Silevertinib CNS Activity Supports Planned Phase 3 in EGFR-Mutant NSCLC

Frontline silevertinib (BDTX-1535), a brain-penetrant EGFR tyrosine kinase inhibitor (TKI), demonstrated favorable efficacy in patients with nonclassical EGFR-mutated non–small cell lung cancer (NSCLC) including those with untreated brain metastases, leading to feedback from the FDA supporting a planned registrational phase 3 trial, according to a news release.¹

In the phase 2 portion of a phase 1/2 trial (NCT05256290), silevertinib resulted in a 60% objective response rate (ORR) and a median progression-free survival (PFS) of 15.0 months in patients with NSCLC harboring nonclassical EGFR mutations. At a median follow-up of 15.9 months and an October 7, 2026, data cutoff, the disease control rate (DCR) was 93% and the median PFS was 15.0 months (95% CI, 11.0-23.5). Eighteen of 43 patients remained on treatment, the longest for 26.2 months.

“There remains significant unmet medical need in NSCLC patients with non-classical EGFR mutations, particularly in patients with brain metastases,” said Alexander Spira, MD, PhD, director of the Thoracic and Phase I Program at Virginia Cancer Specialists, chief scientific officer of NEXT Oncology, and an investigator on the trial, in the news release.

Drug and Trial Background

Silevertinib is an investigational fourth-generation, covalent EGFR TKI that selectively targets classical EGFR mutations as well as more than 50 nonclassical EGFR mutations in NSCLC and EGFR alterations seen in glioblastoma.¹ The updated results come from 43 patients in the United States and Canada treated at 200 mg once daily who had received no prior treatment for advanced NSCLC.

The median age in this population was 70.0 years, 42% of whom were never-smokers.² Additionally, 72% were female and 74% were White. The 43 patients had 35 unique nonclassical mutation types, 25 patients with PACC mutations, and 16 with 2 or more 2 nonclassical mutations. The primary end point is ORR by RECIST v1.1.

Intracranial Findings Stand Out

Of 16 patients with untreated brain metastases at baseline, 7 were evaluable by Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, and the central nervous system (CNS) ORR among them was 86%. Systemic median PFS in this subgroup was 12.2 months (95% CI, 8.1-not estimable [NE]).¹

Among 24 patients without brain metastases, the median PFS was 23.5 months (95% CI, 11.0-NE), and none had disease progression in the brain. In the news release, the trial sponsor Black Diamond Therapeutics characterized the brain metastasis subgroup’s PFS as double that of currently available EGFR TKIs, a cross-trial comparison it acknowledged is limited by differences in trial design and populations.

“Along with the exciting CNS response rate and [PFS] data from this phase 2 trial, it is remarkable that not a single frontline patient treated with silevertinib has developed de novo brain metastases,” Spira stated in the news release.

The release stated that no new safety signals were observed. In an earlier analysis of the 43 patients presented at the 2026 ASCO Annual Meeting, grade 3 treatment-related adverse events (TRAEs) included rash (19%), diarrhea (19%), stomatitis (9%), and paronychia (5%). Serious TRAEs occurred in 12% of patients, 9% discontinued because of TRAEs, and 77% required dose reductions.²

FDA Feedback and Phase 3 Plan

At an end-of-phase 2 meeting on October 1, 2026, the FDA provided feedback on a phase 3 program in treatment-naive patients with locally advanced or metastatic NSCLC harboring oncogenic EGFR mutations other than exon 19 deletions, L858R, or exon 20 insertions, according to the company.¹

Black Diamond said the agency indicated that CNS ORR by RANO-BM per blinded independent central review (BICR) could support accelerated approval and that PFS per RECIST v1.1 by BICR could support full approval. Systemic ORR and overall survival will need to be evaluated to show similarity in systemic response and no survival detriment vs the control arm.¹

The planned global phase 3 trial would randomly assign 300 patients with non-classical EGFR mutations and untreated brain metastases 1:1 to silevertinib 150 mg once daily or physician’s choice of osimertinib (Tagrisso) or afatinib (Gilotrif). The trial would also include single-arm cohorts of 80 patients without brain metastases and 20 patients with leptomeningeal disease. The company anticipates initiating the trial in the second quarter of 2027, with preliminary data in 2028.¹

The FDA acknowledged the company’s rationale for 150 mg once daily as the pivotal dose but is requiring safety data from enough patients treated at that dose before the phase 3 trial opens. Cohort 4 of the phase 2 trial is enrolling 20 frontline patients at 150 mg and dosed its first patient in the third quarter of 2026.¹

“This trial design offers a differentiated path to potential accelerated approval in EGFR-NCM patients, who represent about 25% of the frontline EGFR-mutant patient population,” Mark Velleca, MD, PhD, president and chief executive officer of Black Diamond Therapeutics, stated in a news release.¹

Additional Development

Silevertinib is also being evaluated at 150 mg once daily in the randomized portion of a phase 2 trial (NCT07326566) in newly diagnosed EGFRvIII-positive glioblastoma, with PFS as the primary end point. The dose was selected after no dose-limiting toxicities were observed in 6 patients treated with silevertinib plus temozolomide in a safety run-in. Approximately 150 patients are expected to be randomly assigned. Patients must have received surgery to remove or reduce the size of the tumor as well as adjuvant radiation therapy and temozolomide.³ The company expects an interim PFS readout during the first half of 2028.¹

REFERENCES

1. Black Diamond Therapeutics Announces Positive Updated Silevertinib Phase 2 Results, FDA Feedback Supporting a Clear Path to Potential Registration in 1L EGFR-NCM NSCLC, and Provides Corporate Update. News release. Black Diamond Therapeutics. November 10, 2026. Accessed November 10, 2026. https://tinyurl.com/nnmpzf2a

2. Rotow JK, Baik CS, Dimou A, et al. Safety and efficacy results of the phase 2 study of silevertinib (BDTX-1535) in treatment-naïve patients with non-small cell lung cancer with non-classical EGFR mutations. J Clin Oncol. 2026;44(suppl 16):8519. doi:10.1200/JCO.2026.44.16_suppl.8519

3. Study of Silevertinib With Temozolomide for the Treatment of Newly Diagnosed GBM With Unmethylated MGMT and EGFRvIII. ClinicalTrials.gov. Updated November 2, 2026. https://clinicaltrials.gov/study/NCT07326566