Silevertinib Shows Robust CNS Activity in EGFR-Mutated NSCLC Trial

Silevertinib (BDTX-1535), an investigational brain-penetrant EGFR inhibitor, demonstrated robust central nervous system (CNS) and systemic activity in patients with treatment-naive non–small cell lung cancer (NSCLC) harboring EGFR non-classical mutations (NCMs), according to updated phase 2 trial results (NCT05256290) announced by the developer, Black Diamond Therapeutics.¹

What were the efficacy outcomes?

As of an October 7, 2026, data cutoff, with a median follow-up of 15.9 months, silevertinib dosed at 200 mg once daily in 43 frontline patients with a broad spectrum of EGFR NCMs produced an overall response rate (ORR) of 60% per RECIST 1.1 criteria, a disease control rate of 93%, and a median progression-free survival (PFS) of 15.0 months (95% CI, 11.0-23.5) in the intention-to-treat population. Additionally, 18 patients remained on therapy, the longest for 26.2 months, with no new safety signals observed.

Among the 16 patients with untreated brain metastases (7 evaluable by RANO-BM), the CNS ORR was 86%, and the systemic median PFS was 12.2 months (95% CI, 8.1-not estimable [NE]) per RECIST 1.1 guidelines. Among the 24 patients without brain metastases, the median PFS was 23.5 months (95% CI, 11.0-NE), with no patients experiencing progression in the brain.

“There remains significant unmet medical need in [patients with] NSCLC with non-classical EGFR mutations, particularly in patients with brain metastases,” said Alex Spira, MD, PhD, director of the thoracic and phase 1 program at Virginia Cancer Specialists, chief scientific officer of NEXT Oncology, and a clinical investigator on the silevertinib phase 2 trial, in a news release.¹ “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.”

What was the FDA feedback and phase 3 plan?

Following an End-of-Phase-2 meeting with the FDA on October 1, 2026, Black Diamond intends to pursue a phase 3 program encompassing all treatment-naive populations with locally advanced or metastatic NSCLC whose tumors harbor an oncogenic EGFR mutation other than a classical mutation (exon 19 deletion, L858R) or an exon 20 insertion. Per the company, the FDA provided feedback on a potential accelerated approval based on CNS ORR per RANO-BM by blinded independent central review (BICR) and a potential full approval based on PFS per RECIST v1.1 by BICR, while indicating that systemic ORR and overall survival (OS) will need to be evaluated to demonstrate systemic ORR similarity to, and no evidence of an OS detriment compared with, the control arm. The planned global registrational trial would enroll 300 patients with EGFR NCMs and untreated brain metastases, randomly assigned 1:1 to silevertinib at 150 mg once daily or physician’s choice of osimertinib (Tagrisso) or afatinib (Gilotrif), with potential initiation in the second quarter of 2027. The trial would also include an 80-patient single-arm cohort of patients without brain metastases and a 20-patient single-arm cohort of patients with leptomeningeal disease.

“We believe the feedback we received supports a clear path to potential accelerated and full approval for silevertinib in [patients with] frontline NSCLC with EGFR [NCMs],” said Mark Velleca, MD, PhD, president and chief executive officer of Black Diamond, noting that patients with EGFR NCMs represent approximately 25% of the frontline EGFR-mutant population.¹

What is silevertinib?

Silevertinib is an investigational oral, covalent, brain-penetrant fourth-generation tyrosine kinase inhibitor (TKI) that selectively targets classical and more than 50 non-classical EGFR mutations in NSCLC. It is also designed to inhibit EGFR alterations seen in glioblastoma, including EGFRvIII, while avoiding the paradoxical EGFR activation reported with reversible TKIs.

The ongoing phase 2 trial is being conducted in the US and Canada; cohort 4 is now enrolling frontline patients with EGFR NCM NSCLC at the planned pivotal dose of 150 mg once daily, with safety data from a sufficient number of patients required by the FDA before opening the phase 3 trial.²

Sergey Yurasov, MD, PhD, chief medical officer of Black Diamond, added that the agent’s “ability to significantly delay CNS progression is the key driver of the durable clinical benefit we are seeing in patients both with and without baseline brain metastases and is the foundation of the pivotal program design in [first-line] NSCLC.”

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, Inc. November 10, 2026. Accessed November 10, 2026. https://tinyurl.com/yc4drpsb
2. Phase 1/2 study of silevertinib (BDTX-1535) in patients with glioblastoma or non-small cell lung cancer with EGFR mutations. ClinicalTrials.gov. Updated July 22, 2026. Accessed November 10, 2026. https://tinyurl.com/5bkwub8r