Safety and efficacy results of the phase 2 study of silevertinib (BDTX-1535) in previously treated patients with non-small cell lung cancer with non-classical and C797S EGFR mutations.

Abstract

8620 Background: Despite significant benefit from FDA-approved EGFR tyrosine kinase inhibitors (TKIs), patients with classical EGFR mutation positive non-small cell lung cancer (NSCLC) ultimately develop progressive disease due to mechanisms of resistance, including alterations of the EGFR pathway. A broad group of non-classical EGFR mutations (NCM), including P-loop and αC-helix compressing (PACC) mutations, and acquired C797S are major mechanisms of EGFR resistance. Silevertinib (BDTX-1535) is a fourth-generation covalent EGFR TKI with high CNS penetrance that targets classical mutations, NCM, and C797S mutations. Antitumor activity and safety of silevertinib in advanced NSCLC were evaluated in an open-label Phase 2 trial (NCT05256290). Methods: Patients (pts) with recurrent NSCLC following ≤ 2 lines of therapy with only 1 prior EGFR TKI (osimertinib preferred) and tumors positive for NCM (NCM Cohort) or C797S mutation (C797S Cohort) were enrolled based on a local molecular test. Based on dose optimization of silevertinib at 100 mg and 200 mg orally once daily, all patients after May 2024 received 200 mg once daily. The primary endpoint was ORR by RECIST v1.1, and secondary endpoints included progression-free survival (PFS), duration of response (DOR), dose optimization, and safety. Results: From August 2023 to January 2025, 41 pts were treated in the NCM Cohort (100 mg, n=11; 200 mg, n=30; 80% female; 56% white; 49% with CNS metastases) and 42 pts were treated in the C797S Cohort (100mg, n=9; 200mg, n=33; 62% female; 48% white; 31% with CNS metastases). In both cohorts, 29% of pts had received 2 prior therapies. As of November 3, 2025, median follow-up was 9.5 months for pts treated with the 200 mg dose. ORR and median duration of treatment (DoT) are shown in the table. Alterations of other oncogenic pathways (e.g. MET, RET, RAS, and RAF) were observed at baseline in approximately 20% of pts in post hoc analyses. For the 200 mg dose, serious treatment-related adverse events (TRAEs) were reported in 7 (11%) pts, and 5 (8%) of pts discontinued treatment due to TRAEs. The most common TRAEs at 200 mg included rash (13%, grade 3), diarrhea (8%, grade 3), stomatitis (2%, grade 3), and paronychia (2%, grade 3). Available PFS, DOR, and dose optimization results will be presented. Conclusions: Silevertinib demonstrated antitumor activity at 200 mg orally once daily in patients with recurrent NSCLC, EGFR NCMs, and acquired resistance C797S mutation with a safety profile consistent with the EGFR TKI class. Clinical trial information: NCT05256290 . Cohort Dose n ORR (%, 95% CI) Median duration of treatment, mo (range) NCM Cohort 200 mg 30 16.7% (5.6–34.7) 4.99 (0.99-11.47) PACC mutations 200 mg 23 21.7% (7.5–43.7) 4.86 (1.28-11.47) C797S Cohort 200 mg 33 36.4% (20.4–54.9) 4.76 (0.46-12.55)