TY - JOUR
T1 - Phase i trial of first-in-class ATR inhibitor M6620 (VX-970) as monotherapy or in combination with carboplatin in patients with advanced solid tumors
AU - Yap, Timothy A.
AU - O'Carrigan, Brent
AU - Penney, Marina S.
AU - Lim, Joline S.
AU - Brown, Jessica S.
AU - De Miguel Luken, Maria J.
AU - Tunariu, Nina
AU - Perez-Lopez, Raquel
AU - Rodrigues, Daniel Nava
AU - Riisnaes, Ruth
AU - Figueiredo, Ines
AU - Carreira, Suzanne
AU - Hare, Brian
AU - McDermott, Katherine
AU - Khalique, Saira
AU - Williamson, Chris T.
AU - Natrajan, Rachael
AU - Pettitt, Stephen J.
AU - Lord, Christopher J.
AU - Banerji, Udai
AU - Pollard, John
AU - Lopez, Juanita
AU - De Bono, Johann S.
N1 - Funding Information:
Editorial coordination and support were provided by Thomas Pickette, PharmD, MBA; statistical support was provided by Yang Song, PhD; and quality control of pharmacodynamic data was provided by Lakshmi Viswanathan. Medical writing and editorial support were provided under the direction of the authors by Christopher Edwards, PhD. Christopher Edwards is an employee of ArticulateScience LLC, which received funding from Vertex Pharmaceuticals Incorporated.
Funding Information:
Supported by Vertex Pharmaceuticals, the Experimental Cancer Medicine Centre (of The Institute of Cancer Research), and the National Institute for Health Research Biomedical Research Centre (jointly of the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research).
Publisher Copyright:
Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
PY - 2020/9/20
Y1 - 2020/9/20
N2 - PURPOSE Preclinical studies demonstrated that ATR inhibition can exploit synthetic lethality (eg, in cancer cells with impaired compensatory DNA damage responses through ATM loss) as monotherapy and combined with DNA-damaging drugs such as carboplatin. PATIENTS AND METHODS This phase I trial assessed the ATR inhibitor M6620 (VX-970) as monotherapy (once or twice weekly) and combined with carboplatin (carboplatin on day 1 and M6620 on days 2 and 9 in 21-day cycles). Primary objectives were safety, tolerability, and maximum tolerated dose; secondary objectives included pharmacokinetics and antitumor activity; exploratory objectives included pharmacodynamics in timed paired tumor biopsies. RESULTS Forty patients were enrolled; 17 received M6620 monotherapy, which was safe and well tolerated. The recommended phase II dose (RP2D) for once- or twice-weekly administration was 240 mg/m2. A patient with metastatic colorectal cancer harboring molecular aberrations, including ATM loss and an ARID1A mutation, achieved RECISTv1.1 complete response and maintained this response, with a progression-free survival of 29 months at last assessment. Twenty-three patients received M6620 with carboplatin, with mechanism-based hematologic toxicities at higher doses, requiring dose delays and reductions. The RP2D for combination therapy was M6620 90 mg/m2 with carboplatin AUC5. A patient with advanced germline BRCA1 ovarian cancer achieved RECISTv1.1 partial response and Gynecologic Cancer Intergroup CA125 response despite being platinum refractory and PARP inhibitor resistant. An additional 15 patients had RECISTv1.1 stable disease as best response. Pharmacokinetics were dose proportional and exceeded preclinical efficacious levels. Pharmacodynamic studies demonstrated substantial inhibition of phosphorylation of CHK1, the downstream ATR substrate. CONCLUSION To our knowledge, this report is the first of an ATR inhibitor as monotherapy and combined with carboplatin. M6620 was well tolerated, with target engagement and preliminary antitumor responses observed.
AB - PURPOSE Preclinical studies demonstrated that ATR inhibition can exploit synthetic lethality (eg, in cancer cells with impaired compensatory DNA damage responses through ATM loss) as monotherapy and combined with DNA-damaging drugs such as carboplatin. PATIENTS AND METHODS This phase I trial assessed the ATR inhibitor M6620 (VX-970) as monotherapy (once or twice weekly) and combined with carboplatin (carboplatin on day 1 and M6620 on days 2 and 9 in 21-day cycles). Primary objectives were safety, tolerability, and maximum tolerated dose; secondary objectives included pharmacokinetics and antitumor activity; exploratory objectives included pharmacodynamics in timed paired tumor biopsies. RESULTS Forty patients were enrolled; 17 received M6620 monotherapy, which was safe and well tolerated. The recommended phase II dose (RP2D) for once- or twice-weekly administration was 240 mg/m2. A patient with metastatic colorectal cancer harboring molecular aberrations, including ATM loss and an ARID1A mutation, achieved RECISTv1.1 complete response and maintained this response, with a progression-free survival of 29 months at last assessment. Twenty-three patients received M6620 with carboplatin, with mechanism-based hematologic toxicities at higher doses, requiring dose delays and reductions. The RP2D for combination therapy was M6620 90 mg/m2 with carboplatin AUC5. A patient with advanced germline BRCA1 ovarian cancer achieved RECISTv1.1 partial response and Gynecologic Cancer Intergroup CA125 response despite being platinum refractory and PARP inhibitor resistant. An additional 15 patients had RECISTv1.1 stable disease as best response. Pharmacokinetics were dose proportional and exceeded preclinical efficacious levels. Pharmacodynamic studies demonstrated substantial inhibition of phosphorylation of CHK1, the downstream ATR substrate. CONCLUSION To our knowledge, this report is the first of an ATR inhibitor as monotherapy and combined with carboplatin. M6620 was well tolerated, with target engagement and preliminary antitumor responses observed.
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U2 - 10.1200/JCO.19.02404
DO - 10.1200/JCO.19.02404
M3 - Article
C2 - 32568634
AN - SCOPUS:85091117833
SN - 0732-183X
VL - 38
SP - 3195
EP - 3204
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 27
ER -