Treatment of TKI-Refractory EGFR-Mutant NSCLC

Heather Wakelee, MD, and Stephen Liu, MD, review the treatment of TKI-refractory EGFR-mutant NSCLC.

John V. Heymach, MD, PhD: We had some interesting new studies in the refractory setting, specifically the osimertinib-refractory setting. Heather, do you want to tell us about the CHRYSALIS study?

Heather Wakelee, MD: The CHRYSALIS study is a study that we’ve heard about a few times, but it’s interesting because it’s a single agent and a combination. The single agent, which we’ll talk about first, is amivantamab. It’s now approved in the United States for patients with EGFR [epidermal growth factor receptor] exon 20. It’s a bispecific hitting both EGFR and MET, so it’s exciting in that way and definitely with some activity. This study also combines it with lazertinib, another third-generation EGFR TKI [tyrosine kinase inhibitor] not much different from other ones we have except it’s made by the same company, so that makes the combination a little easier in the trial setting. What we saw in the updates from our big meetings of the summer were the primary CHRYSALIS study, which was looking at amivantamab alone or with lazertinib in patients who had previously had osimertinib. It’s a much bigger study, but the reports were on that subgroup.

With the amivantamab alone post-osimertinib, we saw a response rate of 19%. That’s pretty respectable. Some of them were for longer term. When you add in the lazertinib, that response rate jumps even higher, so it’s up to 36%. One of the caveats that’s important to note is that the combination is more effective in the brain than the antibody alone. The antibody alone can work in the brain, but when you add in the third-generation TKI, as expected, you got better brain activity. That’s 1 thing to keep in mind as we’re trying to choose. There are some relatively long durations of response.

There was a related study, CHRYSALIS-2, looking at giving the amivantamab and lazertinib to patients who had had not just osimertinib but also some chemotherapy. In that group, the response rate in patients who had had only 2 lines of prior treatment—who had gone from osimertinib to chemotherapy to the trial—was around 40%. That’s pretty similar to what we got immediately post-osimertinib, so putting in the chemotherapy alone didn’t seem to matter. In much more heavily pretreated patients—many, many lines—the response rates dropped down closer to 20%.

Overall, 40% response rates with this combination is exciting. If we think about prior combination regimens—EGFR TKI plus EGFR antibody—in those trials, the response rates were a little lower than what we’re seeing when you add in the MET. There’s been a lot of interesting work showing that depending on what the resistance mechanism is. Thus, if it’s MET dependent, if it’s EGFR dependent, then those response rates are higher. If it’s unknown, they’re pretty good. If it’s clearly something else, then this doesn’t work that well. We’re going to be seeing more of this. It’s certainly something I’m starting to wonder about in my clinical practice.

John V. Heymach, MD, PhD: Coming up on a 40% response rate, that’s pretty exciting. If those data were to hold up and this regimen were approved, and you had somebody progress on osimertinib, would you go toward this or toward chemotherapy next?

Heather Wakelee, MD: That’s the question. Obviously, we’d like to know the resistance mechanism, and if it’s something that’s EGFR or MET in a way where this is going to be 1 of those higher response rates, then I’d go there. I’m still a believer in chemotherapy, especially chemotherapy plus VEGF [vascular endothelial growth factor] inhibition. It’s a discussion with the patient because this is 1 of those things where it’s not that you’re going to use 1 and never use the other. Ideally, you’d use 1 and then go to the other, so it’s about that sequencing.

It’s important to note that amivantamab does have some toxicity, particularly the first infusion. There’s a high rate of infusion reactions, so you have to premedicate, you have to make sure the nursing staff in your infusion center is ready and poised. We’ve had to call for emergency responses. Once they get through that first cycle, and we split the dose so they get a day 1 and day 2, then it goes to everything altogether and they seem to be fine. But that first-day infusion reaction is a little hairy, so it’s important that everybody is ready for that. That’s 1 thing I worry about with this drug as it gets broadly used if people aren’t as accustomed to it and haven’t prepped the patient adequately for it. We’ve had some rashes that were impressive, so we have to be cautious. For many people it’s been well tolerated, but if we compare that vs chemotherapy, sometimes chemotherapy is pretty well tolerated and sometimes it’s horrendous. We’re trying to figure out the best option for an individual patient.

John V. Heymach, MD, PhD: Yes, we’re used to dealing with adverse effects—for example, from Taxol—and dealing with those infusion reactions. But that’s a broad range of patients we’re treating with it. Here, in most clinics, this is something where the teams aren’t going to have as much experience. It’s certainly going to take some education.

Heather Wakelee, MD: Exactly.

John V. Heymach, MD, PhD: A study that surprised a lot of people—it came a little out of nowhere, Stephen—was the treatment of the HER3 [human epidermal growth factor receptor 3] antibody conjugated to patritumab deruxtecan in EGFR inhibitor–resistant disease. Do you want to talk about that study presented by Pasi Jӓnne and colleagues?

Stephen Liu, MD: This wasn’t on my radar either. Patritumab deruxtecan is an antibody-drug conjugate. We’re seeing a lot of those enter the discussion, a lot of impressive activity. As you mentioned, this targets HER3, so it’s a HER3 IgG1 [immunoglobulin G1] linked to a topoisomerase 1 inhibitor. This was a dose-escalation expansion study, ultimately settling on a dosage of 5.6 mg/kg every 3 weeks. It looked at 57 patients with EGFR-mutant lung cancer who all had prior osimertinib. Most, 91%, had also had prior chemotherapy. About 40% had prior immunotherapy, so pretty heavily pretreated. The results were pretty impressive. They saw a response rate of 39%, which is certainly encouraging, plus a disease-control rate of 72% and a progression-free survival of 8 months, which is very respectable.

As Heather mentioned, resistance is heterogeneous, and we’re looking into the details, the mechanisms, maybe treating MET, or definitely treating RET. What was interesting is that they saw efficacy across various mechanisms of resistance, sort of a utility player. In addition, they also saw efficacy across the spectrum of HER3 protein expression, and so it wasn’t that the high expressers did better. We’re still learning what the best predictive markers are for antibody-drug conjugates. But the drug seemed safe. The ILD [interstitial lung diseases] rate is certainly a concern for antibody-drug conjugates—only 5%, and only 1 of those was grade 3. Now, it’s being explored post-TKI. It’s also being explored post-osimertinib in combination with osimertinib. As Heather mentioned, sometimes we need that TKI to get better CNS [central nervous system] coverage. More to come, but that’s certainly an impressive signal.

John V. Heymach, MD, PhD: HER3 has not been on our radar in lung cancer. In breast cancer, you’ve got pertuzumab, which prevents dimerization, HER2 [human epidermal growth factor receptor 2] and HER3, but in lung cancer it’s not something we’ve spent a lot of time targeting. It’s interesting to have a new target that’s relevant in this space. Certainly, there are encouraging data there. That covers some of our classic EGFR mutations, so a lot is happening in this space.

Transcript Edited for Clarity

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