Poziotinib Shows Clinical Benefit in EGFR Exon 20-Positive NSCLC

Poziotinib showed significant antitumor activity for patients with EGFR exon 20 positive non–small cell lung cancer (NSCLC) with efficacy of the treatment highly dependent on the location of the exon 20 loop insertion, according to new research published in Cancer Cell.¹

The results came from a phase 2 study (NCT03066206) which looked at 50 patients with advanced NSCLC who had point mutations or insertions in EGFR exon 20. The study achieved its primary end point with a confirmed objective response rate (ORR) of 32% (95% CI, 20.7%-45.8%) and 31% (95% CI, 19.1%-46%) by investigator and blinded independent review, respectively.

Moreover, researchers found a median progression-free survival (PFS) of 5.5 months (95% CI, 5.4-10.4) with a PFS rate of 43% (95% CI, 30%-60%) at 6 months, and 29% (95% CI, 18%-46%) at 12 months. Median overall survival also appeared to be beneficial at 19.2 months (95% CI, 11.8-24.1) with a disease control rate of 84% (95% CI, 71.5%-92%).

“EGFR exon 20 mutant lung cancers typically don’t respond well to the types of tyrosine kinase inhibitors that have been largely successful in targeting classical EGFR mutations, leaving this patient population with few effective treatment options,” said senior author of the study, John Heymach, MD, PhD, chair of the Thoracic/Head & Neck Medical Oncology at the MD Anderson Cancer Center, in a press release.² “Our study gives hope for not only a potentially beneficial treatment option, but for a new level of precision to better target EGFR exon 20 mutations and to design more effective clinical trials.”

According to the researchers, response to poziotinib was mostly heterogeneous, which prompted investigators to look at the drug’s relationship with exon 20 insertions. What they found was that those patients with insertions occurring in the near-loop region near the αC helix (amino acids A767–P772) had a significantly higher ORR than those with insertions in the distal far-loop region (H773–C775) at 46% vs 0% (P = 0.0015), respectively.

Moreover, patient RECIST responses were correlated with mutation location (R = 0.32, P = 0.03), but the median PFS did not have a significant difference between patients with near- and far-loop insertions at 5.6 months vs 5.5 months (HR 0.76; 95% CI, 0.37-1.6, P = 0.45), respectively. However, the 6-month PFS rate favored patients with near-loop insertions at 47% (95% CI, 33%-67%) vs 30% (95% CI, 12%-76%) of patients with far-loop insertions and with the 12-month PFS rate at 32% (95% CI, 19%-52%) vs 20% (95% CI, 6%-68%). According to the investigators, while this study was limited by sample size, the better results show that poziotinib is more active in patients with near-loop EGFR exon 20 insertions.

“Defining EGFR exon 20 as a targetable mutation was a major step, and now we’ve taken one step further to find that even within exon 20, not all mutations are the same,” said lead author, Yasir Elamin, MD, assistant professor of Thoracic/Head & Neck Medical Oncology at the MD Anderson Cancer Center, in a press release that explained how this research has built on earlier findings, showing the potential for targeted EGFR exon 20 mutations in patients with cancer. “While further research is needed, these findings may be applicable to other exon 20 inhibitors, and future clinical trials should take exon 20 insertion location into consideration.”

The study was made up of heavily pretreated patients with 94% of patients having at least 1 prior systemic therapy with 68% of patients having received 2 or more prior lines of therapy. This included 6 patients (12%) who had received 4 or more prior lines of treatment. Patient characteristics showed that 60% were female with a median age of 62 years, and racial demographics showed 76% were white, 16% Asian, and 8% Black.

All patients were given 16 mg orally of poziotinib until objective disease progression, but patients could continue beyond their progression if clinical benefit was still observed.

Most patients experienced grade 1 or 2 toxicities with most experiencing diarrhea (92%), skin rash (90%), oral mucositis (68%), paronychia (68%) and dry skin (60%). Skin rash was the most common grade 3 toxicity (34%). According to the researchers, skin rash mostly presented as acneiform eruption, exfoliative dermatitis, or an overlapping of the 2 conditions. In order to manage skin rash, patients were offered a follow-up with a dermatologist during the first month of treatment, and patients with exfoliative dermatitis, a combination of medium-potency topical steroids, was given.

Just 3 patients discontinued treatment due to adverse events (AE), but 72% (n = 36) of patients had dose reductions due to AEs. At the time of data cutoff, 56% of patients had died, but there were no grade 4 or 5 treatment related AEs. While dose reductions were common, researchers saw this as tolerable data for the use of poziotinib in this patient population.

“These data demonstrate that poziotinib is a clinically active and tolerable inhibitor of EGFR exon 20 insertion mutations with meaningful clinical activity in platinum-refractory patients, for whom limited therapeutic options are currently available, and that mechanisms of resistance to poziotinib in patients with EGFR exon 20-mutant NSCLC at least in part overlap with reported mechanisms of resistance to other EGFR inhibitors in patients with classical EGFR-mutant NSCLC,” the researchers concluded.

References

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 Jul 11;40(7):754-767.e6. doi:10.1016/j.ccell.2022.06.006

2. Poziotinib is active in EGFR exon 20 mutant non-small cell lung cancer with efficacy highly dependent on insertion location. MD Anderson Cancer Center. July 11, 2022. Accessed July 18, 2022. https://bit.ly/3RLRp2T