Promising Efficacy Seen With Poziotinib in Heavily Pretreated EGFR/HER2+ NSCLC

Kristie L. Kahl

Promising efficacy was seen with the novel targeted therapy poziotinib in patients with metastatic, heavily pretreated&nbsp;<em>EGFR&nbsp;</em>and&nbsp;<em>HER2 </em>exon 20 mutant non&ndash;small cell lung cancer, with a best response rate to date of 55%, according to phase II study results presented at the 19th World Conference on Lung Cancer.

John V. Heymach, MD, PhD

Promising efficacy was seen with the novel targeted therapy poziotinib (NOV120101, HM781-36B) in patients with metastatic, heavily pretreatedEGFRandHER2exon 20 mutant non—small cell lung cancer (NSCLC), with a best response rate to date of 55%, according to phase II study results presented at the 19th World Conference on Lung Cancer (WCLC) in Toronto, Canada.

John V. Heymach, MD, PhD, who presented data of the investigator-initiated study of poziotinib inEGFRandHER2exon 20 mutant NSCLC (NCT03066206), added that a 43% confirmed objective response rate (ORR) was observed among evaluable patients with EGFRexon 20 mutant NSCLC in the study.

“Standard tyrosine kinase inhibitors [TKIs] have proven generally ineffective against exon 20 mutant disease,” said Heymach, principal investigator and professor in the Department of Thoracic Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center.

“For first- and second-generation TKIs, the response rate is 3%, or 8% if you include the known sensitive 763insFQEA, with the median progression-free survival of 2 months,” he added. “HER2exon 20 mutations’ responses are a little higher at 11.9%. The most promising data to date is for T-DM1 (ado-trastuzumab emtansine [Kadcyla]), which shows 6 out of 11 responses in a recent report. Standard-of-care options in these patients would include docetaxel and PD-1/PD-L1 inhibitors with response rates ranging from 3.6% to 19%.”

Poziotinib is a novel, orally available quinazoline-based TKI that irreversibly blocks signaling through the HER family of tyrosine kinase receptors andEGFRandHER2mutations, which in turn can lead to blocking of downstream signaling and inhibition of the proliferation of tumor cells.

Heymach added that the size and shape of poziotinib helps to overcome the hindered binding pocket of the quinazoline core, and that the agent demonstrated clinical activity as a selective inhibitor ofEGFRandHER2exon 20 mutations in vitro.

Therefore, in an open-label, single-center phase II study, the investigators administered 16 mg of oral poziotinib to 2 cohorts of patients—EGFR(n = 50) andHER2(n = 30) exon 20 mutant NSCLC—until progression, death, or withdrawal.

The majority of theEGFRandHER2exon 20 cohorts were female (60% and 85%, respectively) at a median age of 62 and 60 years. Overall, 86% of the EGFR cohort and 77% of the HER2cohort previously received platinum-based therapy, and 54% and 62%, respectively, had prior PD-1/PD-L1 inhibitor therapy.

ORR served as the primary endpoint, and secondary endpoints included PFS, disease control rate, duration of response, and safety and toxicity.

In theEGFRexon 20 cohort, 44 patients were evaluable. ORR was 55%, with a confirmed ORR of 43%. Nineteen of these patients remain on treatment as of the data cutoff on September 12, 2018. In the intent-to-treat population, median PFS was 5.5 months (95% CI, 5.2-NA).

“Durable responses have been observed, with 6 treated patients already treated for a year thus far,” Heymach added. “This compares favorably to historical response rates of less than 8% for approved TKIs and less than 19% for standard-of-care, second-line agents.”

In theHER2exon 20 cohort, 12 patients were evaluable. The ORR was 50%, with a 42% confirmed ORR. Among all 13 patients in this arm, PFS was 5.1 months. Five patients remained on treatment at the data cutoff.

“This encouraging activity has prompted a confirmatory, international, multicenter study inEGFRandHER2exon 20 mutant patients, which is currently enrolling, and now includes a first-line cohort, as well as development of a separate pan-tumor basket study,” Heymach said.

Fifty-six percent of patients experienced grade 3/4 treatment-related adverse events (TRAEs), which led to dose reductions in 38 patients (60%) and treatment discontinuation in 2 (3%). The most common grade 3/4 TRAEs included skin rash (34.9%) and diarrhea (17.5%).

“EGFR-related toxicities—including rash, diarrhea, and paronychia—were substantial but manageable,” Heymach noted.

Reference:

Heymach J, Negrao M, Robichaux J, et al. A phase II trial of poziotinib in EGFR and HER2 exon 20 mutant non-small cell lung cancer (NSCLC). Presented at: The IASLC 19th World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada. Abstract OA02.06.