BLU-495 Demonstrates Safety and Activity in Advanced EGFR-Mutant NSCLC

Results from the Phase 1/2 SYMPHONY Study

The next-generation, oral tyrosine kinase inhibitor (TKI) BLU-945 was well tolerated and demonstrated robust on-target EGFR circulating tumor DNA (ctDNA) reduction with tumor shrinkage among heavily pretreated patients with EGFR-mutant non-small cell lung cancer (NSCLC), both as a monotherapy and in combination with osimertinib. 

This abstract was presented by lead author Yasir Y Elamin, MD, The University of Texas MD Anderson Cancer Center, Houston, Texas at the 2023 ASCO Annual Meeting. 

SYMPHONY is an ongoing first-in-human, phase 1/2 study of BLU-945 as monotherapy or in combination with osimertinib. This trial enrolled 108 patients with 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. In the phase 1 dose escalation study, patients received BLU-945 monotherapy starting at 25 mg once a day (25 mg 600 mg once daily; 100 mg to 300 mg twice daily). Patients who progressed on osimertinib could receive BLU-945 with 80 mg osimertinib starting at 50% of the highest safe BLU-945 monotherapy dose (n = 25; 200 mg to 400 mg once daily or 100 mg to 200 mg twice daily of BLU-945). Outcomes included safety, pharmacokinetics, and ctDNA mutational status.

Additionally, at ≥400 mg/d doses, there was robust on-target EGFR activity with ctDNA reduction on day 15 in 90%, 85% and 70% of EGFR T790M, C797S, and L858R alleles, respectively.  Tumor reductions, including partial responses occurring in 2 patients who were progressing on osimertinib, were observed at ≥300 mg/d. Dose escalation is currently ongoing. At doses of ≥400 mg/d, 48% of patients had tumor shrinkage, including partial responses.

Dose-limiting toxicities in this trial included alanine transaminase and aspartate transaminase elevation, hepatic cytolysis, fatigue, nausea, vomiting, and hyponatremia, which occurred at doses of ≥400 mg per/ day (mg/d). The maximum tolerated dose was 500 mg/d. The most common adverse events were nausea (42%), headache (40%), increased alanine transaminase (38%), increased aspartate transaminase (37%), and vomiting (32%). The most common adverse events for patients in the combination therapy arm included fatigue (36%), diarrhea (32%), headache (32%), and nausea (28%). 

Dr Elamin and colleagues concluded, when combined with osimertinib, BLU-495 “showed responses at BLU-945 doses lower than in [monotherapy], consistent with additive benefit” adding the safety profile and activity “provide rationale for further development in [the] front line.”

Source:

Elamin Y, Nagasaka M, Shum E, et al. 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. Presented at 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract 9011