recently published in Clinical Lung Cancer was experience with combination chemotherapy plus osimertinib for patients with brain metastases that were trying to treat different departments.

In that study, they were remarkably well tolerated together. There’s no reason to think that mobocertinib in combination with carboplatin and pemetrexed—or maybe amivantamab in combination with carboplatin and pemetrexed, because cetuximab gets along with chemotherapy, so MET inhibitors should too—shouldn’t be compatible with chemotherapy and lead to more durable responses.

Alexander I. Spira, MD, PhD, FACP: I agree. It’s an interesting world because you can imagine all the different combos, how you can go forward, and which 1 is going to play out and which 1 is going to win. Certainly, some people will even talk about combining amivantamab with mobocertinib. I’m a little concerned about the toxicity there, but certainly, from a logical standpoint, it makes sense. You have monoclonal, you have a small molecule TKI, and you can get over some of the adverse effects.

One of the important things you just brought up is the brain metastases situation. Neither of these drugs—mobocertinib nor amivantamab—has shown a huge amount of CNS [central nervous system] penetration, leaving a big void there. Pemetrexed, as a chemotherapy, has modest activity, but perhaps that’s 1 of the best ways going forward, to combine these all. Time will tell, of course. It’s going to be an interesting time.

Joel Neal, MD, PhD: Yeah, I will point out J&J [Johnson & Johnson] has a lazertinib drug, which is felt to be pharmacokinetically much like osimertinib. It’s being tested in combination with amivantamab in the CHRYSALIS-2 study that we’ve opened at our site. That’s an intriguing combination because osimertinib did have activity in exon 20, and amivantamab is newly FDA approved. Maybe there will be some synergy between those 2 drugs or, as you said, between 1 of these other TKIs, specifically against exon 20.

Alexander I. Spira, MD, PhD, FACP: Exactly.

This transcript has been edited for clarity.