EGFR Exon 20 Insertion as a Therapeutic Target in Non-small Cell Lung Cancer - Episode 5
An explanation of the EXCLAIM Trial and the mechanism of action, clinical development, and the overall clinical development program of mobocertinib.
Alexander I. Spira, MD, PhD, FACP: Let’s talk about mobocertinib. Do you want to describe the older mechanism of action and why it’s hard to get exon 20 insertions?
Joel Neal, MD, PhD: Mobocertinib is a small-molecule tyrosine kinase inhibitor. Like all the other EGFR inhibitors, it’s ATP mimetic and binds to the ATP-binding site. There’s something about the confirmation of the exon 20 insertion protein that excludes most of the other inhibitors and doesn’t allow them to shut down the ATP-binding action. It can bind despite that, and was rationally developed with cell-line models, to inhibit this in cell lines. The clinical development, started with, of course, a phase 1 clinical trial. First there were human subjects, although the trial was rationally designed to look at both the population with EGFR exon 20 mutations and HER2 [human epidermal growth factor receptor 2] because we should know that HER2 exon 20 insertions are structurally analogous and also hard to treat. The clinical development progressed through. We were part of that phase 1 clinical trial and saw dose escalation through many levels. That paper has finally been published in Cancer Discovery. Do you want to share some of the top-line results from that early clinical development, Alex?
Alexander I. Spira, MD, PhD, FACP: It’s amazing you are going from early phase 1/2 clinical studies—we both were involved very early on. The bottom line of that study is that we got patients to tolerate a dose of 160 mg, which was what the dose is going forward. An insignificant number patients need to be dose reduced to 120 mg, just because of toxicities. The response rates—if you look at some of the studies, they’re slightly different depending on whom you are looking at, but I generally call it as people having response rates in the high 20s to low 30s. There was a slight difference between those who were investigator assessed and those under as central review. Just looking at it, especially considering the patient population—remember, this is a very heavily pretreated population, starting as a phase 1 clinical study—there was no limit on the number of lines of therapy. Some of the early patients were allowed to have brain metastases. We learned over time that these drugs don’t have a lot of CNS [central nervous system] penetration. That was 1 of the cohorts. This initial study that you and I were on had 7 cohorts, I think—I lost track at the end about EGFR and HER2, so there are a lot of data with it. In the end, it’s a pretty impressive response rate, especially from that very heavily pretreated population. That’s what’s lost, right? There was no limit earlier on. We put patients on, and patients who responded, their duration responses were well over a year on median. It’s impressive. What are your thoughts?
Joel Neal, MD, PhD: We were all impressed once we got up to the maximal tolerated dose, which was called at 160 mg. A lot of patients said 120 or even 80 mg was better tolerated for them, but our initial response rate that we reported for all the patients above 120 mg was 43%, which is eyebrow raising. It’s not as high as we would expect, necessarily, for other targetable alterations in other pills, but certainly it’s in the range of what we’re seeing with the recent FDA approval is sotorasib for KRAS G12C. That’s another nontargetable alteration that was suddenly targeted. The duration of response was over a year, with progression-free survival of 7 months, which was little lower than we would have wanted. But because this is an additional option after everything else the patients had, it’s clearly an active drug in a patient population that has an unmet need.
Alexander I. Spira, MD, PhD, FACP: We’re a victim of our own spoils, because over the last year, we’ve seen RET and c-MET, as well as updated data on osimertinib, with phenomenal response rates, right? There are things you wouldn’t have heard of with great CNS penetration. This probably didn’t quite need that bar, and people are very critical of it, but compared with the other options—which were none—it’s huge, a home run. For me, 1 of the key points, is to bury the heavily pretreated nature, especially with all the patients. We had 1 patient who was on 6 lines of therapy. He’s still on the study right now. That’s what gets lost when you do the cross-trial comparison. Remember, it’s a first-generation drug, right? It’s the first stab at any of these things. For me, it’s a huge boon to our patients.
This transcript has been edited for clarity.