Safety and preliminary efficacy from the phase 1 portion of MasterKey-01: A First-in-human dose-escalation study to determine the recommended phase 2 dose (RP2D), pharmacokinetics (PK) and preliminary antitumor activity of BDTX-189, an inhibitor of allosteric ErbB mutations, in patients (pts) with advanced solid malignancies.
Authors: Schram Alison M. , Rodon Ahnert Jordi , Patel Manish R. , Jauhari Shekeab , Sachdev Jasgit C. , Zhu Viola Weijia , LoRusso Patricia , Nguyen Danny , Le Xiuning , O'Connor Matthew , Waters Nigel , Cook Carl , Witt Karsten , Humphrey Rachel W. , Janne Pasi A. , Hamilton Erika P. 
Published: June 2021

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Background: BDTX-189 is an orally available, ATP-competitive and irreversible inhibitor directed against families of allosteric HER2 and EGFR oncogenic mutations. In preclinical studies BDTX-189 achieved potent inhibition of 48 allosteric HER2 and EGFR/HER2 exon 20 insertion mutant variants with selectivity versus EGFR wild-type (WT) and demonstrated tumor growth inhibition and regression in vivo. The primary objective of the Ph 1 portion of this trial (NCT04209465) is to determine the RP2D and schedule of monotherapy BDTX-189 in pts with advanced solid tumors. Methods: Eligibility includes pts with relapsed or refractory locally advanced or metastatic solid tumors with no standard therapy available whose tumor harbors an allosteric HER2 or HER3 mutation; EGFR or HER2 exon 20 insertion mutation; HER2 amplification or overexpression; or EGFR exon 19 deletion or L858R mutation. BDTX-189 is dosed continuously orally in 3-wk cycles QD and BID in separate dose escalation cohorts. A separate cohort is also evaluating the high- and low-fat food-effect (FE) on BDTX-189 PK. Results: As of 1/11/21, 46 pts have been dosed, with 36 in the QD (fasting) schedule (25-1200 mg), including pts from the FE cohort who received 800 mg QD fasting after FE evaluation: 58% female; 67% white; median age 63.5 yrs; 53% received ≥ 3 prior tx lines. Cancer types: 12 NSCLC, 5 breast, 4 ovary, 3 biliary, and 12 other. Genomic alterations: 23 HER2 amplification and the following mutations: 11 allosteric HER2, 5 EGFR exon 20 insertion, 5 HER2 exon 20 insertion, 3 EGFR exon 19 del./L858R, and 2 HER3. At ≥ 800 mg QD, 3 and 2 pts had EGFR or HER2 exon 20 mutations, respectively. The maximum tolerated dose (MTD) for QD (fasting) was 800 mg, with 2/6 pts with DLTs at 1200 mg. DLTs: gastrointestinal (G3 diarrhea; G1/2 nausea/vomiting). The most frequent (≥20%) related adverse events were diarrhea (36%, 8% G3), nausea (28%, 0% G3), and vomiting (25%, 3% G3). The rate of skin disorders was 11% with the highest severity of G2 in 1 pt. Dose-dependent exposure increases were observed, with the exposure at 800 mg QD fasting within the projected efficacious range. Pilot FE data suggest possible increased exposure with food. 27 pts were evaluable for efficacy, 15 at ≥ 800 mg QD, with 2 partial responses observed: 1 PR confirmed and ongoing (800 mg QD, CUP, HER2 amp, 3 prior lines of chemo) and 1 PR unconfirmed (NSCLC with brain mets, 1200 mg QD, HER2 amp + exon 19 del., 2 prior EGFR TKIs). 3 pts had a best response of SD and 10 with progressive disease. Conclusions: BDTX-189 has a generally manageable safety profile with early evidence of anti-tumor activity. Enrollment is ongoing in non-fasting QD and BID cohorts, and the FE cohort, prior to RP2D identification. Clinical trial information: NCT04209465.