Black Diamond Therapeutics (BDTX) Study Update summary

Key findings from phase II silevertinib study in NSCLC

• Silevertinib showed a 60% confirmed overall response rate in frontline NSCLC patients with 35 unique non-classical EGFR mutations, with responses across all mutation subclasses and a disease control rate over 90%.

• Robust CNS activity was observed, with confirmed CNS responses in 6 of 7 patients with target brain lesions and molecular responses in all evaluable patients, including 81% with complete ctDNA clearance; an 86% CNS response rate was reported.

• Median follow-up was 7.2 months; median PFS and duration of response are not yet reached, but early durability trends are encouraging, with 29 patients remaining on therapy and the longest ongoing for over 19 months.

• Silevertinib was generally well tolerated; most adverse events were managed with dose reductions to 150 mg or 100 mg or with supportive care, without compromising efficacy.

• The study population reflected real-world diversity, with over a third presenting with baseline brain metastasis and a wide range of EGFR NCMs.

Clinical expert perspectives and unmet need

• Current EGFR TKIs offer only modest efficacy for patients with non-classical EGFR mutations, especially regarding CNS penetration and control.

• About half of EGFR-mutated NSCLC patients will develop brain metastasis, highlighting the need for brain-penetrant therapies.

• Silevertinib demonstrated favorable responses in patients with uncommon EGFR mutations, including those with bulky brain metastasis and resistance to earlier TKIs.

• EGFR TKI-associated toxicities are manageable with established protocols, and dose reductions do not compromise efficacy or quality of life.

Planned phase II trial in glioblastoma (GBM)

• Silevertinib is designed to overcome past failures of EGFR inhibitors in GBM by targeting multiple EGFR variants, avoiding paradoxical activation, and achieving high CNS penetrance.

• Preclinical and early clinical data show silevertinib inhibits EGFR variant 3 and other alterations, with improved survival in intracranial GBM models.

• Over 60 recurrent GBM patients have been treated, with encouraging tolerability and efficacy, and pharmacologically relevant brain tumor exposure confirmed.

• The upcoming randomized phase II trial will enroll about 150 newly diagnosed, unmethylated MGMT-negative GBM patients with EGFR variant 3, randomizing to temozolomide alone or silevertinib plus temozolomide; initial data are expected in 2028.

• Primary endpoint is PFS by blinded review, with OS as secondary; an Independent Data Monitoring Committee will oversee the trial.