Dose expansion cohort of a phase I trial of M6620 (formerly VX-970), a first-in-class ATR inhibitor, combined with gemcitabine (Gem) in patients (pts) with advanced non-small cell lung cancer (NSCLC).

Background: Ataxia telangiectasia and Rad3-related protein (ATR) is an essential regulator of the DNA damage response and is required for the survival of proliferating cells. DNA-damaging agents often induce replicative stress leading to activation and reliance on ATR. Thus, inhibition of ATR signalling is considered 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 data for a dose expansion cohort of a phase I trial of M6620 combined with Gem in pts with advanced NSCLC (NCT02157792). Methods: Eligible pts had measurable (RECIST 1.1) advanced NSCLC and had received up to 2 lines of therapy, with one containing 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 sensitivity to ATR inhibitors in preclinical studies), and 10 neither TP53+ nor ATM-; status determined using fresh or archival tissue. Pts received Gem 1,000 mg/m on days 1 + 8 and M6620 210 mg/m on days 2 + 9 of each 21-day cycle. The primary endpoints were safety and overall response rate (ORR). Results: 33 pts received =1 dose of therapy and were included in the safety set (female, 18; 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 pts who had received =1 dose of therapy and had baseline and ontreatment assessments, 3 pts had a PR (ORR 12.5%) and 18 pts had SD. Four pts had PR or SD for =6 months (clinical benefit rate 16.7%). Conclusions: The ATR inhibitor M6620 combined with Gem showed signs of activity in advanced NSCLC; tolerability was acceptable.