EGFR Exon 20 Insertion as a Therapeutic Target in Non-small Cell Lung Cancer - Episode 1

Identification of EGFR Exon 20 Insertion+ mNSCLC

Joel Neal, MD, PhD, and Alexander I Spira, MD, PhD, FACP, discuss the recent identification of EGFR exon 20 insertion+ mNSCLC and how patients responded before the new drugs were introduced.

Joel Neal, MD, PhD: Hello, and thank you for joining us for this Targeted Oncology presentation titled “EGFR Exon 20 Insertion as a Therapeutic Target in Non–Small Cell Lung Cancer.” Patients with EGFR exon 20 insertion–positive non–small cell lung cancer have poor prognoses and few treatment options. Recently, data from multiple phase 1 and 2 clinical trials suggested that tyrosine kinase inhibitors [TKIs] and other molecules have promised targeted therapy for this patient population. In today’s Precision Medicine in Oncology® discussion, we will talk about the role of EGFR, in particular exon 20 insertion, in non–small cell lung cancer growth and progression, and a review the mechanism of action and current safety and efficacy data from these phase 1 and 2 clinical trials. I’m Joel Neal, an associate professor of oncology at Stanford Cancer Institute in Palo Alto, California. Joining me is my colleague Dr Alex Spira, the director of the Virginia Cancer Specialists Research Institute in Fairfax, Virginia. Thank you so much for joining us. Let’s begin. Dr Spira, both of us—as well as a number of other colleagues—have been interested in how to unlock the key to targeting EGFR exon 20 insertion non–small cell lung cancer for many years, and I’ve personally found it a frustrating target. These drugs that we have that give miraculous, unbelievable responses in the more common EGFR exon 19 and L858R mutations do not really seem to work in this. Can you tell us a little about how the subset of patients was identified and how common this mutation is?

Alexander I. Spira, MD, PhD, FACP: It’s relatively uncommon. It’s probably about 4% of patients with lung cancer overall. We’ve known about them for quite some time, especially in patients for whom we did an in-depth analysis or in-depth NGS [next-generation sequencing] testing. Obviously, as you talked about, with no drugs out there for this—especially with the advent of NGS—we’ve noticed these a lot more over the last few years vs the hot spot testing, which was coming up until really just a few years ago. We have known a little about this for a while, but for me, about 3 or 4 years ago with the advent of all the NGS testing, it came about. I started noticing it more. I guess the frustrations start to set in, because you knew you had drugs for exon 19 and exon 21, but you couldn’t really target this at all.

Joel Neal, MD, PhD: I know that some organizations were testing using a PCR [polymerase chain reaction]–based sizing assay for a while because you can put a PCR primer against exon 20 and then look for that increase in size of a fragment. We’re still doing that at Stanford for routine, fast analysis, but the NGS testing has certainly taken the lead in terms of being much more effective for testing, for this as well as a lot of other gene mutations. Alex, do you have experience with patients before the new drugs were in clinical trials? How did they do with the typical disease course and prognosis? How did they respond to other agents?

Alexander I. Spira, MD, PhD, FACP: For me, these patients did OK. They traditionally never benefited from immunotherapy, so carboplatin and pemetrexed are what we give most of our patients with this subtype. They probably didn’t benefit as well as patients who could benefit from immunotherapy, and of course second-line treatment left a lot to be desired. Clearly, there’s a big unmet need. I’m curious what your thoughts are. A lot of these patients progressed in the central nervous system [CNS], so there was early and common propensity for brain metastases. Joel, is that something you saw as well?

Joel Neal, MD, PhD: Yes, Alex. My early experience was that I try the usual carboplatin and pemetrexed, and sometimes add in bevacizumab, which as we know is sometimes a little more effective in overall EGFR-mutated lung cancer. Many of those early patients who I had did develop brain metastases, including leptomeningeal carcinomatosis often on these treatments. When immunotherapy came out, my experience was that it was rarely effective, that it was behaving basically like EGFR-mutant lung cancer but without an EGFR inhibitor to really go after it. One of my thoughts about the CNS metastases is for most cases of EGFR-mutant lung cancer, even the first-generation EGFR TKIs got into the brain enough to control the disease somewhat for a while. With osimertinib in the third generation, it’s much better, but we never had drugs that had decent CNS penetration—carboplatin, pemetrexed a little, but really nothing else gets into the CNS, so I did see a lot of CNS metastases.

Alexander I Spira, MD, PhD, FACP: It’s something we got spoiled with, right? With all those other EGFR inhibitors, they had a little—or obviously a lot of—CNS penetration, and these patients just didn’t respond at all, which is hugely frustrating for me and of course patients as well.

This transcript has been edited for clarity.