Poziotinib Elicits Encouraging, Insertion Location–Specific Response Rates in EGFR Exon 20–Mutant NSCLC

Poziotinib, a covalent TKI inhibiting EGFR, demonstrated a 32.0% confirmed objective response rate (ORR) in patients with EGFR exon 20–mutated non–small cell lung cancer (NSCLC), said Yasir Y. Elamin, MD. He added that the benefit was driven entirely by the population of patients with near-loop mutations vs those with far-loop mutations, warranting further study.

Results from a phase 2 study (NCT03066206) established the efficacy and safety of poziotinib in patients with NSCLC harboring EGFR exon 20 mutations. Findings from this study recently published in Cancer Cell showed near-loop exon 20 insertions to be more sensitive to poziotinib than far-loop insertions. Specifically, the ORR in those with near-loop insertions was 46% vs 0% in those with far-loop insertions.

“[These insertion location data] may be applicable to other drugs in this arena,” lead study author Elamin said. “Other drugs [targeting] exon 20 should also be investigated for this binding, and perhaps future clinical trials could consider the location of the insertion.”

In an interview with OncLive^®, Elamin, an assistant professor of Thoracic/Head & Neck Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, explained the rationale, design, and key findings of the phase 2 study. He also elaborated on how insertion location affects poziotinib binding and receptor conformation, and how data from this trial can inform future research in this population.

OncLive^®: What preclinical models show with poziotinib?

Elamin: Poziotinib is a covalent TKI. It inhibits EGFR and other [mutations in the] ErbB family. In preclinical models, we observed and published in the past that it’s particularly active in a subset of EGFR mutations, exon 20 insertions, and in a subset of HER2 mutations, HER2 exon 20 insertions.

What was the rationale for the phase 2 study?

This study was designed to translate our preclinical findings into a clinical trial. It included patients with EGFR exon 20 mutations; the vast majority had exon 20 insertions and 2 patients had exon 20 point mutations. The aim was to identify the clinical efficiency of poziotinib in this subset of patients with lung cancer measured by ORR.

Could you discuss the study design and the patient population?

The trial was investigator-initiated, and it enrolled patients with metastatic NSCLC. It originally had 2 cohorts: the first cohort included patients with EGFR exon 20 mutations, and the second cohort included patients with HER2 exon 20 mutations. What we reported in the recent publication [were data from] the first cohort, which is patients with EGFR exon 20–mutant NSCLC. This was a single-arm study, and all patients were treated with poziotinib at a starting dose of 16 mg daily.

Could you walk through the key efficacy findings from the trial?

The key finding was the ORR. [We reported a] 32.0% confirmed ORR in the intention-to-treat population per the investigator. There was also a blinded independent review of the response rate, which was consistent at 31%. Additionally, we observed a median progression-free survival [PFS] of 5.5 months and duration of response of 8.6 months.

Could you expand on what you observed with poziotinib in those with near-loop vs far-loop mutations?

This was one of the key findings of the study. We wanted to better understand why some patients did well on the drug while others progressed quickly. One of the things we looked at was patients with near-loop mutations vs those with far-loop mutations. In patients with near-loop [mutations], the response rate was 46%. [In patients with] far-loop mutations, the response rate was 0%. Not a single patient responded in the far-loop mutation population.

We also looked at the median PFS. Although it wasn’t statistically different between the 2 groups, there was a trend toward better outcomes in those with near-loop mutations. Additionally, we looked at the PFS rates at 6 months and at 12 months. Again, we observed that patients with near-loop mutations had better outcomes compared with those with far-loop mutations. We confirmed this finding in preclinical models using Ba/F3 cells, and we observed the same thing: patients with near-loop mutations are more sensitive to poziotinib. We concluded that the insertion location affects the efficacy and activity of poziotinib in these mutations.

How did EGFR exon 20 insertion location affect receptor conformation and drug binding?

Another key finding of this study was that the location of the insertion affected the efficacy of poziotinib. We found that the location of the insertion at the C-terminal end of the αC helix influences the orientation of distinct residues of the P-loop that stabilizes EGFR TKIs and therefore influences the drug binding affinities. Our findings support the structure and mechanism for the differential sensitivity of poziotinib in near-loop mutations compared with far-loop mutations.

What did you learn about acquired resistance mechanisms?

We learned that exon 20 insertions treated with an EGFR TKI develop resistance similar to classical EGFR mutations, where resistance is mediated by 2 key mechanisms. The first key mechanism is EGFR-dependent mechanisms. For poziotinib, we saw that 1 of the EGFR-dependent mechanisms was acquired T790M, which affects the binding of poziotinib to the receptor. We confirmed that T790M also drove resistance in preclinical models. We also observed EGFR amplification as a possible resistance mechanism to poziotinib.

Regarding EGFR-independent mechanisms, we saw other normal resistance mechanisms to TKIs, such as MET amplification. We also observed epithelial mesenchymal transition as a possible resistance mechanism to poziotinib.

What adverse effects (AEs) are important to note?

The safety data were consistent with what we have seen in patients treated with EGFR TKIs. All the AEs were related to the wild-type activity of the drug. The most common AE we observed was diarrhea, followed by skin rash, followed by paronychia.

What are the next steps for this research?

There is already a multicenter trial going on. One of the key issues that this subsequent trial is trying to address is: What is the safest way of giving poziotinib? When the drug is given [twice daily], it may be far better tolerated, and that would hopefully translate into better efficacy. The next step is to see the final outcomes of that study of the [twice-daily] dosing and to define the proper dosing of the drug.

What is the clinical significance of these data for this population?

Poziotinib is safe and active. We need to figure out the tolerable dose. The other important finding is that the insertion location matters. It affects the drug binding and the receptor conformation. This is something that needs to be considered when designing future trials and when analyzing the current trial being carried out in exon 20 insertions.

Reference

1. Elamin YY, Robichaux JP, Carter BW, et al. Poziotinib for EGFR exon 20-mutant NSCLC: clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity. Cancer Cell. 2022;40(7):754-767.e6. doi:10.1016/j.ccell.2022.06.006