On September 23, 2024 Black Diamond Therapeutics, Inc. (Nasdaq: BDTX), a clinical-stage oncology company developing MasterKey therapies that target families of oncogenic mutations in patients with cancer, reported initial Phase 2 data demonstrating encouraging clinical responses and durability of BDTX-1535 in patients with relapsed/refractory epidermal growth factor receptor (EGFR)-mutant (EGFRm) non-small cell lung cancer (NSCLC) (Press release, Black Diamond Therapeutics, SEP 23, 2024, View Source [SID1234646811]).

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"Patients often become resistant to osimertinib with the emergence of on-target resistance EGFR mutations," said Sergey Yurasov, M.D., Chief Medical Officer of Black Diamond Therapeutics. "Our preliminary Phase 2 data demonstrate the potential of BDTX-1535 to deliver durable responses for these patients."

"Patients with recurrent EGFRm 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, M.D., Assistant Clinical Professor, 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."

Phase 2 preliminary data overview:

The phase 2 trial began in August of 2023, and enrolled relapsed/refractory patients with non-classical EGFR mutations (NCMs) (Cohort 1) and those with C797S resistance mutations (Cohort 2). Safety assessment and dose selection were based upon the first 40 patients randomized to receive BDTX-1535 once daily at either 100 mg or 200 mg across both Cohorts. Preliminary response rate and durability were assessed in 27 patients at 200 mg with an August 17, 2024, data cutoff, including 22 response-evaluable patients who met protocol eligibility criteria.

Key takeaways:

200 mg daily selected for pivotal clinical development. Dose selection was based primarily on pharmacokinetics, safety and tolerability data from 20 patients at 100 mg, and 20 patients at 200 mg.
Favorable tolerability profile at 200 mg, consistent with prior BDTX-1535 clinical data. The majority of adverse events were mild or moderate, and no new safety signals were observed. The most common on-target treatment-related adverse events were rash (70%) and diarrhea (35%). There were 2 cases of grade 3 rash, and no reported cases of grade 4 rash or grade 3/4 diarrhea.
Preliminary objective response rate (ORR) of 42% achieved in 19 patients. For the 22 response-evaluable patients, the preliminary ORR was 36%. Nineteen of these 22 patients expressed known osimertinib resistance mutations: either C797S or P-loop alpha-C helix compressing (PACC, a major subset of NCMs). Of these 19 patients, 8 achieved a response (42%): 5 with a confirmed partial response (PR), including 1 patient who converted from a PR to an unconfirmed complete response (CR) at 8 months (and awaits confirmatory scan); and 3 with an unconfirmed PR at first scan and awaiting a confirmatory scan. An additional 9 patients experienced stable disease.
Encouraging durability observed, with duration of response (DOR) of approximately 8 months or more for first 3 patients with PR; 14 of 19 patients remain on therapy. Mean follow-up time is 4.7 months.
"We are pleased to see significant Phase 2 clinical activity and tolerability that are consistent with our Phase 1 results," said Mark Velleca, M.D., Ph.D., 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."

Black Diamond continues to enroll patients in the second- and third-line cohorts, as well as in the first-line setting for patients with non-classical EGFR mutations. In Q1 2025, the Company expects to disclose initial results from the first-line cohort and to outline potential registrational paths in the recurrent setting based on FDA feedback.

About BDTX-1535

BDTX-1535 is an oral, brain-penetrant MasterKey inhibitor of oncogenic EGFR mutations in NSCLC, including classical driver mutations, non-classical driver mutations, and the acquired resistance C797S mutation. BDTX-1535 is a fourth-generation tyrosine kinase inhibitor (TKI) that potently inhibits, based on preclinical data, more than 50 oncogenic EGFR mutations expressed across a diverse group of patients with NSCLC in multiple lines of therapy. Based on preclinical data, BDTX-1535 also inhibits EGFR extracellular domain mutations and alterations commonly expressed in glioblastoma (GBM) and avoids paradoxical activation observed with earlier generation reversible TKIs. A "window of opportunity" trial of BDTX-1535 in patients with GBM is ongoing (NCT06072586) and a Phase 2 trial is ongoing in patients with NSCLC (NCT05256290).