EGFR Exon 20 Insertion as a Therapeutic Target in Non-small Cell Lung Cancer - Episode 6

Amivantamab and Poziotinib as Treatment Options

Joel Neal, MD, PhD, and Alexander I Spira, MD, PhD, FACP, review amivantamab and poziotinib as other treatment options for EGFR Exon 20 Insertion+ NSCLC.

Alexander I. Spira, MD, PhD, FACP: We’re talking about mobocertinib, but it’s not the only drug in the class. This isn’t the only drug targeting exon 20. There’s a little plethora of riches with some other drugs.

Joel Neal, MD, PhD: From the beginning, I alluded to the recent the FDA approval of amivantamab. Amivantamab was a surprise to all of us. I’m not sure if we still know how it works, even though we know what the structure of the drug is. Nobody expected it to work in EGFR exon 20. It seems to have some activity in other EGFR-MET lung cancer too. It is a bispecific antibody. Half of it binds to EGFR, and half binds to c-MET. MET, as we know, is 1 of the mechanisms of acquired resistance to EGFR inhibitors that are seen as often as often as 10%, 20%, or even 30% of the time, depending on the patient population that you’re looking at. This EGFR-MET bispecific antibody took us all by surprise because we tested plenty of EGFR antibodies: cetuximab and necitumumab, with or without EGFR TKIs [tyrosine kinase inhibitors]. They were modestly active and fairly toxic—a lot of rashes, diarrhea, and other problems. The c-MET antibodies have been tested as well. Separately, they didn’t seem to have much effect, but there’s something about this bispecific antibody that does seem to work as a class effect against EGFR mutations, working on just the cell service. The CHRYSALIS study that led to FDA approval had a 40% response rate and an 8.3-month progression-free survival [PFS], so it was very similar to what we reported from the mobocertinib clinical trial program early on. It was the first drug, although probably not the last. We expect other FDA approvals soon, maybe even mobocertinib for this patient population, because there was such an unmet need.

Alexander I. Spira, MD, PhD, FACP: It’s interesting. I’ve asked some of my colleagues who worked on amivantamab, “Why do you think it works?” I haven’t gotten a really good answer from them. As you said, we’re all pleasantly surprised because it’s a class of monoclonal that makes amivantamab special compared with cetuximab and some of these other drugs. Obviously, we don’t know, but it works, which is great. There are some other drugs coming on the pipe. You want to talk a little about poziotinib?

Joel Neal, MD, PhD: Poziotinib was another early on EGFR exon 20 inhibitor that had activity on the HER2 [human epidermal growth factor receptor 2] exon 20 insertion mutation patient population. That test was led by [The University of Texas] MD Anderson [Cancer Center], and the early clinical trial showed response rates that were higher, in the 30s/40s. Another AACR [American Association for Cancer Research] trial reports that the response rate, the PFS, was a little lower, at 15%, and there was 5.5-month progression-free survival a year ago. We were a bit disappointed. Since then, the ZENITH20 trial—as shown in patients who were untreated, around 80 patients—response rates are closer to 30%. We’ll get into the toxicities of mobocertinib and potentially amivantamab, but poziotinib certainly appeared, in clinical trials and anecdotally, to have more rash, more diarrhea, and more mucositis. There seemed to be some tolerability issues. On a personal experience, I’m reading that the twice-daily dosing seems to be better tolerated, and they’re moving forward with that.

Alexander I. Spira, MD, PhD, FACP: Yeah, poziotinib has an interesting story because it was the first in its class. Poziotinib is a resurrection of an old drug that was just sitting on the shelf, and they found it had some activity. It’s a tough drug. I don’t know if you’ve ever given it, but I’ve given it. It’s a tough drug, but it may resurrect itself with this twice-a-day dosing. We have a lot of new drugs. Once there is 1, there will be a few others. CLN-081 is another drug in this class that’s finishing its phase 1 trial. Black Diamond has 1 [BDTX-189]. There were just some updated data from a DZD compound and DZD-0008 that were published recently at ASCO [American Society of Clinical Oncology Annual Meeting]. If we’re going to have a plethora of riches, it’s going to be a little challenging to finish some of these studies because we already have 1 approved drug; there will be other ones. We’re trying to figure out where these other drugs are going. Are they going to be better? Are they going to be the same? What are people going to think about? The comparisons about where they fall about are interesting.

Joel Neal, MD, PhD: We also need to keep an eye on tarloxotinib, which is a little unusual because it’s in IV [intravenous] formulations and hypoxia induced, so it’s activated in the hypoxic environment of the tumor, leading to an IV drug. It’s like a TKI. There are a bunch of TKIs that we’ve talked about, and then there are bispecific antibodies. There are a lot of approaches, and I’m wondering about future combinations. If more than 1 goes forward, will 1 of these drugs show activity after the other? It can go both ways if a drug is different enough.

Alexander I. Spira, MD, PhD, FACP: Right. Then of course, as these drugs form a uniform, they’re going to be proving what second line will look like. What happens to the front-line setting? That’s the big unknown, and there’s a lot of room to figure this out.

This transcript has been edited for clarity.