Mobocertinib Treatment-Emergent EGFR Mutations and Subsequent Therapy Selection


Zosia Piotrowska, MD, explains how she might treat a patient with EGFR exon 20-mutated mNSCLC who develops an EGFR T790M mutation after mobocertinib treatment.

Joel Neal, MD, PhD: After mobocertinib, patient gets progression. Let's say they do a repeat biopsy like we talked about before. Interestingly, we showed some data from ASCO that says that not a small number of these patients out of a series of nine patients with repeat liquid biopsies developed EGFR T790M mutations. That's actually an on-target mutation. It's an acquired resistance mutation historically most commonly seen for the common EGFR mutations and first and second-generation EGFR TKIs. But both T790M mutations happened as well as a variety of secondary EGFR Exon 20 insertion mutations that develop suggesting that these compound EGFR Exon 20 insertions are particularly troublesome. Zosia, if you repeat biopsy and you saw an EGFR T790M or a compound EGFR Exon 20 by liquid biopsy, would you hesitate to give the other approved drug next, amivantamab?

Zosia Piotrowska, MD: I think one thing to say is this is a very small number of patients, and we don't have a lot of data to guide us here yet, and I hope we will in the future. But the short answer is no. I think I would move amivantamab. I would feel encouraged that the patient developed in on-target resistance mutation hopefully is still dependent on EGFR and therefore, amivantamab is an appealing strategy. One word of caution is for many years we saw T790M, and we thought, OK, T790M positive, let's use a third-generation EGFR inhibitor like osimertinib. And I don't think that can be the reflex here because I think all of the caveats that we talked about earlier about the fact that Osimertinib in general for these mutations is not as effective for the Exon 20 insertions. That's due to the structure of the Exon 20 insertions and the way that osimertinib fits into that pocket. And I think even with a T790M mutation, the reflex should not be here to use osimertinib as it might be in other types of EGFR mutations. I would go for amivantamab in this patient next unless I had a clinical trial option to offer them.

Joel Neal, MD, PhD: And I think as you said earlier, some of those newer clinical trial TKI seem a little bit more effective, tolerable, and may have better CNS penetration. I think thinking about clinical trials even before the patient gets the TKI is worthwhile. And some of these, the next steps now are these drugs are moving toward the frontline setting. There's a head-to-head trial ongoing now of mobocertinib versus carboplatin and pemetrexed chemotherapy as well as an amivantamab plus carboplatin and pemetrexed chemotherapy both versus the chemotherapy arm alone. We may see emergence of these therapies into the frontline setting, either in combination with chemotherapy or by themselves. Then as I think about subsequent lines of therapy outside of clinical trials after mobocertinib and amivantamab, I think about single-agent chemotherapies. For this patient with high PD-L1, we'd think about immunotherapy probably as a single agent after we're done with the TKI specifically. And many patients in my experience at least, do have many lines of therapy even after the EGFR Exon 20 drugs and tend to respond well overall.

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