On June 27, 2023 Black Diamond Therapeutics, Inc. (Nasdaq: BDTX), a clinical-stage precision oncology company developing MasterKey therapies that target families of oncogenic mutations in patients with genetically defined cancers, reported initial clinical data from the dose escalation portion of the Phase 1 clinical study of BDTX-1535 (Press release, Black Diamond Therapeutics, JUN 27, 2023, View Source [SID1234632928]). BDTX-1535 is an investigational fourth-generation epidermal growth factor receptor (EGFR) MasterKey inhibitor being developed for the treatment of non-small cell lung cancer (NSCLC) and glioblastoma multiforme (GBM). The new data from the dose escalation portion of the Phase 1 study demonstrated clinical proof of activity of BDTX-1535 in NSCLC patients harboring both acquired resistance and intrinsic driver EGFR mutations.

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"These initial safety and clinical activity data support the continued development of BDTX-1535 as a potential first and best-in-class treatment option for osimertinib-resistant NSCLC patients. Importantly, BDTX-1535 is the first EGFR TKI to show radiographic responses across NSCLC patients whose cancers are driven by diverse mutation families including acquired resistance mutations after osimertinib therapy, as well as in patients whose cancers are driven by classical and intrinsic driver mutations, providing clinical validation for our MasterKey approach of targeting families of mutations with a single drug," said Sergey Yurasov, M.D., Ph.D., Chief Medical Officer of Black Diamond Therapeutics. "With a favorable tolerability profile in dose escalation, a long half-life to support once-daily dosing and ease of administration, we believe that BDTX-1535 has the potential to become an important treatment option for patients suffering from EGFR-mutated NSCLC. With these data in hand, we look forward to working with the FDA to define our recommended Phase 2 dose selection strategy and, ultimately, discussing a path to potential accelerated approval in NSCLC patients with newly diagnosed and recurrent intrinsic and acquired resistance EGFR mutations."

"Intrinsic and acquired resistance to osimertinib remains a significant challenge for patients with EGFR-mutant lung cancers. There is a large unmet need to personalize therapies based on acquired EGFR resistance mechanisms post treatment with osimertinib but also an equally important unmet need to address intrinsic resistance, with a focus on EGFR mutation subtypes that do worse with current therapies such as EGFR L858R or atypical EGFR mutations such as EGFR exon 18 mutations. That is why a fourth-generation EGFR TKI that addresses intrinsic and acquired resistance by effectively targeting these EGFR alterations – combined with ease of administration and brain penetrance – may be an impactful treatment option for patients. I am eager to see BDTX-1535 continue to advance in the clinic," said Helena Yu, M.D., Associate Attending Physician at Memorial Sloan Kettering Cancer Center.

BDTX-1535 Phase 1 Study Design

This Phase 1 first-in-human, open-label clinical trial of BDTX-1535 consists of dose escalation followed by dose expansion cohorts. The dose escalation part is based on a Bayesian Optimal Interval adaptive design to evaluate the safety, pharmacokinetics (PK), and preliminary anti-tumor activity of BDTX-1535 in adult patients with either advanced/metastatic NSCLC harboring EGFR mutations with or without central nervous system (CNS) disease, or recurrent GBM expressing EGFR alterations. Following the dose escalation portion, the study includes several disease specific expansion cohorts to assess objective response rate (ORR), CNS ORR and progression-free survival and further evaluate safety, tolerability and PK.

Initial Phase 1 Dose Escalation Data

As of the data cutoff date of May 20, 2023, a total of 51 patients (24 patients with recurrent EGFR+ NSCLC and 27 patients with recurrent GBM with EGFR alterations) were treated with BDTX-1535 in the dose-escalation portion of the Phase 1 clinical trial at seven dose levels ranging from 15mg to 400mg once-daily (QD). NSCLC patients (n=24) were heavily pretreated with a median of two prior therapies (range 1-9); all patients received prior treatment with EGFR TKI with the majority receiving osimertinib (79%) as first- or second-line treatment, 67% of patients receiving prior chemotherapy, and 42% of patients receiving prior anti-angiogenesis drug or checkpoint inhibitors. All glioblastoma patients had a recurrent disease after standard of care surgery, radiation and chemotherapy. The Company will provide a clinical update on BDTX-1535 Phase 1 dose escalation data in recurrent GBM patients in the fourth quarter of 2023.

The BDTX-1535 PK profile obtained during dose escalation in NSCLC and GBM patients showed a linear increase in exposure with an average half-life of approximately 15 hours that supports a daily dosing schedule with sufficient and sustained steady state target mutation coverage achieved at 100 mg QD dose level and above.
BDTX-1535 was generally well tolerated by NSCLC and GBM patients and the overall safety profile was consistent with the EGFR tyrosine kinase inhibitor (TKI) class of drugs. The most common drug-related adverse events were mild to moderate rash, diarrhea, stomatitis, paronychia, nausea and fatigue. No patients experienced dose limiting toxicity at 15-200 mg QD doses. One of 15 patients treated at the 300 mg QD dose experienced dose limiting diarrhea and 5 of 12 patients at the 400 mg QD dose experienced dose limiting toxicity (diarrhea, 2 patients; rash, stomatitis, fatigue and decreased appetite, 1 patient each). No unexpected safety signal was identified during dose escalation.
Based on additional data updates as of June 16, 2023, 5 of 12 NSCLC patients in a subgroup, who had measurable disease at study start, and underwent post baseline tumor assessment by RECIST1.1, demonstrated radiographic confirmed partial response (PR). One additional patient demonstrated unconfirmed PR awaiting confirmation, while the remaining six patients had stable disease.
Confirmed PRs were observed in NSCLC patients with a wide range of EGFR mutations including classical and intrinsic driver mutations and acquired C797S resistance mutation, as well as complex mutations that include a combination of classical, intrinsic, and acquired resistance mutations. Radiographic improvement of CNS metastasis was documented in 2 NSCLC patients.
Based on emerging PK, safety, tolerability and radiographic response data, enrollment will commence at the BDTX-1535 200 mg QD dose in two expansion cohorts of NSCLC patients with acquired resistance or intrinsic driver mutations who received up to two prior lines of therapy including a third-generation EGFR TKI. Additional doses may be further evaluated after review of the totality of dose escalation data during a meeting with the U.S. Food and Drug Administration (FDA) later in 2023. The objective of expansion cohorts will be ORR by RECIST 1.1 and durability of response to support future discussion with the FDA of a potential accelerated approval path in EGFR-mutated NSCLC. In addition, BDTX plans to open an expansion cohort in newly diagnosed NSCLC patients with intrinsic driver mutations after discussion with the FDA.
Black Diamond anticipates the following key milestones for BDTX-1535:

Initiation of the dose expansion cohorts of NSCLC patients with EGFR acquired resistance and intrinsic driver mutations after progression on third generation EGFR TKI with the objective of ORR by RECIST 1.1 in the second half of 2023
Presentation of the full BDTX-1535 dose escalation data in NSCLC at a medical conference in the fourth quarter of 2023
Meeting with the FDA in the fourth quarter of 2023 to align on dosing strategy to enable a potential accelerated approval pathway in NSCLC
Initiation of an expansion cohort in newly diagnosed NSCLC patients with intrinsic driver mutations after discussion with the FDA
Clinical update on BDTX-1535 Phase 1 dose escalation data in recurrent GBM patients in the fourth quarter of 2023
Conference Call Information

Black Diamond will host a conference call and webcast on Tuesday, June 27, 2023, at 8:00 a.m. ET to discuss the initial results from the Phase 1 dose escalation study of BDTX-1535 in patients with NSCLC. The webcast may be accessed online here or by visiting the Events page in the Investors section of the Company’s website at www.blackdiamondtherapeutics.com.

A replay of the webcast will be available for 30 days on the Investors section of Black Diamond’s website.