Silevertinib Displays Robust Antitumor Activity in EGFR-Mutated NSCLC

Silevertinib (BDTX-1535) displayed robust antitumor activity and central nervous system (CNS) responses among patients with non–small cell lung cancer (NSCLC) harboring non-classical EGFR mutations in a phase 2 trial (NCT05256290), according to a news release from the developer, Black Diamond Therapeutics.¹

Topline efficacy data revealed that the investigational agent delivered an objective response rate (ORR) of 60% per RECIST v1.1 criteria and a CNS ORR of 86% per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria among 43 patients treated on the trial. There was a total of 25 confirmed partial responses and 1 confirmed complete response. The disease control rate was 91%.

Furthermore, after a median follow-up of 7.2 months, 29 patients were receiving ongoing therapy, including 5 patients who had experienced disease progression. One patient receiving ongoing treatment had been on therapy for more than 19 months.

Moreover, no new safety signals were observed with silevertinib, and adverse effects (AEs) were managed with standard supportive care. No dose interruptions/reductions were observed without comprising depth or durability of response. The most common AEs included rash, stomatitis, diarrhea, and paronychia.

“We are pleased to share these initial data in frontline patients [with NSCLC] showing silevertinib’s activity against a broad spectrum of 35 distinct non-classical EGFR mutations,” said Mark Velleca, MD, PhD, president and chief executive officer of Black Diamond Therapeutics, in the news release on the phase 2 data.¹ “We are particularly encouraged by the CNS activity of silevertinib in treating patients [with NSCLC] with brain metastases, as published data clearly demonstrate that CNS metastases are a key factor in early disease progression for patients [with NSCLC with non-classical EGFR mutations] treated with second- and third-generation EGFR [tyrosine kinase inhibitors].”

In the phase 2 NSCLC trial, patients with NSCLC harboring 35 distinct non-classical EGFR mutations were enrolled, including 16 patients with brain metastases, 7 of whom had targetable CNS lesions. In the phase 1 portion of the trial, patients with glioblastoma harboring EGFR alterations were included.² All patients received 200 mg of the investigational agent orally as a monotherapy in the phase 2 portion of the trial.

The primary end point of phase 1 portion of the trial was the maximum tolerated dose; the primary end point of the phase 2 portion of the study was ORR. Secondary end points included incidence and severity of treatment-emergent AEs, plasma concentrations of silevertinib, duration of response, and progression-free survival (PFS).

Additionally, the developers have outlined plans for a randomized phase 2 trial evaluating silevertinib among patients with newly diagnosed glioblastoma, given that approximately 50% of these patients present with an oncogenic EGFR alteration that can be targeted by the agent. Investigators will enroll approximately 150 patients and randomly assign them to receive temozolomide (Temodar) alone or with silevertinib. Patients with EGFRvIII-positive and unmethylated status will undergo random assignment following surgical resection and radiation, and the trial will be governed by an independent data monitoring committee.

The primary end point will be PFS per RANO criteria by blinded independent committee review, and the secondary end point will be overall survival (OS). The trial is planned to start in the first half of 2026, and preliminary findings are expected by 2028.

“Prior attempts to treat [patients with] EGFR-altered [glioblastoma] have been limited by poor brain penetrance of targeted therapies and/or lack of potency of these therapies on the full spectrum of EGFR alterations,” Elizabeth Buck, PhD, chief scientific officer of Black Diamond Therapeutics, expressed in the news release.¹ “Based on encouraging CNS activity demonstrated by silevertinib across multiple trials, and its preclinical potency on all EGFR alterations found in [glioblastoma], we believe that silevertinib has the potential to be the first targeted therapy for these patients.”

References

1. Black Diamond Therapeutics announces preliminary phase 2 data for silevertinib in 1L NSCLC and plans for a phase 2 trial of silevertinib in GBM. News release. Black Diamond Therapeutics. December 3, 2025. Accessed December 4, 2025. https://tinyurl.com/4rws8pdd
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 11, 2025. Accessed December 4, 2025. https://tinyurl.com/ycvvun95