TY - JOUR
T1 - Molecular profiling-based assignment of cancer therapy (NCI-MPACT)
T2 - A randomized multicenter phase II trial
AU - Chen, Alice P.
AU - Kummar, Shivaani
AU - Moore, Nancy
AU - Rubinstein, Lawrence V.
AU - Zhao, Yingdong
AU - Williams, P. Mickey
AU - Palmisano, Alida
AU - Sims, David
AU - O'Sullivan Coyne, Geraldine
AU - Rosenberger, Christina L.
AU - Simpson, Mel
AU - Raghav, Kanwal P.S.
AU - Meric-Bernstam, Funda
AU - Leong, Stephen
AU - Waqar, Saiama
AU - Foster, Jared C.
AU - Konaté, Mariam M.
AU - Das, Biswajit
AU - Karlovich, Chris
AU - Lih, Chih Jian
AU - Polley, Eric
AU - Simon, Richard
AU - Li, Ming Chung
AU - Piekarz, Richard
AU - Doroshow, James H.
N1 - Funding Information:
This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names,
Funding Information:
This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The authors thank Naoko Takebe, Elad Sharon, Howard Streicher, Sheila Prindiville, and Barbara Conley (National Cancer Institute) for their clinical contributions, and Robin Harrington, Courtney Bouk, and Kneshay N. Harper (Molecular Characterization Laboratory, Frederick National Laboratory for Cancer Research) for their excellent technical assistance.
Publisher Copyright:
© 2021 American Society of Clinical Oncology. All rights reserved.
PY - 2021/1
Y1 - 2021/1
N2 - PURPOSE This trial assessed the utility of applying tumor DNA sequencing to treatment selection for patients with advanced, refractory cancer and somatic mutations in one of four signaling pathways by comparing the efficacy of four study regimens that were either matched to the patient's aberrant pathway (experimental arm) or not matched to that pathway (control arm). MATERIALS AND METHODS Adult patients with an actionable mutation of interest were randomly assigned 2:1 to receive either (1) a study regimen identified to target the aberrant pathway found in their tumor (veliparib with temozolomide or adavosertib with carboplatin [DNA repair pathway], everolimus [PI3K pathway], or trametinib [RAS/RAF/MEK pathway]), or (2) one of the same four regimens, but chosen from among those not targeting that pathway. RESULTS Among 49 patients treated in the experimental arm, the objective response rate was 2% (95% CI, 0% to 10.9%). One of 20 patients (5%) in the experimental trametinib cohort had a partial response. There were no responses in the other cohorts. Although patients and physicians were blinded to the sequencing and random assignment results, a higher pretreatment dropout rate was observed in the control arm (22%) compared with the experimental arm (6%; P =.038), suggesting that some patients may have had prior tumor mutation profiling performed that led to a lack of participation in the control arm. CONCLUSION Further investigation, better annotation of predictive biomarkers, and the development of more effective agents are necessary to inform treatment decisions in an era of precision cancer medicine. Increasing prevalence of tumor mutation profiling and preference for targeted therapy make it difficult to use a randomized phase II design to evaluate targeted therapy efficacy in an advanced disease setting.
AB - PURPOSE This trial assessed the utility of applying tumor DNA sequencing to treatment selection for patients with advanced, refractory cancer and somatic mutations in one of four signaling pathways by comparing the efficacy of four study regimens that were either matched to the patient's aberrant pathway (experimental arm) or not matched to that pathway (control arm). MATERIALS AND METHODS Adult patients with an actionable mutation of interest were randomly assigned 2:1 to receive either (1) a study regimen identified to target the aberrant pathway found in their tumor (veliparib with temozolomide or adavosertib with carboplatin [DNA repair pathway], everolimus [PI3K pathway], or trametinib [RAS/RAF/MEK pathway]), or (2) one of the same four regimens, but chosen from among those not targeting that pathway. RESULTS Among 49 patients treated in the experimental arm, the objective response rate was 2% (95% CI, 0% to 10.9%). One of 20 patients (5%) in the experimental trametinib cohort had a partial response. There were no responses in the other cohorts. Although patients and physicians were blinded to the sequencing and random assignment results, a higher pretreatment dropout rate was observed in the control arm (22%) compared with the experimental arm (6%; P =.038), suggesting that some patients may have had prior tumor mutation profiling performed that led to a lack of participation in the control arm. CONCLUSION Further investigation, better annotation of predictive biomarkers, and the development of more effective agents are necessary to inform treatment decisions in an era of precision cancer medicine. Increasing prevalence of tumor mutation profiling and preference for targeted therapy make it difficult to use a randomized phase II design to evaluate targeted therapy efficacy in an advanced disease setting.
UR - http://www.scopus.com/inward/record.url?scp=85100340651&partnerID=8YFLogxK
U2 - 10.1200/PO.20.00372
DO - 10.1200/PO.20.00372
M3 - Article
C2 - 33928209
AN - SCOPUS:85100340651
SN - 2473-4284
SP - 133
EP - 144
JO - JCO Precision Oncology
JF - JCO Precision Oncology
IS - 5
ER -