On December 13, 2023 Black Diamond Therapeutics, Inc. (Nasdaq: BDTX), a clinical-stage oncology company developing MasterKey therapies that target families of oncogenic mutations in patients with genetically defined cancers, reported topline results from the dose escalation portion of the Phase 1 clinical trial of BDTX-1535 in patients with recurrent glioblastoma (GBM) who expressed epidermal growth factor receptor (EGFR) alterations at the time of their initial diagnosis (Press release, Black Diamond Therapeutics, DEC 13, 2023, View Source [SID1234638526]). BDTX-1535, a fourth-generation, brain-penetrant, covalent EGFR inhibitor, is under investigation in a Phase 1 clinical trial for the treatment of patients with non-small cell lung cancer (NSCLC) or GBM.
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"These initial results in patients with recurrent GBM are encouraging, as there are no approved therapies available for those who progress following initial treatment, and there is strong rationale for a brain penetrant, covalent EGFR inhibitor such as BDTX-1535 to have a meaningful impact in earlier lines of therapy," said Patrick Wen, M.D., Director of The Center for Neuro-Oncology at Dana-Farber Cancer Institute.
Clinical data as of November 2023 reflect 27 patients with recurrent GBM who received a range of doses spanning 15mg to 400mg once daily (QD) in the dose escalation cohort. Combined pharmacokinetic (PK) and safety data from these 27 patients with GBM and 27 patients with NSCLC were previously presented on October 14, 2023 at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper). No new safety signals were observed; adverse events were consistent with the EGFR tyrosine kinase inhibitor (TKIs) class of drugs, including primarily Grade 1 and 2 diarrhea and rash. Patients with NSCLC dosed at 100mg QD or greater demonstrated confirmed partial responses in lung lesions and CNS metastases.
Key enrollment and inclusion factors
Of the 27 patients with recurrent GBM, 22 were started at or escalated to a dose of 100mg QD or greater and reached at least one post baseline tumor assessment.
Patients were heavily pretreated, with a median of 2 prior lines of therapy (range 1-4). All patients except one had received prior temozolomide. Other prior treatments included chemotherapy, bevacizumab, checkpoint inhibitors or investigational agents.
Patients were required to have EGFR alterations at the time of diagnosis, but EGFR status was not known at time of treatment with BDTX-1535 as biopsies are not commonly performed for recurrent disease.
Key results
Of the 22 patients evaluable for efficacy, 3 patients were on therapy longer than 10 months, 1 patient longer than 6 months, and 5 patients longer than 4 months. Historical progression-free survival (PFS) in this population is in the range of 2-4 months.
The patient on therapy the longest remains on BDTX-1535 at 100mg QD for over 15 months with prolonged disease stabilization. This patient had previously progressed after 3 months of temozolomide treatment.
Of the 19 patients with measurable disease by Response Assessment in Neuro-Oncology (RANO) criteria, 1 patient achieved a confirmed partial response (PR) and 8 patients experienced stable disease (SD). The patient with the PR stayed on treatment for longer than 4 months at 200 mg QD.
Black Diamond plans to submit results from the dose escalation GBM cohort for presentation at a medical meeting in the second quarter of 2024. Enrollment is ongoing in a "window of opportunity" clinical trial of BDTX-1535 in second-line patients with high-grade glioma. The trial (NCT06072586) is sponsored by the Ivy Brain Tumor Center in Phoenix, Arizona and is enrolling patients prior to a planned resection in order to assess PK and pharmacodynamics (PD) in brain tissue. Patients achieving adequate drug levels in the gadolinium non-enhancing regions of the tumor will continue with treatment following surgery. The trial will enroll up to 22 patients, and clinical data is expected in the second quarter of 2024.
"We believe the ‘window of opportunity’ trial of BDTX-1535 will provide valuable information on both drug levels in the brain and clinical activity in second-line patients, and will inform potential next steps in our development program," said Sergey Yurasov, M.D., Ph.D., Chief Medical Officer of Black Diamond Therapeutics. "More than half of all newly diagnosed GBM patients express an altered form of EGFR, and preclinical data demonstrate BDTX-1535 potently inhibits this spectrum of alterations. Therefore, BDTX-1535 may be optimally suited to benefit first-line patients."
About BDTX-1535
BDTX-1535 is an oral, brain-penetrant MasterKey inhibitor of oncogenic epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer (NSCLC), including families of non-classical driver mutations (e.g., L747P, L718Q), acquired resistance C797S mutation, and complex mutations. BDTX-1535 is a fourth generation TKI that potently inhibits, based on preclinical data, more than 50 oncogenic EGFR mutations expressed across a diverse group of patients with NSCLC in multiple lines of therapy. Based on preclinical data, BDTX-1535 also inhibits EGFR extracellular domain mutations and alterations commonly expressed in glioblastoma (GBM) and avoids paradoxical activation observed with earlier generation reversible TKIs. Dose escalation of BDTX-1535 in patients with GBM is complete and dose expansion is currently ongoing in patients with NSCLC (NCT05256290).