Novel TKI Earns FDA Breakthrough Therapy Designation in HER2-Mutated NSCLC

Supporting data for the breakthrough therapy designation came from an open-label, multicenter, first-in-human phase 1 trial (NCT05099172) assessing the preliminary efficacy, safety, and pharmacokinetics of BAY 2927088 in adult patients with HER2- or EGFR-mutated NSCLC.

The FDA has granted breakthrough therapy designation to BAY 2927088, a novel oral small molecule tyrosine kinase inhibitor (TKI), as a treatment for patients with unresectable or metastatic HER2-mutated non–small cell lung cancer (NSCLC) who have previously received systemic therapy, according to a press release from Bayer.¹

Supporting data for the breakthrough therapy designation came from an open-label, multicenter, first-in-human phase 1 trial (NCT05099172) assessing the preliminary efficacy, safety, and pharmacokinetics of BAY 2927088 in adult patients with HER2- or EGFR-mutated NSCLC. Investigators presented preliminary evidence from the phase 1 trial as an abstract at the 2023 European Society for Medical Oncology Congress (ESMO).

Data from the trial highlighted an overall response rate (ORR) of 26% (n = 18/69), which included unconfirmed partial responses (PRs) in 4 patients.² Additionally, the ORR was 60% among 20 evaluable patients with HER2 exon 20 insertion mutant NSCLC; among this group, investigators reported 1 complete response (CR), 8 PRs, and 3 unconfirmed PRs.

Among 76 patients evaluable for safety, treatment with BAY 2927088 resulted in 5 dose-limiting toxicities. Additionally, any grade and grade 3/4 drug-related treatment-emergent adverse effects (TEAEs) affected 87% and 25% of patients, respectively. There were no drug-related TEAEs that resulted in treatment discontinuation. Common drug-related TEAEs included diarrhea (75%), paronychia (25%), and dry skin (22%).

“Early clinical evidence suggests that BAY 2927088, our investigational novel oral [TKI], has the potential to benefit patients with NSCLC harboring a HER2 mutation that has progressed on a prior systemic therapy and currently has no other approved treatment available,” Dominik Ruettinger, MD, PhD, head of Research and Early Development for Oncology at Bayer’s Pharmaceuticals Division, said in the press release.¹ “This breakthrough therapy designation is a significant milestone in our relentless efforts to develop innovative therapies for the treatment of lung cancer characterized by specific genomic markers. We will continue working closely with the FDA to advance BAY 2927088 through the clinic and look forward to providing these patients with lung cancer and their physicians with a targeted, effective treatment option.”

In the phase 1 trial, investigators administered oral BAY 2927088 once a day in 21-day cycles based on a Bayesian adaptive dose-selection model. The dose-escalation and backfill portions of the trial ran concurrently.

The trial’s primary end points included TEAE, serious TEAEs, the maximum tolerated dose, dose-limiting toxicities, and ORR as assessed by blinded independent central review (BICR) per RECIST v1.1 criteria. Secondary end points included disease control rate, duration of response, progression-free survival, and overall survival.

Patients 18 years and older with histologically or cytologically confirmed locally advanced, recurrent, or metastatic NSCLC and documented disease progression following 1 or more prior lines of therapy for advanced disease were able to enroll on the trial. Additional eligibility criteria included having measurable disease per RECIST v1.1 guidelines, documented EGFR and/or HER2 mutations, an ECOG performance status of 0 or 1, and a life expectancy of at least 12 weeks. Patients were also required to have adequate bone marrow, kidney, and liver function to enroll on the trial.

Those who had prior treatment with a systemic anti-cancer therapy or radiotherapy within 14 days of study entry were not eligible to enroll on the trial. Patients were also unsuitable for enrollment if they had any unresolved toxicity of grade 2 or higher following prior anti-cancer treatment, any primary brain or leptomeningeal disease, symptomatic central nervous system (CNS) metastases, or CNS metastases requiring local treatment.

References

1. Bayer receives U.S. FDA breakthrough therapy designation for BAY 2927088 for non-small cell lung cancer harboring HER2 activating mutations. News release. Bayer. February 26, 2024. Accessed February 26, 2024. http://tinyurl.com/ypyny52h
2. Loong HHF, Daniele G, Yang TY, et al. Early evidence of efficacy in patients (pts) with non-small cell lung cancer (NSCLC) with HER2 exon20 insertion (ex20ins) mutations treated in a phase I study with BAY 2927088. Ann Oncol. 2023;34(suppl 2):S761-S762. doi:10.1016/j.annonc.2023.09.2409