Black Diamond Therapeutics (NASDAQ:BDTX) reported updated Phase 2 data for silevertinib in treatment-naive non-small cell lung cancer patients with EGFR Non-Classical Mutations, saying the investigational therapy produced a preliminary median progression-free survival of 15.2 months in the study cohort.
During a company webcast, Chief Executive Officer Mark Velleca said the results would be presented at the ASCO annual meeting on May 30 by Dr. Julia Rotow of the Dana-Farber Cancer Institute. Velleca described the data as showing “robust progression-free survival” in a patient population with significant unmet medical need.
Phase 2 Cohort Enrolled 43 Frontline Patients
Chief Medical Officer Sergey Yurasov said the update came from cohort 3 of the company’s Phase 2 study, which enrolled 43 treatment-naive non-small cell lung cancer patients with EGFR Non-Classical Mutations, or NCMs. Patients were enrolled based on local next-generation sequencing testing, and those with asymptomatic brain metastases were allowed. The trial required CNS surveillance by MRI.
All patients began treatment with silevertinib at 200 mg once daily. As of the April 11 data cut, median follow-up was 11.2 months. Yurasov said 74% of patients were Caucasian and 16% were Asian, and that the demographics reflected clinical practice.
Black Diamond said 44% of patients had baseline brain metastases, most of which were untreated. Seven patients had untreated and measurable brain metastases that could be evaluated using RANO-BM criteria. Patients presented with 33 unique Non-Classical Mutations, including PACC and classical-like NCMs, and more than one-third had compound mutations.
Company Reports Responses Across Mutation Subtypes
Yurasov said 26 of 43 patients achieved a confirmed radiographic response by RECIST 1.1 criteria, including 25 confirmed partial responses and one confirmed complete response. He said responses were observed across mutation subclasses, with objective response rates ranging from 56% to 73%. The disease control rate was reported at more than 90%.
The company said silevertinib also showed pharmacodynamic activity, with clearance of variant allele frequency in all evaluable patients across 25 unique mutations. Yurasov said these data supported the drug’s potential clinical activity across a broad spectrum of EGFR NCMs, including PACC mutations.
On durability, Yurasov said more than half of patients remained on treatment, with the longest patient on therapy for 23.5 months. The preliminary median progression-free survival was 15.2 months, which the company said represented a greater than 40% improvement compared with historical data for currently available therapies in this setting. Median duration of response had not been reached.
CNS Activity Highlighted as Key Data Point
Black Diamond executives emphasized CNS activity throughout the webcast. Velleca said patients with EGFR NCMs are vulnerable to CNS metastases, with approximately 40% presenting with brain metastases at diagnosis, and said CNS metastases are a major mechanism of progression on therapy.
Yurasov said no patient in the Phase 2 cohort had developed de novo brain metastasis while on silevertinib. Among the seven patients with untreated and measurable brain metastases, six had a confirmed CNS response, producing a CNS objective response rate of 86%. Responses were observed across a range of EGFR NCMs, including four patients with PACC mutations and three with compound mutations.
In response to a question from Robert Driscoll of Wedbush Securities, Yurasov said the absence of new brain metastases after roughly 12 months of follow-up could have “a direct positive impact” on progression-free survival. Velleca noted that some patients with CNS lesions that were not target lesions remained on treatment.
Dose Reduction and Safety Profile Discussed
Yurasov said the tolerability profile was consistent with other EGFR tyrosine kinase inhibitors, with the most common adverse events including rash, diarrhea, paronychia and stomatitis. He said these events were managed with supportive care and dose reductions.
All patients started at 200 mg daily, but the majority had dose reductions to 150 mg or 100 mg. The median dose intensity was 134 mg daily. Yurasov said the rate of Grade 3 or greater adverse events was reduced by half to 30% following dose reduction, while Velleca later said the overall rate of Grade 3 adverse events after dose reduction was 28%.
In response to Laura Prendergast of Stifel, Yurasov said adverse events were alleviated after dose reduction, adding that the drug showed a linear relationship between dose and adverse-event frequency. In response to another safety question, he said six patients discontinued study treatment due to an adverse event and that adverse events were successfully managed through dose reductions and supportive measures, typically improving to Grade 1 or resolving.
Black Diamond said the totality of the data supports using a 150 mg dose in a pivotal trial. Yurasov said the company has treated more than 200 patients with silevertinib across its program and believes 150 mg could present an optimal risk-benefit profile in the frontline setting, subject to discussion with the FDA.
Regulatory Path and Comparator Questions Remain Open
Executives said Black Diamond plans to discuss a pivotal development plan with the FDA but has not yet requested a meeting. Velleca said the company believes the data are strong enough to request a meeting and that updated data could be brought to the agency when the meeting occurs.
Asked about a potential accelerated approval pathway, Yurasov said the company looks forward to bringing the data to regulators. He said PACC mutations represent about half of EGFR NCM patients and are a structure-function-defined subgroup recognized by the FDA, but also said the company’s broader objective is to develop therapy for the full EGFR NCM population.
When asked about Phase 3 design considerations, including potential CNS endpoints and comparator arms, Velleca said the company would reserve specific comments until after discussions with the agency. He said potential pre-specified subset analyses could include CNS or certain mutation groups, while the comparator arm remains “a very open question.”
About Black Diamond Therapeutics (NASDAQ:BDTX)
Black Diamond Therapeutics, Inc is a precision oncology company focused on the discovery and development of small-molecule therapies that selectively target oncogenic proteins bearing tumor-driving mutations. Leveraging its proprietary Genetic Defined Allosteric (GDA) therapeutic platform, the company aims to identify unique allosteric binding sites in mutant proteins and engineer highly selective inhibitors. Headquartered in Cambridge, Massachusetts, Black Diamond applies structure-based drug design and molecular modeling to advance personalized cancer treatments.
The company’s development pipeline includes lead candidate BDTX-189, an allosteric inhibitor of mutant HER2, as well as programs directed at clinically relevant EGFR and KRAS mutations.
