BLU-945 monotherapy and in combination with osimertinib (OSI) in previously treated patients with advanced EGFR-mutant (EGFRm) NSCLC in the phase 1/2 SYMPHONY study.
Authors: Elamin Yasir Y , Nagasaka Misako , Shum Elaine , Bazhenova Lyudmila , Camidge D. Ross , Cho Byoung Chul , Felip Enriqueta , Goto Koichi , Lin Chia-Chi , Piotrowska Zofia , Planchard David , Rotow Julia K. , Spigel David R. , Tan Daniel Shao-Weng , Yoshida Tatsuya , Minchom Anna Rachel , De Langen Adrianus , Kato Terufumi , Zalutskaya Alena , Reckamp Karen L. 
Published: June 2023

9011 Background: Despite improved frontline OSI treatment outcomes, patients (pts) with advanced EGFRm NSCLC inevitably progress, with worse outcomes in the EGFR L858R subgroup (median PFS of 14.4 vs 21.4 mo in pts with exon 19 deletions). BLU-945 is an investigational, next-generation, oral tyrosine kinase inhibitor (TKI) that targets common EGFR-activating and T790M and C797X resistance mutations, while being selective against EGFR wild type (WT). Preclinically, BLU-945 in combination (combo) with OSI had enhanced potency on L858R and extended antitumor response durability versus OSI alone. SYMPHONY (NCT04862780) is an ongoing first-in-human phase 1/2 study of BLU-945 monotherapy (mono) or combo with OSI. Methods: In the phase 1 dose escalation, pts (aged ≥18 y; metastatic EGFRm NSCLC; ECOG PS 0–1; treated with ≥1 EGFR TKI) received BLU-945 mono starting at 25 mg QD. Pts progressing on OSI could receive BLU-945 with 80 mg OSI starting at 50% of the highest safe BLU-945 mono dose. Each dose escalation followed a Bayesian Optimal Interval design. Safety, including dose-limiting toxicities (DLT), PK, and circulating tumor DNA (ctDNA) mutational status were assessed. Results: As of Jan 6, 2023, 108 pts received BLU-945 mono (25–600 mg QD; 100–300 mg BID). Pts had a median of 3 lines of prior therapy and were genomically complex with ctDNA detectable EGFR on-target and/or off-target resistance alterations (46%) at baseline. DLTs included alanine transaminase (ALT) and aspartate transaminase (AST) elevation, hepatic cytolysis, fatigue, nausea, vomiting, and hyponatremia, occurring at doses of ≥400 mg/d. The maximum tolerated dose was 500 mg/d. The most common AEs were nausea (42%), headache (40%), increased ALT (38%), increased AST (37%), and vomiting (32%). Robust on-target EGFR activity was observed with ctDNA reduction on day 15 in 90%, 85% and 70% of EGFR T790M, C797S, and L858R alleles at ≥400 mg/d doses, respectively. At ≥400 mg/d, 48% had tumor shrinkage, including partial responses (PRs). Twenty-five pts received BLU-945 (200–400 mg QD; 100–200 mg BID) combo with OSI. Pts had a median of 2 lines of prior therapy. The most common combo AEs were fatigue (36%), diarrhea (32%), headache (32%), and nausea (28%). Other EGFR WT AEs were dry skin (20%) and rash (8%). One DLT (Grade 4 pneumonitis) was reported in the BLU-945 300 mg QD with OSI group. Tumor reductions, including PRs in 2 pts progressing on OSI, were observed at ≥300 mg/d. Dose escalation is ongoing. Conclusions: BLU-945 mono and combo with OSI were generally well tolerated and showed robust on-target EGFR ctDNA reduction, with tumor shrinkage in genomically heterogeneous, heavily pretreated pts. Combo showed responses at BLU-945 doses lower than in mono, consistent with additive benefit. The combo safety profile and on-target activity provide rationale for further development in front line. Clinical trial information: NCT04862780 .