FDA Grants Breakthrough Therapy Designation to BAY 2927088 for HER2-Mutated NSCLC


BAY 2927088 has received breakthrough therapy designation by the FDA for pretreated non–small cell lung cancer harboring activating HER2 mutations.



The FDA has granted breakthrough therapy designation to the small molecule TKI BAY 2927088 for the treatment of patients with unresectable or metastatic non–small cell lung cancer (NSCLC) whose tumors have activating HER2 mutations, and who have received prior systemic therapy, according to a press release from Bayer.1

The oral, reversible, noncovalent TKI is highly potent and selective for both HER2 exon 20 insertions, HER2 point mutations, and EGFR mutations.

The designation was supported by initial results from a phase 1/2 study (NCT05099172) of BAY 2927088 in adult patients with advanced NSCLC harboring HER2 or EGFR mutations.

Early efficacy and safety data from the dose-escalation and backfill portions of the study were reported during the 2023 ESMO Congress, and demonstrated anti-tumor activity as well as a manageable safety profile with BAY 2927088 when administered up to 60 mg a day in patients with HER2– or EGFR-mutated NSCLC. This was seen particularly in patients whose disease expressed HER2 exon 20 mutations.2

At the data cutoff of August 18, 2023, the overall response rate (ORR) with BAY2927088 was 26% (95% CI, 16.3%-38.1%) in all efficacy-evaluable patients (n = 69), including 1 complete response, 13 partial responses (PR), and 1 unconfirmed PR. Notably, the ORR was 60% (95% CI, 36.1%-80.9%) in patients with HER2 exon 20 insertion mutant disease (n = 20). In the overall population, 29% of patients achieved stable disease (SD), and 29.0% experienced progressive disease (PD). In the HER2 exon 20 mutation subgroup, 30.0% of patients had SD and 5.0% of patients experienced PD. The disease control rates were 55.1% (95% CI, 42.6%-67.1%) in the overall population and 80.0% (95% CI, 56.3%-94.3%) in the HER2 exon 20 mutation subgroup.

“Early clinical evidence suggests that BAY 2927088, our investigational novel oral [TKI], has the potential to benefit patients with NSCLC harboring a HER2 mutation [who] have progressed on a prior systemic therapy and currently have no other approved treatment available,” Dominik Ruettinger, MD, PhD, head of Research and Early Development for Oncology in Bayer’s Pharmaceuticals Division, stated in the press release. “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.”

This open-label, multicenter, first-in-human study evaluated the safety, pharmacokinetics, and preliminary efficacy of BAY 2927088 in patients 18 years or older with advanced NSCLC harboring HER2 or EGFR mutations.2 Patients were required to be relapsed/refractory to 1 or more systemic therapies; have adequate archival tumor tissue available from primary or metastatic sites; have measurable disease as per RECIST v1.1 criteria; and have an ECOG performance status of 0 or 1.3

In the dose-escalation phase, BAY 2927088 was orally administered once a day in 21-day cycles, following a Bayesian adaptive dose-selection model. The study included concurrent dose-escalation and backfill portions. Once-daily LSF doses ranged from 10 mg to 40 mg; once-daily tablet doses ranged from 20 mg to 60mg; and twice-daily tablet doses ranged from 20 mg to 40 mg. Backfill was initiated at doses shown to be safe and reached a predicted efficacious level or an ORR during dose escalation, with a maximum of 24 patients evaluable for efficacy per backfill cohort.

The study enrolled patients at 77 sites across 16 countries. A total of 76 patients were treated during the dose-escalation/backfill phase at the cut-off and were evaluable for safety. Other HER2 or EGFR mutations occurred in 73.7% of patients, with 26.3% of patients harboring HER2 exon 20 mutations.

The primary end points of the study are safety, tolerability, pharmacokinetics, and the maximum tolerated dose. Secondary objectives include ORR per RECIST v1.1 criteria by investigator assessment and the recommended phase 2 dose of the agent.2,3

Regarding safety, 5 patients experienced dose-limiting toxicities, including 3 patients at the twice-daily 40-mg dose, 1 at the twice-daily 30-mg dose, and 1 at the daily 60-mg dose. No discontinuation due to treatment-related adverse effects (TRAEs) was observed; however, 26.3% of patients underwent dose reductions due to TRAEs. A total of 86.8% of all patients experienced any-grade AEs. Most AEs were reversible and manageable, and only 2.6% of patients experienced serious TRAEs.2

Enrollment in the dose-expansion phase of the trial is ongoing. The study has an estimated completion date of July 31, 2028.3

“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,” Ruettinger concluded.


  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. https://www.bayer.com/media/en-us/bayer-receives-us-fda-breakthrough-therapy-designation-for-bay-2927088-for-non-small-cell-lung-cancer-harboring-her2-activating-mutations/
  2. Loong HHF, Daniel G, Yang T, 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):S755-S851. doi:10.1016/j.annonc.2023.09.2409
  3. First in human study of BAY2927088 in participants who have advanced non-small cell lung cancer (NSCLC) with mutations in the genes of Epidermal Growth Factor Receptor (EGFR) and/​or human Epidermal Growth Factor Receptor 2 (HER2). ClinicalTrials.gov. Updated January 29, 2024. Accessed February 26, 2024. https://clinicaltrials.gov/study/NCT05099172
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