Black Diamond Therapeutics Teases Next-Quarter PFS Data for Silevertinib at TD Cowen Conference

Black Diamond Therapeutics (NASDAQ:BDTX) used a presentation at the 46th annual TD Cowen Healthcare Conference to highlight progress for its lead program, silevertinib, a fourth-generation epidermal growth factor receptor (EGFR) inhibitor being developed for patients with non-small cell lung cancer (NSCLC) harboring non-classical EGFR mutations and for glioblastoma (GBM).

Chief executive officer Mark Velleca said the company expects a key near-term catalyst next quarter, when it plans to present progression-free survival (PFS) data for silevertinib in frontline NSCLC patients. He also said Black Diamond has a “lean operating model” that provides more than two years of runway and funds the company through the phase 2 readout of its planned GBM study.

Focus on non-classical EGFR mutations in NSCLC

Velleca contrasted the treatment landscape for “classical” EGFR mutations—where multiple generations of inhibitors are approved and most patients now receive osimertinib (Tagrisso)—with the large and heterogeneous set of more than 50 “non-classical” EGFR mutations, which he said lack good treatment options.

He estimated that about one-quarter of EGFR-mutant NSCLC patients present with a non-classical mutation. According to Velleca, frontline patients with non-classical mutations are often treated with chemotherapy, afatinib, or osimertinib, with reported PFS in the range of six to 10 months in recent studies.

Black Diamond’s thesis is that silevertinib is designed to address these patients by combining:

• Broad mutational coverage across the non-classical EGFR spectrum
• High brain penetrance, aimed at treating central nervous system (CNS) metastases
• Once-daily oral dosing

Frontline phase 2 data: response rates and CNS activity

Velleca reviewed the company’s phase 2 development approach in NSCLC, noting that the trial began in 2023 in the recurrent setting (cohorts 1 and 2) and later expanded to enroll frontline patients (cohort 3) in 2024. He said final data from the recurrent cohorts are expected to be presented at a medical meeting in the second quarter of this year.

In frontline cohort 3, Velleca said Black Diamond enrolled 43 patients representing what he described as a real-world spectrum of non-classical EGFR mutations, with 35 distinct mutations and more than a third of patients harboring multiple or compound mutations. He also emphasized that more than one-third of patients had untreated brain metastases. Patients received 200 mg once daily.

Based on data the company disclosed in December, Velleca highlighted:

• Confirmed objective response rate (ORR): 60%
• Disease control rate (DCR): 93%
• CNS response rate: 86%

He said early durability signals were “encouraging,” citing 29 patients remaining on therapy and the longest on treatment for more than 19 months. The company expects to present preliminary duration of response and PFS data at a medical meeting in the second quarter.

In the Q&A, TD Cowen’s Marc Frahm asked how silevertinib’s data compares with other efforts in non-classical EGFR NSCLC, including furmonertinib. Velleca pointed to several distinctions: Black Diamond’s larger cohort (43 patients versus 22 cited for the comparator), the U.S.-heavy enrollment for Black Diamond versus primarily China enrollment for the referenced study, and broader mutation representation in Black Diamond’s cohort. He also underscored the difference in CNS response rates, stating that the comparator’s CNS response rate was 47% versus 86% with silevertinib.

Tolerability and dose reductions

Velleca said adverse events observed with silevertinib were typical of EGFR tyrosine kinase inhibitors, with grade 3 events described as EGFR-mediated (including rash, diarrhea, stomatitis, and paronychia). He said less than 10% of patients discontinued due to adverse events.

Frahm asked about a higher rate of dose reductions in the frontline cohort compared with prior trials. Velleca attributed this to frontline patients being more sensitive to EGFR-mediated adverse events than patients treated in later lines, and said the events were manageable with standard supportive care and/or dose reductions without compromising efficacy. He added that the company had not seen patients lose response after dose reduction to 150 mg and that some patients achieved their first response after a dose reduction.

On dosing strategy, Velleca said Black Diamond previously held a dose optimization meeting with the FDA in the recurrent setting, where the agency had no objections to moving forward with 200 mg, which is why 200 mg was selected for the frontline cohort. He said additional data are expected to inform discussions with regulators at an end-of-phase-2 meeting, including exposure-response analyses, population pharmacokinetics, and median dose intensity.

Plans to initiate randomized phase 2 trial in newly diagnosed GBM

Velleca also outlined Black Diamond’s plan to develop silevertinib in GBM, citing the high unmet need and the role of EGFR alterations in the disease. He said approximately 50% of GBM patients have an oncogenic EGFR alteration, with EGFR variant III present in about 30% of patients.

He said previous EGFR approaches in GBM have been limited by insufficient potency across the range of EGFR alterations and inadequate brain penetrance. Velleca stated that Black Diamond has treated more than 60 patients with recurrent GBM with silevertinib and has seen encouraging tolerability, preliminary evidence of clinical activity, and brain penetrance. He also described a phase 1 “window of opportunity” study showing pharmacologically relevant exposures in tumor tissue from non-contrast-enhancing brain regions, which he said had not been documented before with an EGFR TKI.

The company plans to initiate a randomized phase 2 trial in newly diagnosed GBM patients next quarter. After surgery and a brief course of chemoradiation, patients will be randomized to standard-of-care maintenance temozolomide (TMZ) or TMZ plus silevertinib. PFS analyses will be performed by an independent data monitoring committee.

During Q&A, Velleca said the trial design is finalized, with protocol feedback addressed and central IRB approval obtained, and that details are available on ClinicalTrials.gov. He described a safety run-in that starts at 150 mg plus TMZ and escalates to 200 mg plus TMZ if no dose-limiting toxicities are observed, with three patients per dose level and 30 days of observation at each level. He expects the safety run-in to be completed by the end of the third quarter, followed by the randomized portion, and said the company expects preliminary PFS data from the study in the first half of 2028.

Partnering and pipeline overview

Velleca said Black Diamond has had partnering discussions starting in late summer, with most interest focused on the frontline NSCLC population and some interest in GBM. He said “indication splits” have not historically worked well in oncology deals and emphasized that any deal structure would need to reflect the value of the drug across multiple indications. He also suggested that a partner could help address capital needs for pivotal lung cancer studies, particularly given higher EGFR prevalence in Asia.

Beyond silevertinib, Velleca briefly highlighted two additional pipeline programs: BDTX-4933, a clinical-stage Ras/Raf inhibitor partnered with Servier, and BDTX-4876, a preclinical FGFR inhibitor. He noted that milestone payments from the Servier agreement and potential partnering revenue for BDTX-4876 were not included in the company’s cash runway assumptions.

In response to investor questions about share-price performance versus the opportunity, Velleca said some investors appear to be waiting for a more mature dataset, including PFS, and cited the competitive landscape and broader swings in sentiment around precision small-molecule oncology.

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.