First-in-Human Data of BBT-176 in NSCLC to be Presented at IASLC WCLC 2022

The results of a first-in-human trial of the investigational agent BBT-176 for patients with advanced non­–small cell lung cancer (NSCLC) will be reported in an oral presentation during the International Association for the Study of Lung Cancer 2022 World Conference in Vienna, Austria from August 6 to 9, according to a press release from Bridge Biotherapeutics.¹

Investigators of the open-label phase 1/2 trial (NCT04820023) are studying the efficacy, tolerability, and safety of BBT-176 in patients with advanced or metastatic stage IIIB/IV NSCLC who have progressed after treatment with an EGFR tyrosine kinase inhibitor (TKI). Interim results from the phase 1 dose escalation presented to the company’s investors showed that it was well tolerated and included 2 partial responses (PRs) to BBT-176.

“We are encouraged by these interim results from our phase 1 trial of BBT-176, a fourth-generation EGFR TKI,” Sang-Yoon Lee, MD, chief medical officer of Bridge Biotherapeutics, said in a statement.

BBT-176 is designed to inhibit the EGFR signaling pathway with C797S triple mutations after progression on third-generation EGFR inhibitors such as osimertinib (Tagrisso).² C797S mutations are the most frequent mutations associated with resistance to EGFR TKIs, developing in between 7% to 24% of patients treated with third-generation EGFR TKIs, and no therapeutic agent is currently available for targeting these mutations.

In vitro data, mouse models, and in vivo data from patient-derived xenografts showed BBT-176’s efficacy in NSCLC with EGFR double mutations such as deletion 19/C797S and L858R/C797S and triple mutations such as deletion 19/T790M/C797S and L858R/T790M/C797S. It demonstrated a dose-dependent effect in patient-derived cancer cell lines/xenografts with deletion 19/T790M/C797S triple mutations.

Mouse models with triple mutations also showed that BBT-176 had efficacy in inhibiting brain metastases, which are present in 20% of patients with stage IV NSCLC. Preclinical data suggested that it was likely to have antitumor activity at a dose of 200 mg to 800 mg in humans. Based on these results, BBT-176 was granted Investigational New Drug status in South Korea and the United States.

The goals of this first-in-human study include determining maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and dose-limiting toxicities. The phase 1 dose escalation part of the trial enrolled approximately 30 patients with EGFR mutations regardless of C797X status, starting at 20 mg daily and increasing doses after 21 days of treatment.

The phase 2 dose expansion part will evaluate the RP2D of BBT-176 with or without cetuximab (Erbitux) in patients with confirmed C797X mutations. The primary end point of the dose expansion part will be objective response rate assessed every 6 weeks. Patients with brain metastases may be enrolled in the phase 2 portion if they are asymptomatic.

According to the interim results presented to investors, 1 PR consisting of a 51% tumor shrinkage was observed at the dose level of 160 mg daily, and another PR consisting of 30% tumor shrinkage was observed at the dose of 320 mg daily.¹ Safety data from the study showed adverse events (AEs) characteristic of EGFR inhibitors with only grade 1 to 3 AEs and overall acceptable toxicity. Pharmacokinetics data demonstrated that BBT-176 exhibits dose-dependent exposure.

The dose escalation part of the trial is continuing with an exploratory cohort to determine MTD and RP2D. The phase 1 and 2 portions of the study are set to enroll approximately 90 total patients. More detailed results will be announced in the oral presentation, which is expected to be given on August 8.

“In addition to continuing the trial, Bridge Biotherapeutics is promoting innovation by exploring the potential clinical value of liquid biopsies for both diagnosis and evaluation of therapeutic responses in NSCLC,” Lee said in a statement. “We believe this will be another innovative aspect of our clinical development of BBT-176. Bridge Biotherapeutics remains focused on delivering novel treatment options to address the high unmet medical needs of [patients with] advanced NSCLC.”

_References:

_{1. Bridge Biotherapeutics to announce updated data from its phase 1 study of BBT-176 in advanced non-small cell lung cancer in an oral presentation at IASLC 2022 World Conference on Lung Cancer. Bridge Biotherapeutics. Published May 10, 2022. Accessed May 12, 2022. https://prn.to/3l4g4AN}

_{2. Lim SM, Kim DW, Jung JE, et al. A phase 1/2, open-label study of BBT-176, a triple mutation targeting EGFR TKI, in patients with NSCLC who progressed after prior EGFR TKI therapy. Poster presented at: 2021 European Society for Medical Oncology Congress; September 16-21, 2021; Paris, France.}