Transcript: John Heymach, MD, PhD: One thing that’s important to highlight for exon 20 mutations is that it’s not a single mutation. Exon 20 refers to an entire region. Most of the mutations in EGFR occur between amino acid 763 and amino acid 780. That’s really the region where these mutations occur. Depending on where those mutations occur, they have different sensitivities. We just had the first FDA approval for a single mutation: the S768I mutation. Afatinib received FDA approval for that single point mutation. But that’s a pretty small minority of exon 20 mutants overall. Given this unmet need, we did a lot of drug screening. The first was to actually make all of these individual mutants occur. And so, we’ve got many, many mutations that have been made in the lab.
This work’s been led by Jacqulyne Robichaux, who’s a postdoctoral Fellow in the laboratory. Dozens and dozens of different drugs were screened to see which was the most active against of all of these different mutations. Across the board, we saw that poziotinib was the most potent, in vitro. We compared it, in clinical testing, to all of the different EGFR inhibitors that were available. This applied for all of the differentiation mutations, although some of the mutations are more sensitive than others. In fact, that S768I mutation that afatinib has been approved for is one that poziotinib is also highly active against.
We then took these results and went into mouse models. This included genetically engineered mouse models that had a particular exon 20 mutation as well as human tumors that were grown in mouse xenograft models. Poziotinib was really the best of all of the ones that we tested in mouse models. So, all of this prompted the clinical trial that we recently reported on at the World Conference on Lung Cancer, in Japan, this past October.
Based on the preclinical results that we described, we initiated a phase II study of poziotinib. It had already been through phase I testing, so the maximum tolerated dose was already identified. This study had 2 major cohorts. It had an EGFR exon 20 cohort and a HER2 exon 20 cohort. The eligibility criteria were really pretty wide open. It allowed for people who had treatment with prior EGFR tyrosine kinase inhibitors. On the EGFR side, we allowed for both previously untreated and treated patients. On the HER2 side, only people who had received prior chemotherapy were included. This was a single-arm study, starting at a dose of 16 mg. Now, as I mentioned before, first-generation inhibitors have an objective response rate of less than 10%, consistently, for this group of patients. We were hoping to get above 20% or 30%.
In Japan, at the World Conference on Lung Cancer, we reported on the initial scan results. Instead of reporting on durable results with progression-free survival and so forth, these were really just the initial scan results because that’s the data that were available at that point. In the first 11 patients who we reported on, 8 of them had partial responses. This was based on more than a 30% shrinkage of their tumors by what we call RECIST criteria. That level of activity, that 73% objective response rate, was certainly very encouraging compared to the standard response rates that have been seen for other tyrosine kinase inhibitors—less than 10%. The drug did have toxicities that were consistent with EGFR inhibitors. In particular, there was acne, which is particularly seen with first- and second-generation inhibitors. Diarrhea was also seen in many of the patients. About 55% of that initial group had dose reductions from the 16-mg dose down to lower doses. The therapy did need to be reduced in a significant number of patients, but we’re certainly very encouraged by that activity level that was seen there.
Shortly, longer-term follow-up for those patients will be published in Nature Medicine. The confirmed objective response rate, meaning that the response was maintained for at least 4 months in our study, ended up being about 64% in that overall group. The median progression-free survival had not yet been reached, and the median follow up for the group was about 6.5 months. So, we don’t know the progression-free survival yet, but we know that it’s longer than 6.5 months. This was really encouraging. For the first time, there was a drug that had a high response rate for EGFR exon 20—mutant disease. And the responses were reasonably durable. We’ll have to see what the ultimate progression-free survival is, but we know it’s longer than 6 months. Keeping in mind that the standard drugs had a median progression-free survival of about 2 months in this exact same population in the study. So, this is certainly an encouraging initial result.
Transcript Edited for Clarity