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Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

4199 - Phase I dose expansion data for 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)


20 Oct 2018


Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research


Clinical Research

Tumour Site


Ruth Plummer


Annals of Oncology (2018) 29 (suppl_8): viii493-viii547. 10.1093/annonc/mdy292


R. Plummer1, N. Cook2, T. Arkenau3, J. Melear4, C. Redfern5, A.I. Spira6, K. Chung7, T. Haddad8, S.S. Ramalingam9, R. Wesolowski10, E. Dean11, T. Goddemeier12, M. Falk13, G. Shapiro14

Author affiliations

  • 1 Northern Centre For Cancer Care, Freeman Hospital, NE2 4HH - Newcastle upon Tyne/GB
  • 2 Department Of Medical Oncology, The Christie NHS Foundation Trust, M20 4BX - Manchester/GB
  • 3 Medical Oncology, Sarah Cannon Research Institute, London/GB
  • 4 Medical Oncology, US Oncology - Texas Oncology - Midtown, Austin/US
  • 5 Clinical Oncology Research, Sharp Memorial Hospital, San Diego/US
  • 6 ,, Virginia Cancer Specialists, Fairfax/US
  • 7 Hematology/oncology, Greenville Health System, Greenville/US
  • 8 ,, Mayo Clinic, 55905 - Rochester/US
  • 9 Department Of Hematology And Medical Oncology, Emory University Winship Cancer Institute, 30322 - Atlanta/US
  • 10 Division Of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus/US
  • 11 Medical Oncology, The University of Manchester and The Christie NHS Foundation Trust, Manchester/GB
  • 12 Biostatistics, Merck KGaA, Darmstadt/DE
  • 13 Global Research & Development, Merck Germany, 64293 - Darmstadt/DE
  • 14 Medical Oncology, Dana-Farber Cancer Institute, 02215 - Boston/US

Abstract 4199


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).


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).


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.


The ATR inhibitor M6620 combined with Gem showed signs of activity in advanced NSCLC; tolerability was acceptable.

Clinical trial identification


Legal entity responsible for the study

Merck KGaA, Darmstadt, Germany.


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).


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.

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