Silevertinib Yields Significant Response Rates in Frontline EGFR Non-Classically–Mutated NSCLC

June 3, 2026 | Kyle Doherty

The covalent, central nervous system (CNS)–penetrant, fourth-generation EGFR TKI silevertinib (BDTX-1535) displayed promising antitumor activity with a manageable safety profile in treatment-naive patients with non–small cell lung cancer (NSCLC) harboring non-classical EGFR mutations, according to data from a phase 2 trial (NCT05256290) presented during the 2026 ASCO Annual Meeting.¹

Patients who received silevertinib (n = 43) experienced an investigator-assessed objective response rate (ORR) of 60% per RECIST 1.1 criteria, including a 2% complete response rate. The disease control rate (DCR) was 91% and the preliminary median progression-free survival (PFS) was 15.2 months (95% CI, 10.8-not evaluable [NE]) at a median follow-up of 11.2 months. The median duration of response (DOR) was not reached (95% CI, 7.0-NE). In a subset of 7 patients with measurable brain metastases at baseline, the CNS ORR by RANO-BM criteria was 86%.

“For treatment-naive patients with EGFR non-classically–mutated NSCLC, there is an unmet medical need for improved activity both for treatment across the spectrum of EGFR mutations as well as for control of CNS disease,” Julia Rotow, MD, the clinical director of the Lowe Center for Thoracic Oncology, the director of clinical research, and a physician at Dana-Farber Cancer Institute, as well as an assistant professor of medicine at Harvard Medical School, both in Boston, Massachusetts, said during the presentation. “Treatment with silevertinib resulted in an [ORR] of 60% and a [median] PFS of 15.2 months, reflecting clinically meaningful efficacy both systemically and in the CNS for this patient population.”

How was the phase 2 study designed?

The phase 2 dose-expansion study enrolled patients with NSCLC harboring non-classical EGFR mutations and asymptomatic brain metastases across 3 cohorts: cohort 1 (recurrent NSCLC after up to 2 prior therapies with EGFR non-classical mutations; n = 41), cohort 2 (recurrent NSCLC with an acquired EGFR C797S mutation; n = 42), and cohort 3 (treatment-naive patients with EGFR non-classical mutations; n = 43). Data from cohort 3 were the focus of the presentation.

Cohort 3 dosing of silevertinib at 200 mg once daily was selected based on dose optimization carried out in cohorts 1 and 2. All patients were required to undergo CNS MRI surveillance every 6 weeks during therapy.

The primary end point in phase 2 was ORR.^1,2 Secondary end points included PFS, DOR, overall survival (OS), safety, and pharmacokinetics.

At baseline the median age in cohort 3 was 70.3 years (range, 44-91).¹ Thirty-one patients (72%) were female, and 44% had baseline brain metastases, of whom 37% had untreated brain metastases. The most common EGFR non-classical mutation was PACC (58%), followed by classical-like mutations (35%), and other non-classical mutations (7%). Compound mutations were present in 37% of patients.

What were the additional efficacy data across mutation subgroups?

Responses were observed across all three EGFR non-classical mutation subgroups. The ORR was 56% in patients with PACC mutations (n = 25), 73% in those with classical-like mutations (n = 15), and 69% in the compound mutation subgroup (n = 16).

What did the safety data reveal?

In cohort 3, the rate of grade 3 or higher treatment-related adverse effects (TRAEs) was 60% at the 200-mg starting dose; following dose reduction, this rate decreased to 28%. Adverse effects (AEs) leading to treatment discontinuation occurred in 14% of patients. Serious AEs were observed in 19% of patients. Dose interruptions were required in 88% of patients, and 84% required a dose reduction; the median dose intensity was 134 mg/day.

The most common any-grade TRAEs occurring in more than 10% of patients at the 200-mg dose included rash (95%), diarrhea (77%), paronychia (77%), stomatitis (77%), nausea (37%), pruritus (33%), decreased appetite (28%), fatigue (28%), and alopecia (26%). Grade 3 or higher rash occurred in 19% of patients at the 200-mg dose and in 8% following dose reduction; grade 3 or higher diarrhea occurred in 19% at the 200-mg dose and in 6% after reduction.

“AEs were dose dependent and manageable with supportive care and dose modification,” Rotow said. “Importantly for this patient population, CNS activity suggests that this is an ongoing, meaningful treatment strategy for patients with CNS involvement.”

Disclosures: Rotow received honoraria from AstraZeneca, Daiichi Sankyo, and Pfizer. She holds consulting or advisory roles with AbbVie, Amgen, AstraZeneca, Blossom Hill, BMS, Boehringer Ingelheim, Catalyst Pharmaceuticals, Daiichi Sankyo, EMD Serono, Gilead Sciences, Johnson & Johnson/Janssen, Merus, Novocure, Nuvalent, Inc., Nuvation Bio, Pfizer, Sanofi/Regeneron, Summit Therapeutics, and Takeda. She received research funding from AbbVie (Inst), Altor BioScience (Inst), AstraZeneca (Inst), BioAtla (Inst), Black Diamond Therapeutics (Inst), Blossom Hill (Inst), Blueprint Medicines (Inst), Bristol-Myer Squibb, Daiichi Sankyo (Inst), DualityBio (Inst), Enliven Therapeutics (Inst), EpimAb (Inst), ImmunityBio (Inst), Loxo (Inst), ORIC Pharmaceuticals (Inst), RedCloud Biotech (Inst), Regeneron (Inst), Summit Therapeutics (Inst), and Synthekine (Inst). She received travel, accommodations, and expenses from AstraZeneca, Black Diamond Therapeutics, BMS, Daiichi Sankyo, Johnson & Johnson/Janssen, and Merus.

References

Rotow J, Baik C, 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

Phase 1/​2 study of silevertinib (BDTX-1535) in patients with glioblastoma or non-small cell lung cancer with EGFR mutations. ClinicalTrials.gov. Updated December 9, 2025. Accessed June 2, 2026. https://clinicaltrials.gov/study/NCT05256290