16P A phase Ib/II trial to evaluate safety and efficacy of aurora kinase inhibitor LY3295668 in combination with osimertinib for patients with EGFR-mutant non-small cell lung cancer

In preclinical studies, EGFR TKI resistant cells displayed vulnerabilities to aurora kinase inhibitors. LY3295668 is an oral, selective aurora kinase A inhibitor with monotherapy RP2D at 25mg twice-daily (BID). The most common adverse events (AEs) were mucositis, diarrhea and corneal deposition. This phase I/II trial (NCT05017025) was designed to evaluate the safety and establish osimertinib combination RP2D in EGFR-mutant NSCLC patients (pts); and preliminarily evaluate the clinical efficacy of the combination in pts whose tumors progress on osimertinib. Pts with NSCLC harboring EGFR mutations and progressed on EGFR TKIs were enrolled. Up to 3 prior lines of therapies were allowed. LY3295668 was administered at 25mg BID with osimertinib 80mg daily. The primary endpoint for safety run-in was DLT; co-primary endpoints for the efficacy cohort were progression-free survival (PFS) at 6 months and best objective response rate (BRR). 30 pts were enrolled (Mar 2022 - Feb 2023) and received at least one dose of treatment (intent-to-treat ITT cohort); 27 pts had at least one efficacy scan (efficacy cohort). Median age in ITT was 60, 77% female, 60% whites, 27% Asians. In the safety (n=10) and the entire cohort, there was no DLT. The RP2D was determined at LY3295668 25mg BID plus osimertinib 80mg daily. In the efficacy cohort (n=27), 6-month PFS rate was 37% (10/27). Three partial responses (PRs, 11%), 17 stable diseases (SD, 63%) and 7 progressive diseases (PD, 26%) were observed, with a disease control rate (DCR 74%). At the data cut-off on 12/12/2023, 5 pts were still on treatment. In the ITT cohort, 100% of pts had any AEs. Treatment-related AEs (TRAEs) were 80%, including 3% grade 4 (n=1, thrombocytopenia), 13% grade 3 (thrombocytopenia, lymphopenia, neutropenia, diarrhea, abdominal pain), and 63% grade 1-2. The most common TRAEs are diarrhea (73%), thrombocytopenia (60%), anemia (47%) and elevated transaminases (47%). The combination of LY3295668 25mg BID plus osimertinib 80mg daily was found to be safe in EGFR-mutant NSCLC pts. The combination yields a 6-month PFS rate of 37% with 11% PR and 63% SD, demonstrating moderate clinical efficacy.