Future of Targeting EGFR Exon 20 Insertion Mutations in NSCLC


Before closing out his discussion on novel therapy in EGFR exon 20 insertion–positive NSCLC, expert Joel Neal, MD, PhD, highlights ongoing clinical trials and the importance of testing.


Joel Neal, MD, PhD: In addition to the 2 FDA-approved drugs, there are many others in development. Some of these include other EGFR TKIs [tyrosine kinase inhibitors], and then there’s the question of combination therapies. Can we use combinations to bring treatment into the frontline setting?

A few of the other EGFR TKIs that have been studied include poziotinib, [which was] last reported with around a 15% response rate, progression-free survival [PFS] of 4.2 months, and many of the adverse effects that mobocertinib has, of diarrhea, rash, and stomatitis. That drug is still in clinical development, as well as 2 other EGFR TKIs that perhaps are slightly more specific, and we’re waiting to see what the CNS [central nervous system] penetration is. There is DZD9008, with a reported response rate of almost 40%, 38% among 56 patients, and CLN-081 with a response rate of 31% among 42 patients.

In addition, osimertinib, which is an EGFR TKI often used for EGFR sensitizing mutations, has been studied in EGFR exon 20 insertion-mutation lung cancer as well. It’s not as effective at the 80-mg PO [oral] daily dose, which is the FDA-approved dose. But Zosia Piotrowska, [MD, MHS,] from Massachusetts General Hospital with an ECOG-ACRIN study demonstrated that among 17 patients, the response rate was 24% with a PFS of around 9.6 months from 160 mg PO daily; that’s double the usual dose. Also, there was a report from ESMO [European Society for Medical Oncology] that 25 patients had a 28% response rate and a PFS of 6.8 months.

Comparing all these agents, there [are] a number of TKIs still in evolution and development, as well as 2 FDA-approved agents. I think looking forward, what I’m hoping to see from some of the new agents is higher penetration into the brain. As you recall, our patient had a 1.5-mm uncertain brain metastasis, a vessel versus a metastasis. I’ll tell you that in my experience, more often than not, patients at the time of progression after chemotherapy will develop new brain metastases. And both mobocertinib and amivantamab seem to have minimal to modest CNS [central nervous system] penetration. Their CNS penetration probably has more to do with the disruption of the blood-brain barrier in the abnormal milieu of metastasis than it does from these drugs getting well into the CNS. Clearly, antibodies don’t get into the cerebrospinal fluid [CSF] very well, and mobocertinib doesn’t seem to get into the CSF much either. But in my experience, we have seen brain metastases shrink from this.

I think some of the new agents in evolution and development hopefully will have better CNS penetration, as well as equivalent or maybe superior efficacy against EGFR exon 20 insertion non–small cell lung cancer. Because in my experience, once we get past second-line to third- or fourth-line treatment for these patients, many of them, probably more than half, eventually develop brain metastases, which are a problem to manage.

In addition, I’m wondering about the first-line treatments. A second-line treatment with both of these drugs is firmly established now, but there [are] 2 interesting first-line studies going on. First is the PAPILLON study, which is amivantamab plus platinum-based chemotherapy, carboplatin plus pemetrexed, in the first-line setting. Its comparison arm is carboplatin, pemetrexed by itself. That’s currently enrolling. If you have a patient who’s newly diagnosed with EGFR exon 20 lung cancer and looking for clinical trials, I think that’s an interesting option, as is the EXCLAIM-2, which is mobocertinib versus carboplatin and pemetrexed. One versus the other head-to-head, as opposed to PAPILLON, which is a combination. I think it will be interesting to see whether one or both of these trials lead to the first-line approval of these agents. And both trials are still enrolling, so if you can look for those in your community for these patients who are newly diagnosed, please try to get patients onto these studies.

I think one important take-home message, as we talked about at the beginning, is if we don’t do testing for these patients and we miss an EGFR exon 20 mutation insertion, then we can miss the opportunity for these approved drugs, and for clinical trials for further development. [We need to do] testing, either by liquid biopsy NGS [next-generation sequencing], tissue DNA NGS sequencing, or potentially as we move to RNA tissue NGS sequencing, which has the opportunity to be slightly more sensitive in some contexts. But for these EGFR mutations, I think all testing methods are quite reliable. For a patient who’s a light or never smoker with adenocarcinoma, keep doing testing until we find the driver mutation. If one test doesn’t work, it’s OK to start treatment and chemotherapy.

But unless we find a definite driver, not just the absence of EGFR, ALK, ROS, or KRAS, or any one of the other 9 drivers we have now that have approvals for non–small cell lung cancer, if we don’t keep looking until we find the driver and just say, “Hey, a quick test off of tissue, which is inadequate, is negative, and move along,” then we’ll miss these mutations and miss the opportunity to give patients these new exciting therapies.

Transcript edited for clarity.

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