FDA Grants Fast Track Designation to BDTX-189 in EGFR/HER2-Mutant Solid Tumors

The FDA granted Fast Track designation to BDTX-189 for the treatment of adult patients with solid tumors harboring allosteric HER2 mutation, EGFR mutation, or HER2 exon 20 insertion.

The FDA granted Fast Track designation to BDTX-189 for the treatment of adult patients with solid tumors harboring an allosteric HER2 mutation or an EGFR or HER2 exon 20 insertion who have progressed following previous treatment and for whom no satisfactory alternative treatments exist, Black Diamond Therapeutics announced in a press release.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. 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 HER2,” said David M. Epstein, PhD, president, and CEO of Black Diamond Therapeutic, in the press release.

BDTX-189 is currently being evaluated in the first-in-human phase 1/2 open-label, 2-part, multicenter Masterkey-01 clinical trial (NCT04209465) to address the issue of allosteric ErbB mutations found in 1% to 2% of solid tumors. These are more heavily observed in colon (2%), gastric (3%), breast (35), endometrial (4%), and bladder tumors (7%), as well as in non–small cell lung cancers (7%). EGFR and HER2-directed therapies have also demonstrated suboptimal antitumor activity in these mutated tumors, leaving an unmet medical need.2

The mechanism of activity associated with BDTX-189, a spectrum-selective inhibitor of oncogenic driver mutations of ErbB kinases in EGFR and HER2, has shown preclinical in vitro activity against allosteric HER2 mutations, EGFR and HER2 exon 20 insertions, EGFR exon 19 insertions, EGFR L858R mutations, HER2 wild-type mutation, HER2-p95 mutations, and HER3 mutations. In vivo tumor regression was seen with various animal models; the agent lead to allografts with HER2-S310F mutations, and treated EGFR A767dupASV and EGFR-NPH in animal models.

In Masterkey-01, 184 patients will be enrolled to assess the primary end points of incidence of dose-limiting toxicities in the phase 1 portion and objective response rate in phase 2 portion.

The phase 1 portion is a dose-escalation analysis that will be conducted in 3 steps, which include an accelerated titration step, enrolling up to 15 patients per dose level in step 2 in an effort to find the recommended phase 2 dose of BDTX-189, and step 3 is a repeat of step 2 with the recommended phase 2 dose of BDTX-189. Patients will be eligible to enroll in phase 1 given they have a histological or cytological confirmation of a locally advanced or metastatic solid tumor that has no standard of care or suitable therapy. Patients are required to have an ECOG performance status of 0 to 1 and adequate organ function. Individuals with central nervous system involvement are eligible if their condition is treated, but patients who received prior concomitant proton pump inhibitors are ineligible for phase 1 of Masterkey-01.

The phase 2 portion of the study plans to follow a Simon 2-stage design. The 4 cohorts being evaluated include patients with non–small cell lung cancer with EGFR or HER2 exon 20 insertion mutations, breast cancer with an allosteric ErbB mutation, solid tumors (except breast) with an S310F/Y mutation, and other tumors harboring allosteric ErbB mutations not included in cohorts 1-3.

The secondary end points will include duration of response, safety, and overall survival. To enroll, patients are required to have a solid tumor harboring an allosteric HER2 mutation or an EGFR or HER2 exon 20 insertion that is detected with a CLIA-certified next-generation sequencing assay. All patients must have tumor tissue available for testing, measurable disease per RECIST v1.1 criteria. Any patients who responded previously to treatment with a HER2-directed tyrosine kinase inhibitor will be excluded from the study.

Masterkey-01 is currently recruiting patients and the study plans to commence in June of 2023.

“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,” Epstein added, in a statement.


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. July 28, 2020. Accessed July 28, 2020. https://bit.ly/330kOzD

Hamilton EP, Patel MR, Rodon J, et al. Masterkey-01: Phase I/II, open-label multicenter study to assess safety, tolerability, pharmacokinetics, and antitumor activity of BDTX-189, an inhibitor of allosteric ErbB mutations, in patients with advanced solid malignancies. J Clin Oncol. 2020:38(suppl):TPS3665. doi:10.1200/JCO.2020.38.15_suppl.TPS3665

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