Molecular Landscape and Actionable Alterations in a Genomically Guided Cancer Clinical Trial: National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH)

PURPOSE Therapeutically actionable molecular alterations are widely distributed across cancer types. The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial was designed to evaluate targeted therapy antitumor activity in underexplored cancer types. Tumor biopsy specimens were analyzed centrally with next-generation sequencing (NGS) in a master screening protocol. Patients with a tumor molecular alteration addressed by a targeted treatment lacking established efficacy in that tumor type were assigned to 1 of 30 treatments in parallel, single-arm, phase II subprotocols. PATIENTS AND METHODS Tumor biopsy specimens from 5,954 patients with refractory malignancies at 1,117 accrual sites were analyzed centrally with NGS and selected immunohistochemistry in a master screening protocol. The treatment-assignment rate to treatment arms was assessed. Molecular alterations in seven tumors profiled in both NCI-MATCH trial and The Cancer Genome Atlas (TCGA) of primary tumors were compared. RESULTS Molecular profiling was successful in 93.0% of specimens. An actionable alteration was found in 37.6%. After applying clinical and molecular exclusion criteria, 17.8% were assigned (26.4% could have been assigned if all subprotocols were available simultaneously). Eleven subprotocols reached their accrual goal as of this report. Actionability rates differed among histologies (eg, > 35% for urothelial cancers and < 6% for pancreatic and small-cell lung cancer). Multiple actionable or resistance-conferring tumor mutations were seen in 11.9% and 71.3% of specimens, respectively. Known resistance mutations to targeted therapies were numerically more frequent in NCI-MATCH than TCGA tumors, but not markedly so. CONCLUSION We demonstrated feasibility of screening large numbers of patients at numerous accruing sites in a complex trial to test investigational therapies for moderately frequent molecular targets. Co-occurring resistance mutations were common and endorse investigation of combination targeted-therapy regimens.

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Details

Published: Nov 20, 2020
Vol/Issue: 38(33)
Pages: 3883-3894

Authors

K

Keith T. Flaherty

Massachusetts General Hospital, Boston, MA

R

Robert J. Gray

ECOG-ACRIN Cancer Research Group Biostatistics Center, Dana Farber Cancer Institute Boston, MA

A

Alice P. Chen

Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD

S

Shuli Li

ECOG-ACRIN Cancer Research Group Biostatistics Center, Dana Farber Cancer Institute Boston, MA

L

Lisa M. McShane

Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD

D

David Patton

Center for Biomedical Informatics and Information Technology, NCI, NIH, Bethesda, MD

S

Stanley R. Hamilton

University of Texas MD Anderson Cancer Center, Houston, TX

P

P. Mickey Williams

Frederick National Laboratory for Cancer Research, Frederick, MD

A

A. John Iafrate

Massachusetts General Hospital, Boston, MA; Harvard University, Boston, MA

J

Jeffrey Sklar

Yale University, New Haven, CT

E

Edith P. Mitchell

Thomas Jefferson University Hospital, Philadelphia, PA

L

Lyndsay N. Harris

Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD

N

Naoko Takebe

Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD

D

David J. Sims

Frederick National Laboratory for Cancer Research, Frederick, MD

B

Brent Coffey

Center for Biomedical Informatics and Information Technology, Frederick National Laboratory for Cancer Research, Frederick, MD

T

Tony Fu

Frederick National Laboratory for Cancer Research, Frederick, MD

M

Mark Routbort

University of Texas MD Anderson Cancer Center, Houston, TX

J

James A. Zwiebel

Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD

L

Larry V. Rubinstein

Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD

R

Richard F. Little

Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD

C

Carlos L. Arteaga

University of Texas Southwestern Simmons Cancer Center, Dallas, TX

R

Robert Comis

ECOG-ACRIN Cancer Research Group, Philadelphia, PA; Deceased.

J

Jeffrey S. Abrams

Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD

P

Peter J. O’Dwyer

Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD

B

Barbara A. Conley

Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD

Cite This Article

Keith T. Flaherty, Robert J. Gray, Alice P. Chen, et al. (2020). Molecular Landscape and Actionable Alterations in a Genomically Guided Cancer Clinical Trial: National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH). Journal of Clinical Oncology, 38(33), 3883-3894. https://doi.org/10.1200/jco.19.03010

Molecular Landscape and Actionable Alterations in a Genomically Guided Cancer Clinical Trial: National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH)

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