Abstract C025: Trial in progress: First-in-human study of BBT-207 in advanced non-small cell lung cancer harboring EGFR mutation after treatment with EGFR TKI

Abstract

Abstract Background: There is a high unmet need for an effective therapy for the treatment of non-small cell lung cancer (NSCLC) following osimertinib or other 3rd generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) failure, especially when resistance is driven by the occurrence of the C797S mutation. BBT-207 is a fourth-generation EGFR inhibitor. Preclinically BBT-207 has shown activity against treatment-emergent complex EGFR mutations containing T790M and/or C797S as well as drug-naïve mutants providing a possibility to overcome resistance to prior TKIs. Activity to intracranial lesions is also anticipated from animal models. Methods: Study BBT207-ONC-001 is an open-label, phase 1/2 study evaluating safety, tolerability, pharmacokinetic profile, pharmacodynamic characterization, and preliminary antitumor activity of BBT-207 monotherapy in approximately 92 patients with EGFR-mutant NSCLC. It consists of 3 phases: Phase 1a (dose escalation), phase 1b (recommended phase 2 dose selection), and phase 2 (dose expansion). Key eligibility criteria include patients ≥18 years of age with advanced stage and refractory NSCLC with an activating EGFR mutation, documented partial response, complete response, or durable stable disease after treatment of an EGFR TKI, and previous treatment with all standard therapeutic options and at least one third-generation EGFR TKI. There is no limit on the number of previous treatments received. Phase 1a requires confirmation that the tumor harbors a classical EGFR mutation (19Del or L858R), and phase 1b and phase 2 require confirmation that the tumor or the blood harbors complex EGFR mutations containing C797S. Patients with asymptomatic brain metastases who are on stable dose of corticosteroid are eligible. Primary endpoints are to determine recommended dose range (RDR) which is defined between the minimal reproducibly active dose, and the maximum tolerated dose or maximum administered dose and to characterize the overall safety and tolerability of BBT-207 (phase 1a); to determine the recommended phase 2 dose (phase 1b); to evaluate preliminary antitumor activity with objective response rate (phase 2). Phase 1a dose escalation will be guided by Bayesian logistic regression model. The safety monitoring committee will determine RDR and two recommended dose levels (RDs) within the RDR to be explored in phase 1b. In phase 1b, up to 20 patients will be randomized to each of the two RDs. At the end of phase 1b, a futility test will be performed in the dose level to be treated with the RP2D using Bayesian analysis. Phase 2 will be a non-randomized, open-label phase with up to 20 patients. Patients may receive treatment until disease progression or unacceptable toxicity. Treatment continuation beyond progression will be allowed if potential benefits are justified. Investigational new drug application was cleared by the U.S. FDA. Patient enrollment will begin in approximately August 2023 in the U.S. and Republic of Korea. Clinical trial information: NCT05920135. Citation Format: NaEun Jeon, Alexander Spira, Douglas Orr, Lyudmila Bazhenova, Misako Nagasaka, Jin Seok Ahn, Dong-Wan Kim, Yu Jung Kim, Jimin Cho, Agnes Jung, Eunsoo Jung, Chul-Won Kim, Taiguang Jin, Yong-Hee Lee, Sang-Yoon Lee. Trial in progress: First-in-human study of BBT-207 in advanced non-small cell lung cancer harboring EGFR mutation after treatment with EGFR TKI [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C025.