Abstract 16P
Background
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.
Methods
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).
Results
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%).
Conclusions
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.
Clinical trial identification
NCT05017025.
Legal entity responsible for the study
Eli Lilly and MD Anderson Cancer Center.
Funding
Eli Lilly.
Disclosure
X. Le: Financial Interests, Personal, Advisory Board: AstraZeneca, Merck KGaA, Spectrum Pharmaceutics, Novartis, Boehringer Ingelheim, Eli Lilly, Hengrui, Janssen, Blueprint, Daiichi Sankyo, Regeneron, ArriVent, Abion, Pinetree therapeutics, AbbVie; Financial Interests, Institutional, Invited Speaker: Eli Lilly, EMD Serono, Regeneron, Janssen; Financial Interests, Institutional, Research Grant: ArriVent; Financial Interests, Institutional, Funding: Teligene. L.A. Byers: Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme Corp, Arrowhead, Chugai Pharmaceutical Co., Genentech Inc, AbbVie, Jazz Pharmaceuticals, Puma Biotechnology, Amgen, Daiichi Sankyo Sanyo, BeiGene; Financial Interests, Personal, Advisory Board, Per our institutional policy compensation from any consulting/etc. would always be <25000 for any 12 month period: AstraZeneca Pharmaceuticals; Financial Interests, Institutional, Funding, Research funding: AstraZeneca Pharmaceuticals, Amgen. C. Gay: Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb, G1 Therapeutics, Monte Rosa Therapeutics, Aptitude Health; Financial Interests, Personal, Invited Speaker: BeiGene, AstraZeneca, Research to Practice, Peerview; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca. A.S. Tsao: Financial Interests, Personal, Advisory Board: Genentech, BMS, Eli Lilly, Roche, Novartis, Ariad, EMD Serono, Merck, Seattle Genetics, AstraZeneca, Boehringer Ingelheim, GSK, Pfizer, Gilead Sciences, Inc., Summit Therapeutics; Financial Interests, Institutional, Research Grant: Ariad, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Epizyme, Genentech, Merck, Millennium, Novartis, Polaris, Settle Genetics. S. Heeke: Financial Interests, Personal, Invited Speaker: AstraZeneca, Guardant Health; Financial Interests, Personal, Research Grant: Thermo Fisher. P.A. Jänne: Financial Interests, Personal, Advisory Board, Consulting fees for advice on drug development: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Eli Lilly, Voronoi, Daiichi Sankyo, Novartis, Sanofi, Takeda Oncology, Mirati Therapeutics, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Esai, Allorion Therapeutics, Accutar Biotech, AbbVie, Duality Biologics; Financial Interests, Personal, Advisory Board, Consulting fees for advice on diagnostic development: Biocartis; Financial Interests, Personal, Advisory Board, Consulting fee for advice on drug development: Merus, Frontier Medicines; Financial Interests, Personal, Advisory Board, Consulting fees for advice on drug development.: Hongyun Biotechnology; Financial Interests, Personal, Stocks/Shares: Gatekeeper Pharmaceuticals, Allorion Therapeutics; Financial Interests, Personal, Royalties, I receive post-marketing royalties from being an inventor on a DFCI owned patent on EGFR mutations licensed to Lab Corp: Lab Corp; Financial Interests, Institutional, Research Grant, Sponsored research agreement with my institution: AstraZeneca, Daiichi Sankyo, PUMA, Eli Lilly, Boehringer Ingelheim, Revolution Medicines, Takeda Oncology. J. Heymach: Financial Interests, Personal, Advisory Board: Genentech, Mirati Therapeutics, Eli Lilly & Co., Janssen Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Regeneron, Takeda Pharmaceuticals, BerGenBio, Jazz Pharmaceuticals, Curio Science, Novartis, AstraZeneca, BioAlta, Sanofi, Spectrum Pharmaceuticals, GSK; Financial Interests, Personal, Full or part-time Employment: MD Anderson Cancer Center; Financial Interests, Personal, Invited Speaker: Spectrum; Financial Interests, Institutional, Other, International PI for clinical trials: AstraZeneca; Financial Interests, Institutional, Other, International PI for two clinical trials: Boehringer Ingelheim; Financial Interests, Personal and Institutional, Other, Developed a drug: Spectrum; Financial Interests, Institutional, Invited Speaker: Takeda. All other authors have declared no conflicts of interest.