Expert perspective on the treatment armamentarium for EGFR exon 20 in non–small cell lung cancer.
Joel Neal, MD, PhD: EGFR exon 20 insertion mutations have been described almost as long as EGFR sensitizing mutations, going back to maybe 2003, 2004, with the initial description. These mutations can be reliably identified even with the original EGFR mutation testing techniques, which was PCR [polymerase chain reaction]-based sequencing of exons 18 all the way through exon 21. And we found that in addition to the common EGFR exon 19 deletions and the exon 21 L858R common mutations, that about 10% of EGFR mutations were uncommon mutations.
These incorporate a spectrum of different mutations. There are point mutations in EGFR exon 18, as well as rarely, EGFR exon 19 insertions. There are EGFR exon 20 insertions as well, and then exon 21 point mutations, all of which have varying sensitivity to EGFR TKIs [tyrosine kinase inhibitors]. These exon 20 insertions, originally well described by Dan Costa, [MD, PhD,] at [Beth Israel] Deaconess [Medical Center] and others, were intriguing because there was one, the EGFR exon 20 insertion FQEA mutation, it’s at the 763 amino acid position, and it was sensitive to initial EGFR TKI treatment.
But all the rest of them, which were subsequent to that 763 amino acid position—commonly 768, 770, 763 are a few of them—but any of those around the 770 range, tend to be resistant to EGFR pill therapies and TKIs. So there was really an unmet need to target these and reduce the tumor. Biologically, otherwise they seemed very similar to what they caused for EGFR mutation-positive lung cancer, commonly metastasis to the lungs, to the adrenal glands, to bones, and even to the brain. Biologically, it appeared very similar to other EGFR-mutated lung cancer, except for the fact that they couldn’t be targeted by TKIs.
For this patient, we can think back to the original treatment. Let’s say that we knew about the EGFR exon 20 insertion mutation up front, from day 1, before we selected our initial therapy. We’ve got a few clinical factors: a question of a brain metastasis, but very small and uncertain; bone metastases; and then a relatively healthy patient who had a light and distant smoking history with good overall organ function. If I had seen this patient initially, I already mentioned that I may have offered carboplatin instead of cisplatin, just for patient convenience and lower toxicities. I think the pemetrexed is completely appropriate.
Then there’s a debate of whether we add a third agent. Like other EGFR-mutated lung cancers, in my clinical experience, and there are some published data from our group and others about this, we find that these tumors are more sensitive to antiangiogenic therapies, such as bevacizumab. I do have an inclination toward regimens like carboplatin, pemetrexed, and bevacizumab in the upfront setting. We can also talk about the role of immunotherapy, drugs like pembrolizumab, or the addition of atezolizumab, or even ipi-nivo [ipilimumab and nivolumab], which all are approved in the frontline setting in combination with platinum-based chemotherapy for these patients, and can be considered.
In our experience and the experience of others, there’s mixed literature to say whether these tumors have average sensitivity to immunotherapy or below average sensitivity to immunotherapy. I probably personally wouldn’t give the upfront regimen of carboplatin, pemetrexed, and pembrolizumab, for example. We could consider drugs like the IMpower150 [trial regimen] of carboplatin, paclitaxel, bevacizumab, and atezolizumab, for example, but that has less CNS [central nervous system] penetration. And the paclitaxel has more adverse effects overall.
In the future, we may think about 4-drug regimens that incorporate pemetrexed. We’re doing some clinical trials right now, but as of now, those are not FDA approved. My preference is to steer away from immunotherapy in the frontline setting. We can think about it in later lines of treatment, but probably not up front. I think carboplatin, pemetrexed, and bevacizumab [are] usually our preference for these patients.
Transcript edited for clarity.