FDA Grants BDTX-189 Fast Track Status to Solid Tumors Harboring Select EGFR, HER2 Mutations

The FDA has granted a fast track designation to BDTX-189 for use in adult patients with solid tumors harboring an allosteric HER2 mutation or an EGFR or HER2 exon 20 insertion mutation who had progressed on previous treatment and have no acceptable options available, according to an announcement from Black Diamond Therapeutics, Inc.¹

“While targeted therapies, such as kinase inhibitors, have transformed the treatment of cancer, only a small percentage of patients with metastatic cancer have tumors with genetic profiles that could make them eligible for an approved precision oncology medicine,” David M. Epstein, PhD, president and chief executive officer of Black Diamond Therapeutics, stated in a recent press release. “The FDA’s decision to grant Fast Track designation is an important recognition of BDTX-189’s potential to treat patients with currently unaddressed oncogenic mutations in EGFR and HER.”

BDTX-189 is an orally available, irreversible small molecule inhibitor that targets undrugged oncogenic driver mutations of EGFR, HER2, and ErbB kinases, according to Black Diamond Therapeutics.² ErbB receptors play a role in important cellular functions, including cell growth and survival. The mutations that the agent was developed to target are prevalent across a broad range ofcancers, including bladder, breast, endometrial, gastric, colon, and non–small cell lung cancer (NSCLC). To date, no single therapy with the ability to target all of these mutations has regulatory approval and is available for use.

In the first-in-human phase 1/2 MasterKey-01 trial (NCT04209465), investigators will examine BDTX-189 in patients with advanced solid tumor that harbor select mutations or aberrations in HER2 or EGFR.³ The main objectives of the study include: determining the recommended dose of the agent, understanding the adverse effects associated with its use, learning what the body does to BDTX-189 after it has been administered, and establishing the antitumor activity of the agent in patients with select allosteric ErbB gene mutations.

In the phase 1 dose-escalation portion of the trial, investigators will evaluate the safety and tolerability of the agent and identify the recommended phase 2 dose (RP2D). The phase 1 portion of the trial will examine BDTX-189 in participants with solid tumors harboring alterations such as allosteric HER2 or HER3 mutations, EGFR or HER2 exon 20 insertion mutations, HER2 amplification or overexpression, and EGFR exon 19 deletion or L858R mutation.

After the RP2D is determined, the phase 2 portion of the trial will examine the antitumor activity and safety of the irreversible small molecule inhibitor. The open-label, multicenter basket trial will utilize a Simon 2-stage design and enroll patients to the following 4 cohorts: NSCLC with EGFR or HER2 exon 20 insertion mutations (cohort 1), breast cancer with an allosteric ErbB mutation (cohort 2), solid tumors with S310F/Y mutation, with the exception of breast (cohort 3), and other tumors harboring allosteric ErbB mutations not included in cohorts 1 to 3 (cohort 4).

Notably, to determine eligibility, mutations must be validated via a next-generation sequencing test that is routinely used by each institution involved with the trial and the test must be done in a CLIA-certified or equivalent laboratory.

The primary end points of the trial include incidence of dose-limiting toxicities as a determinant of the RP2D and then objective response rate (ORR) as a measure of antitumor activity for the phase 2 portion of the trial. Key secondary end points include incidence of treatment-emergent adverse effects in both phases of the trial, plasma concentration of BDTX-189 in both phases, and ORR as a preliminary measure of antitumor activity in phase 1. Additional secondary end points for both phases of the trial include duration of response, disease control rate, progression-free survival, and overall survival with BDTX-189.

In the dose-escalation phase of the trial, patients will be given increasing doses of BDTX-189. A total of 50 patients are anticipated to enroll on this portion of the trial, although up to 24 additional patients are allowed to enroll if an alternative schedule is under examination. Patients with receive daily BDTX-189 via oral administration as part of a 3-week treatment cycle. In the dose-expansion phase of the trial, patients will be given the RP2D of the small molecule inhibitor, delivered orally, once daily, as part of a 3-week cycle. A total of 100 patients are anticipated to enroll on the second portion of the trial.

“We look forward to working closely with the FDA as we continue to enroll and dose patients in the MasterKey-01 trial, our phase 1/2 clinical study of BDTX-189, as part of our mission to discover and develop novel, tumor-agnostic, precision oncology therapies for genetically defined cancers,” added Epstein.

References

1. Black Diamond Therapeutics granted fast track designation by the FDA for BDTX-189 for the treatment of adult patients with a solid tumor harboring an allosteric HER2 mutation or an EGFR or HER2 exon 20 insertion mutation. News release. Black Diamond Therapeutics, Inc. July 28, 2020. Accessed July 28, 2020. https://bit.ly/3g6qegg.
2. BDTX-189: a mutation spectrum-selective, oral, irreversible TKI. Black Diamond Therapeutics, Inc. Accessed July 28, 2020. https://bit.ly/2Ej900X.
3. A study of BDTX-189, an orally available allosteric ErbB inhibitor, in patients with advanced solid tumors. (MasterKey-01). ClinicalTrials.gov. Updated June 22, 2020. Accessed July 28, 2020. https://clinicaltrials.gov/ct2/show/NCT04209465.