Abstract P230: A phase 1/2 study of BLU-945, a highly potent and selective inhibitor of epidermal growth factor receptor (EGFR) resistance mutations, in patients with EGFR-mutant non-small cell lung cancer (NSCLC)
Authors: Spigel David , Goto Koichi , Camidge D. Ross , Elamin Yasir , de Langen Adrianus J. , Leighl Natasha B. , Minchom Anna , Piotrowska Zofia , Planchard David , Reckamp Karen , Albayya Faris , Green Jennifer , Kim Sean , Louie-Gao Melinda , Sawtell Renata , Zalutskaya Alena , Co Byoung Chul 
Published: December 2021

BACKGROUND Activating EGFR mutations such as exon 19 deletion (ex19del) and L858R mutations, exon 19 insertions (ex19ins), and point mutations L861Q, G719X, and S768I are oncogenic drivers in lung adenocarcinoma, the most common NSCLC subtype. Although EGFR-targeted therapies, including first-, second-, and third-generation tyrosine kinase inhibitors (TKIs), have improved outcomes in patients (pts) with EGFR-mutant (EGFRm) NSCLC, resistance to these drugs is inevitable. BLU-945 is an investigational fourth-generation EGFR TKI designed to suppress both activating and on-target resistance EGFR mutations, such as C797S and T790M. Preclinical data showed BLU-945 has nanomolar potency against EGFRm/T790M double and EGFRm/T790M/C797S triple mutants with &gt;450-fold selectivity for these mutants over wild-type EGFR in biochemical and cellular assays, and demonstrated robust preclinical antitumor activity, including in intracranial tumors harboring these mutations, providing the therapeutic rationale for BLU-945 clinical development. METHODS BLU-945-1101 (NCT04862780) is an international, open-label, first-in-human, phase 1/2 study designed to evaluate safety, tolerability, and antitumor activity of BLU-945 in pts with EGFRm NSCLC. Key eligibility criteria include adults with pathologically confirmed metastatic NSCLC with an activating EGFR mutation per local assessment (including ex19del or L858R); Eastern Cooperative Oncology Group performance status 0–2; and previous treatment with ≥1 EGFR-targeted TKI. Pts with asymptomatic brain metastases and on stable doses of corticosteroids are eligible. Key exclusion criteria are any additional known primary driver alterations, including but not limited to pathologic aberrations of EGFR exon 20 (insertions), KRAS, BRAF V600E, NTRK1/2/3, HER2, ALK, ROS1, MET, or RET. Phase 1 primary endpoints are maximum tolerated dose, recommended phase 2 dose (RP2D), and safety. The phase 2 primary endpoint is overall response rate (ORR) by RECIST 1.1. Phase 1 secondary endpoints include ORR, duration of response (DOR), pharmacokinetics (PK), and pharmacodynamics (PD); phase 2 secondary endpoints include DOR, disease control rate (DCR), clinical benefit rate (CBR), progression free survival (PFS), overall survival (OS), time to intracranial progression and intracranial response rate, PK, PD, and safety. Phase 1 dose escalation (N≈60) will be conducted using Bayesian optimal interval design. In the phase 2 dose expansion (N≈61), pts will be enrolled into 3 groups based on mutation profile and treated at the RP2D: primary group 1 for pts with EGFR T790M and C797S (n≈37); exploratory group 2 for pts with EGFR T790M but not C797S (n≈12); exploratory group 3 for pts with EGFR C797S but not T790M (n≈12). Group 1 will use Simon’s 2-stage design to test the null hypothesis of ORR ≤20% against a 1-sided alternative of ≥40%. Pts may receive treatment until disease progression or unacceptable toxicity. Recruitment has started and approximately 30 sites will be open for enrollment across North America, Europe, and Asia.

Citation Format: David Spigel, Koichi Goto, D. Ross Camidge, Yasir Elamin, Adrianus J. de Langen, Natasha B. Leighl, Anna Minchom, Zofia Piotrowska, David Planchard, Karen Reckamp, Faris Albayya, Jennifer Green, Sean Kim, Melinda Louie-Gao, Renata Sawtell, Alena Zalutskaya, Byoung Chul Co. A phase 1/2 study of BLU-945, a highly potent and selective inhibitor of epidermal growth factor receptor (EGFR) resistance mutations, in patients with EGFR-mutant non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P230.