Background: Despite recent advances in the treatment of EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC), most patients treated with third-generation (3G) EGFR tyrosine kinase inhibitors (TKIs), such as osimertinib, experience disease progression. The most common on-target EGFR resistance mutation is at the EGFR C797 residue (i.e., C797S), which prevents covalent binding to 3G EGFR TKIs. While 3G TKIs are effective in patients with EGFR activating and T790M mutations (commonly seen post-progression after first-/second-generation TKIs), there are no targeted therapies approved after their failure. BLU-945 is an investigational, reversible, and selective next-generation EGFR TKI intended for use as a single agent or in combination with other agents to suppress activating and on-target resistance EGFR mutants, including T790M and C797S, while sparing wildtype (wt) EGFR. BLU-945 has shown in vivo antitumor activity in 3G EGFR TKI-naïve as well as resistant NSCLC patient-derived xenograft models with EGFR T790M and C797S mutations. Based on this, we started SYMPHONY (NCT04862780), a phase 1/2 study in patients with metastatic EGFRm NSCLC, to determine the maximum tolerated dose and/or the recommended phase 2 dose (RP2D); and to assess the safety, pharmacokinetics (PK), and antitumor activity of BLU-945.

Methods: In the ongoing phase 1 dose-escalation part of the study, patients aged ≥18 years with metastatic EGFRm NSCLC previously treated with ≥1 EGFR TKI (Eastern Cooperative Oncology Group performance status of 0-2) received BLU-945 once daily (QD) on a 28-day cycle following a Bayesian Optimal Interval escalation design. Adverse events (AEs), dose-limiting toxicities (DLTs), PK, ctDNA (in real-time using FoundationOne Liquid panel), and radiographic antitumor activity (by RECIST 1.1 criteria) were assessed in the first 4 treatment cohorts.

Results: As of the January 7, 2022, data cut, 18 patients have been treated with BLU-945 at 25-200 mg QD. Of these, 14 (77.8%) patients had received ≥2 lines of prior systemic anticancer therapy in the metastatic setting. There were no DLTs, and most AEs were low grade. Treatment-related AEs (all Grade 1) occurred in 8 (44.4%) patients with the most common being nausea (n=3). EGFR mutation allele fraction assessment by ctDNA at C1D1 and C1D15 showed that tumors were heterogeneous at baseline. At doses of 50 mg QD and higher, reductions in EGFR resistance mutation allele fraction were seen in all patients (n=3) with EGFR C797S (n=2) and/or T790M (n=3) resistance mutations, with a median 48% reduction of these mutations. 50% of patients remain on treatment and dose escalation continues to determine the RP2D.

Conclusion: As of the data cut, BLU-945 was generally well tolerated in heavily pre-treated patients with EGFRm NSCLC. There was also early evidence of a reduction in EGFR mutation allele fractions by ctDNA.

Citation Format: Elaine Shum, Yasir Elamin, Karen L. Reckamp, Zofia Piotrowska, Julia Rotow, Daniel S. Tan, Koichi Goto, Jagan Parepally, Faris Albayya, Melinda Louie-Gao, Renata Sawtell, Alena Zalutskaya, David Spigel. Emerging evidence of activity of BLU-945 in patients with advanced EGFR-mutant NSCLC utilizing circulating tumor DNA (ctDNA) in the phase 1/2 SYMPHONY study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT184.