BDTX-1535, a fourth-generation EGFR tyrosine kinase inhibitor (TKI), is showing early signals of robust clinical activity and durability in patients with relapsed/refractory, EGFR-mutant non-small cell lung cancer (NSCLC), including those harboring classical, non-classical, or C797S resistance mutations. These initial findings come from a phase 2 trial (NCT05256290).
Promising Phase 2 Results
As of the data cutoff on August 17, 2024, 27 patients were evaluable for preliminary overall response rate (ORR) and durability, with 22 meeting protocol criteria. Among these 22 patients, the preliminary ORR was 36%. Notably, 19 of these patients had disease expressing known osimertinib (Tagrisso) resistance mutations, specifically EGFR C797S or PACC. In this subgroup of 19 patients, the ORR was 42%, with 5 patients achieving a confirmed partial response (PR), including one who converted from a PR to an unconfirmed complete response at 8 months. Furthermore, 9 patients experienced stable disease.
Optimal Dose Selected
A daily dose of 200 mg of BDTX-1535 has been chosen for pivotal clinical development based on pharmacokinetics, safety, and tolerability data from 20 patients each who received the agent at 100 mg or 200 mg.
Expert Commentary
"Patients with recurrent EGFR-mutant NSCLC have few treatment options, with chemotherapy delivering limited benefit and significant toxicity, and initial phase 2 data with BDTX-1535 look quite promising," said Danny Nguyen, MD, Assistant Clinical Professor in the Department of Medical Oncology and Therapeutics Research at City of Hope. "There is a significant unmet medical need for an effective and well-tolerated oral therapy for patients who progress on osimertinib, as well as newly diagnosed patients with non-classical mutations."
Trial Design and Patient Population
The phase 2 trial began enrollment in August 2023, enrolling relapsed/refractory NSCLC patients with non-classical EGFR mutations (cohort 1) and those with C797S resistance mutations (cohort 2). The safety assessment and dose selection were based on data from the first 40 patients randomized to receive once-daily BDTX-1535 at either 100 mg or 200 mg across both cohorts. Eligible patients were at least 18 years old with measurable disease per RECIST 1.1 criteria, adequate organ and bone marrow function, a life expectancy of at least 3 months, and confirmed NSCLC without small cell lung cancer transformation. Patients with brain metastases were allowed, provided they had disease progression following standard-of-care therapies.
Endpoints and Durability
The primary endpoint of the phase 2 trial is ORR. Key secondary endpoints include treatment-emergent adverse effects (AEs), plasma concentration, preliminary antitumor activity, duration of response (DOR), progression-free survival, central nervous system ORR, and identification of the optimal dose of BDTX-1535. At a mean follow-up of 4.7 months, the median DOR was approximately 8 months or more for the first 3 patients to achieve a PR. 14 of the 19 patients with known osimertinib resistance mutations remained on treatment as of the data cutoff.
Tolerability and Safety Profile
BDTX-1535 at 200 mg was found to be tolerable. Most AEs were mild or moderate, with no new safety signals observed. The most common on-target treatment-related AEs were rash (70%) and diarrhea (35%). Two cases of grade 3 rash were reported, but no cases of grade 4 rash or grade 3/4 diarrhea occurred.
Future Directions
"We are pleased to see significant phase 2 clinical activity and tolerability that are consistent with our phase 1 results," said Mark Velleca, MD, PhD, Chief Executive Officer of Black Diamond Therapeutics. "We believe that the activity observed in the recurrent setting can translate to robust clinical benefit in the first-line setting, and we look forward to sharing data from our trial in newly diagnosed patients in Q1 2025."
The phase 2 trial is ongoing, enrolling patients in second- and third-line cohorts, as well as a first-line cohort of patients with non-classical EGFR mutations. Black Diamond Therapeutics anticipates reporting initial results from the frontline cohort and outlining potential registrational paths for BDTX-1535 in recurrent NSCLC in Q1 2025, based on FDA feedback.
