Silevertinib Drives CNS Responses in First-Line NSCLC With Non-Classical EGFR Mutations

Silevertinib produced responses in NSCLC harboring non-classical EGFR mutations and will also be investigated in newly diagnosed glioblastoma.

Treatment with the brain-penetrant, fourth-generation EGFR inhibitor silevertinib (BDTX-1535) yielded central nervous system (CNS) responses in the first-line treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring non-classical EGFR mutations, according to data from the phase 2 BDTX-1535-101 trial (NCT05256290).1

Findings announced by Black Diamond Therapeutics showed that evaluable patients with first-line NSCLC (n = 43) achieved an objective response rate (ORR) of 60%, including 25 confirmed partial responses and 1 confirmed complete response. Furthermore, these patients achieved a CNS ORR of 86% per RANO-BM criteria. The disease control rate with silevertinib was 91%. As of data cutoff, 29 of 43 patients remained on treatment, including 5 patients who received the agent after disease progression. Notably, the longest ongoing response has persisted for more than 19 months.

Regarding safety, no new signals were reported. Common adverse effects (AEs) comprised rash, stomatitis, diarrhea, and paronychia.

“We are pleased to share these initial data in [patients with] frontline NSCLC showing silevertinib’s activity against a broad spectrum of 35 distinct non-classical EGFR mutations,” Mark Velleca, MD, PhD, president and chief executive officer of Black Diamond Therapeutics, stated in a news release. “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 non-classical EGFR–mutated] NSCLC treated with second- and third-generation EGFR TKIs. We also believe that silevertinib is uniquely positioned as a potential treatment for patients with newly diagnosed EGFR-altered glioblastoma [GBM], and plan to initiate a randomized phase 2 trial in the first half of 2026, while progression-free survival [PFS] data mature in our phase 2 NSCLC study and we continue our partnering discussions.”

Silevertinib in Frontline NSCLC With Non-Classical EGFR Mutations

  • The fourth-generation, brain-penetrant EGFR TKI silevertinib yielded a 60% ORR and 86% CNS ORR in the first-line treatment of patients with advanced NSCLC harboring non-classical EGFR mutations.
  • The first-line NSCLC cohort included 43 patients who had 35 distinct non-classical EGFR mutations.
  • A randomized phase 2 trial evaluating silevertinib in patients with newly diagnosed GBM is expected to launch in 2026.

How was the phase 1/2 study evaluating silevertinib designed?

BDTX-1535-101 was an open-label phase 1/2 trial that enrolled patients at least 18 years of age with locally advanced or metastatic NSCLC who had measurable disease per RECIST 1.1 criteria, a life expectancy of at least 3 months, adequate performance status, and adequate bone marrow and organ function.2 Patients could not have small cell lung cancer transformation, and the study included patients with or without brain metastases. Patients needed to display at least 1 non-classical EGFR mutation per next-generation sequencing.

In phase 2, investigators enrolled patients onto 1 of 3 cohorts:

  1. Cohort 1 included patients with locally advanced/metastatic NSCLC with non-classical EGFR driver mutations after up to 2 lines of therapy with only 1 prior EGFR TKI regimen.
  2. Cohort 2 featured patients with locally advanced/metastatic NSCLC harboring acquired EGFR C797S resistance mutations after up to 2 lines of therapy, including only one EGFR TKI, which needed to be a third-generation EGFR TKI such as osimertinib (Tagrisso).
  3. Cohort 3 enrolled treatment-naive patients with locally advanced/metastatic NSCLC harboring non-classical EGFR driver mutations; however, patients were allowed to have received 1 cycle of chemotherapy or an immune checkpoint inhibitor. Those with co-occurring EGFR exon 21 L858R mutations and non-classical mutations were allowed to participate.

In all cohorts, oral silevertinib was given as monotherapy in 21-day cycles.

The primary end point of phase 1 was to establish the maximum tolerated dose and recommended phase 2 dose. Investigator-assessed ORR per RECIST 1.1 criteria was the primary end point in phase 2. Secondary end points included safety, pharmacokinetics, duration of response, and PFS.

“These highly encouraging data speak to the potential of silevertinib to be the treatment of choice for [patients with] frontline NSCLC with the full spectrum of non-classical EGFR mutations,” Sergey Yurasov, MD, PhD, chief medical officer of Black Diamond Therapeutics, added in the news release.1 “We are struck by the compelling CNS response rate, which may translate to prolonged durability of response for patients with CNS metastases. Based on these data, and promising phase 0/1 and phase 1 GBM results, we are preparing to initiate a randomized phase 2 trial of silevertinib in newly diagnosed [patients with] GBM, one of the highest unmet needs in oncology.”

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 3, 2025. https://investors.blackdiamondtherapeutics.com/news-releases/news-release-details/black-diamond-therapeutics-announces-preliminary-phase-2-data
  2. Phase 1/​2 study of silevertinib (BDTX-1535) in patients with glioblastoma or non-small cell lung cancer with EGFR mutations. Updated July 11, 2025. Accessed December 3, 2025. https://clinicaltrials.gov/study/NCT05256290

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