| Title: |
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). |
| Authors: |
Plummer, Elizabeth Ruth; Cook, Natalie; Arkenau, Hendrik-Tobias; Melear, Jason M.; Redfern, Charles H.; Spira, Alexander I.; Chung, Ki Y.; Shapiro, Geoffrey; Haddad, Tufia C.; Ramalingam, Suresh S.; Wesolowski, Robert; Goddemeier, Thomas; Falk, Martin H.; Dean, Emma |
| Source: |
Plummer, E R, Cook, N, Arkenau, H-T, Melear, J M, Redfern, C H, Spira, A I, Chung, K Y, Shapiro, G, Haddad, T C, Ramalingam, S S, Wesolowski, R, Goddemeier, T, Falk, M H & Dean, E 2018, '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).', pp. e21048-e21048. https://doi.org/10.1200/jco.2018.36.15_suppl.e21048 |
| Publication Year: |
2018 |
| Collection: |
The University of Manchester: Research Explorer - Publications |
| Subject Terms: |
ResearchInstitutes_Networks_Beacons/mcrc; name=Manchester Cancer Research Centre |
| Description: |
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/m2 on days 1 + 8 and M6620 210 mg/m2 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 on-treatment 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. |
| Document Type: |
conference object |
| Language: |
English |
| DOI: |
10.1200/jco.2018.36.15_suppl.e21048 |
| Availability: |
https://research.manchester.ac.uk/en/publications/f9e68c1a-57da-4cef-a3aa-2a62fe44f535; https://doi.org/10.1200/jco.2018.36.15_suppl.e21048 |
| Rights: |
info:eu-repo/semantics/restrictedAccess |
| Accession Number: |
edsbas.567C6DCB |
| Database: |
BASE |