Abstract 4199
Background
Ataxia telangiectasia and Rad3-related protein (ATR) is an essential DNA damage response regulator, and is required for proliferating cell survival. DNA-damaging agents often induce replicative stress leading to activation and reliance on ATR; inhibition of ATR signalling is an attractive strategy to sensitize tumors to DNA-damaging chemotherapy. M6620 is a potent, selective inhibitor of ATR with preclinical anticancer activity in combination with DNA-damaging chemotherapy. Here, we report dose expansion cohort data for a phase I trial of M6620 plus Gem in pts with advanced NSCLC (NCT02157792).
Methods
Eligible pts had measurable (RECIST 1.1) advanced NSCLC with up to 2 lines of prior therapy, with one including a platinum analog. Of 40 pts planned for enrollment, ≥20 had to have a TP53 mutation (TP53+), ≤10 ATM loss of expression (ATM–) (both alterations associated with ATR inhibitor sensitivity in preclinical studies), and ≈10 neither TP53+ nor ATM–; status was determined from fresh or archival tissue. Pts received Gem 1000 mg/m2 on days 1 + 8 and M6620 210 mg/m2 on days 2 + 9 of each 21-day cycle. Pharmacokinetics was assessed on day 2 of cycle 1. Primary endpoints were safety and overall response rate (ORR).
Results
The safety set included 33 pts who received combination therapy (median age, 62.0 years [range 36–76]; TP53+, 19; WHO PS 0/1, 9/23). 31/33 pts had a treatment-emergent adverse event (TEAE), with 19 (57.6%) having grade ≥3 TEAEs: fatigue (n = 6), neutropenia (4), anemia (3), thrombocytopenia (3), malaise (2), vomiting (2), ALT increase (2), AST increase (2), pneumonia (2), sepsis (2) (grade ≥3 TEAES occurring in ≥ 2 pts). Of the 24 treated pts with baseline and on-treatment assessments, 3 pts had a partial response (PR; ORR 12.5%) and 18 pts (75%) had stable disease (SD). Four pts had PR or SD ≥ 6 months (clinical benefit rate 16.7%). Updated efficacy and PK data will be presented from an upcoming analysis.
Conclusions
The ATR inhibitor M6620 combined with Gem showed signs of activity in advanced NSCLC; tolerability was acceptable.
Clinical trial identification
NCT02157792.
Legal entity responsible for the study
Merck KGaA, Darmstadt, Germany.
Funding
Merck KGaA, Darmstadt, Germany.
Editorial Acknowledgement
Medical writing assistance (funded by Merck KGaA, Darmstadt, Germany) was provided by Martin Quinn, PhD of Bioscript Science (Macclesfield, UK).
Disclosure
R. Plummer: Clinical trial costs to institution to conduct the trial; Personal honoraria: Vertext Pharmaceuticals for advisory board. C. Redfern: Stock holdings: Pfizer. A.I. Spira: Research funding (to institution): Merck for study. T. Haddad: Research funding (institution): Takeda Oncology; Consulting: TerSera Therapeutics (fee donated to institution). S.S. Ramalingam: Consultant: Amgen, Abbvie, AstraZeneca, BMS, Lilly, Genentech/Roche, Loxo, Nektar and Merck. E. Dean: Commercial income to institution for the conduct on the study; Employment and owns stock: AstraZeneca. T. Goddemeier, M. Falk: Employee: Merck KGaA. G. Shapiro: Research funding: Merck/EMD Serono, Lilly, Pfizer; Advisory Board: Roche, Merck/EMD Serono, Lilly, Pfizer, G1 Therapeutics. All other authors have declared no conflicts of interest.