John Heymach, MD, PhD: EGFR and HER2 are 2 very similar genes. They’re highly homologous. In fact, if you line up the exons between EGFR and HER2, they really map, one for one. But there are some differences. EGFR often gets these exon 19 deletions and this L858R. Those same mutations don’t occur very frequently in HER2 disease. Instead, HER2 almost always gets exon 20 mutations and they most commonly get insertions. There’s one insertion, 775YVMA, that’s really the most prevalent. YVMA refers to the 4 amino acids that are inserted there, at that particular location.
HER2-mutant lung cancer, these exon 20 insertions, also do not respond to the standard drugs that are available. We don’t have any HER2 tyrosine kinase inhibitors approved for lung cancer. But for breast cancer, there’s lapatinib. Lapatinib does not appear to be effective. Afatinib, which is an EGFR inhibitor, also inhibits HER2 under normal circumstances. It inhibits wild-type HER2. It does not seem to inhibit exon 20-mutant HER2 in regular clinical use. There’s always excitement about antibodies like Herceptin (trastuzumab). Trastuzumab, by itself, does not appear to be particularly effective for HER2 exon 20 insertion non—small cell lung cancer. So, again, this is a space that really needs new therapeutic options. It needs new targeted drugs, and that’s been an area of active investigation for us.
Right now, the options that are available for any non—small cell lung cancer patient, namely chemotherapy and immunotherapy, are available to patients with HER2 exon 20 insertions or EGFR exon 20 insertions. But we are really looking for targeted agents that can help these. Targeted agents specifically hone in on the gene that’s altered here: HER2 or EGFR. They have the potential to give a durable benefit with a much deeper response, a higher likelihood of response, if we’re able to develop effective inhibitors. We’ve certainly learned this from EGFR, ALK, BRAF, and other diseases where targeted agents can be spectacularly effective. So, that’s why finding inhibitors for HER2 exon 20-mutant disease or EGFR exon 20-mutant disease is such a pressing issue.
It’s also worth mentioning that while we’re focused on lung cancer, in my group, these HER2 and EGFR exon 20 mutations occur in a wide variety of other diseases. It’s well known that HER2 exon 20 insertions occur in breast cancer. That’s one of the most common places where they occur. But they also occur in gastric cancer. These mutations occur in glioblastomas, adenoid cystic cancers, and in a variety of different gastrointestinal malignancies. Recently, we’ve gone back and reviewed the molecular profiling from MD Anderson Cancer Center. We’ve identified more than 20 tumor types that have EGFR or HER2 exon 20 mutations. So, while lung cancer has the greatest absolute number—if you look, as a total—there’s more non—lung cancer exon 20 mutations than there are lung cancer exon 20 mutations. So, this is a case where things that we learn from lung cancer can actually benefit all of these other diseases as well. We’ve seen this happen time and time again. An example would be BRAF in melanoma. A lot was learned about that, and it’s now been applied to lung cancer.
Recently, what’s exciting to us is the approval for a TRK (tropomyosin receptor kinase) inhibitor or an NTRK (neurotrophic tyrosine kinase) inhibitor, larotrectinib (Vitrakvi), for different histologies. Those tumors occur in all different histologic subtypes or, I should say, those mutations occur in all different histologic subtypes. This seems to be the case with exon 20 mutations. They occur not only in lung cancer but in a wide variety of other cancer types.
Right now, we don’t have any approved agents for exon 20-mutant disease. So, in the last few years, we’ve set about screening all of the available drugs. We have even looked at drugs that were discontinued in the past, for other applications, to see if any of those could be repurposed for exon 20-mutant disease. We identified one drug, poziotinib. This is a drug that had previously been tested in breast cancer and lung cancer for standard mutations or the standard resistant mutation, T790M. It had activity there, but it was not better than the standard drugs that were out there.
So, based on that, the drug was discontinued for lung cancer testing. Well, we found out that even though the drug did not distinguish itself as an EGFR inhibitor or a T790M inhibitor for the classical or standard mutations, it was highly active against exon 20 insertions. From a lot of molecular modeling in our group, and testing in vitro and in looking at mouse models, I think we’ve come to appreciate that among all of the drugs that are approved, poziotinib is significantly more potent for exon 20, even if it wasn’t as good for all of the other types of mutations. And so, this prompted us to initiate a clinical trial, which we’ve recently reported the results of.
Transcript Edited for Clarity