Zipalertinib Displayed Promising Preliminary Antitumor Activity Among Patients With EGFR-Mutant NSCLC

According to results of an international, multi-center, phase 1/2a study, zipalertinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with enhanced selectivity for EGFR exon 20 insertions (ex20ins)-mutant vs wild-type EGFR, displayed promising preliminary antitumor activity with acceptable safety among patients with heavily pretreated EGFR ex20ins-mutant non-small cell lung cancer (NSCLC).

Zofia Piotrowska, MD, MHS, Massachusetts General Hospital, Boston, Massachusetts, and coauthors, stated “EGFR TKIs targeting classical EGFR mutations have little to no efficacy in NSCLC harboring EGFR ex20ins…despite recent progress in the development of EGFR ex20ins-targeting therapies, there remains a significant need for novel agents that will maximize clinical efficacy while achieving a more favorable safety profile.”

A total of 73 patients with recurrent or metastatic NSCLC with an EGFR ex20ins mutation were enrolled. All patients had been previously treated with platinum-based chemotherapy, while 36% received previous non-ex20ins EGFR TKI therapy, and 4.1% received previous EGFR ex20ins TKI therapy. All patients received zipalertinib twice daily in 21-day cycles. Patients received zipalertinib in doses of 30 mg (n = 8), 45 mg (n = 1), 65 mg (n = 14), 100 mg (n = 13), and 150 mg (n = 11) until disease progression, unacceptable adverse events, patient withdraw, or discontinuation at investigator’s discretion, to assess for safety, tolerability, and antitumor activity in this patient population.

At the data cutoff date of May 9, 2022, patients experienced objective responses across all dose levels with confirmed partial response observed in 38.4% of response-evaluable patients. In patients in the 100 mg cohort, there was a confirmed partial response rate of 41% among response-evaluable patients. The median time to response was 1.5 months. At the initial 6-week disease assessment, 74% of patients had experienced a tumor regression, 33% of which had achieved an objective response.

The most frequent treatment-related adverse events included rash (80%), paronychia (32%), diarrhea (30%), and fatigue (21%). There were no grade ≥3 drug-related reactions of rash or diarrhea when patients were treated at doses of 100 mg twice daily or below.

Dr Piotrowska et al concluded, “zipalertinib may represent a more tolerable oral treatment option for patients with EGFR exon 20 insertion mutations than other currently available agents.” Associate editor for Journal of Clinical Oncology, Thomas E. Stinchcombe, MD, Duke University, Durham, North Carolina, added, “The preliminary efficacy and safety profile of zipalertinib are promising, and further investigation is justified."

Source: 

Piotrowska Z, Tan DSW, Smit EF, et al. Safety, tolerability, and antitumor activity of zipalertinib among patients with non–small cell lung cancer harboring epidermal growth factor receptor exon 20 insertions. J Clin Oncol. Published online June 29, 2023. doi:10.1200/JCO.23.00152