Recent Advances in Treatment of EGFR Exon 20 Insertion Mutations in NSCLC

Ben Levy, MD: We’re going to move on to EGFR exon 20 insertions. It’s a slightly different alteration, difficult to drug, has a narrow therapeutic window, and it’s very difficult for these TKIs [tyrosine kinase inhibitors] to fit into the pocket. But we’ve had some new data and drug approvals in this setting. Fernando, do you want to walk us through the amivantamab [Rybrevant] and mobocertinib [Exkivity] data?

Fernando C. Santini, MD: Yes. It’s a breakthrough. In 2021, we had 2 approvals for these very heterogeneous groups of mutations. It’s very important to know that unlike EGFR, they’re born the same, are very heterogeneous, and you can have rare mutations with different sensitivities. Of note, EGFR exon 20 insertions have a very low response rate to first- and second-generation TKIs. We had only standard of care chemotherapy as of last year, but now we have 2 new approvals, amivantamab and mobocertinib.

Amivantamab is a fancy bispecific EGFR and MET antibody that works by inhibiting the ligand binding and with receptor degradation, ADCC [antibody-dependent cellular cytotoxicity], natural killer cells, and macrophages. It’s a very powerful drug that acts against EGFR and some MET alterations.

We recently had the report of the data from the EGFR exon 20 insertion cohort with patients post–platinum therapy from the CHRYSALIS trial, which is a phase 1 dose escalation expansion trial with 81 patients. Fifty percent of the patients had previous IO [immuno-oncology], 20% had brain metastases, 25% had already used a TKI, and the median number of previous therapies like 2. They showed an overall response rate of 40%, with 3 patients having complete response, median PFS [progression-free survival] at 8.3 months, and a median duration of response of 11 months.

It’s important to note that the activity was across the spectrum of the different EGFR exon 20 insertions. No MTD [maximum tolerable dose] was identified. It’s important to note that with the adverse event profile, you can find a little from the MET and the EGFR world, like rashes, dermatitis, diarrhea, paronychia, and some peripheral edema, but it was quite safe. The incidence of grade 3 or higher adverse events was about 35%, and rash was the most common infusion-related reaction. It was very common. More than 60% of the patients developed infusion-related reactions. It’s usually in the first 2 days of the first cycle.

There are several ways to mitigate these infusion reactions. The first is by splitting the first dose in the first week in 2 days, a very slow rate of infusion, and premedication. Most of the patients didn’t have any subsequent infusion reactions in cycle 2 or 3. It’s something that we need to try to understand in all the settings to know how to best manage this infusion reaction.

Mobocertinib is an oral drug. It’s first in class, very powerful, and selective against EGFR exon 20 insertions. It was also approved in 2021. We have reported data from the 3-part phase 1/2 dose escalation, expansion, and extension with more than 110 patients. Overall response rate was 28%, which is a little lower than amivantamab. There was a good disease control rate of 80%. The median duration of response was 17.5 months, which is a little longer than amivantamab. In terms of adverse events, diarrhea is the main issue, with more than 30% to 35% of the patients with grade 3 or higher diarrhea, and 17% of the patients had to discontinue the drug because of that.

We now have 2 good drugs in a space where we were lacking targeted therapies. There are several challenges on how to best sequence it, if it’s durable, and if 1 has activity against the other.

Ben Levy, MD: How do you choose between the 2 in your clinic off of a clinical trial? Because the data is a little different and we don’t like to do cross-trial comparisons, but we do. What’s your go-to for an EGFR exon 20 patient? Would you use it first line? What drugs are you using first line and second line?

Fernando C. Santini, MD: It’s important to note that all this data is in the post-platinum setting. The approval is after progression on first-line platinum. Chemotherapy is still the standard first line. I usually don’t add immunotherapy in this setting, even though we have some retrospective data showing that the exon 20 insertions might have a little better response rate. But it’s more or less the paradigm of all the oncogene-driven cancers.

I’d go for chemotherapy only first line. In the second line, we need to discuss with the patients how the toxicity profile is different. One is an oral drug, while the other is an infusion. We still await data from CNS [central nervous system] control, but we don’t expect any of these drugs to have very good CNS control. It’s sharing with patients. I’ll probably go for mobocertinib as the first drug. There’s a lot of push that the amivantamab data show a greater response rate, but mobocertinib showed a good duration of response. As far as sequencing, there’s a good rationale on placing the antibody after the small molecule. If you think about resistance mechanisms, like C797S, where the mobocertinib binds, amivantamab might have some activity after that. There are still a lot of unanswered questions.

Ben Levy, MD: That’s a very nice overview. The thing you hit on that we’re all struggling with in regard to all these genotypes is, what’s the optimal sequencing? How do we move forward with combination strategies? How do we sequence in the way that can give the best quality of life and improve the outcome for patients? It’s getting incredibly complicated for each of these genotypes as the field is getting more crowded.

Transcript edited for clarity.