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Molecular Landscape and Actionable Alterations in a Genomically Guided Cancer Clinical Trial: National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH)
Open accessAbstract
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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“However, as shown in several clinical trials161–165, only a small proportion of patients (approx. 10–20%) have an actionable alteration that can be coupled to a specific intervention161.”
From Organoids (2022) · cites this paper as [165]
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Metadata
- Authors
- Flaherty, K. T., Gray, R. J., Chen, A. P., Li, S., McShane, L. M., Patton, D., Hamilton, S. R., Williams, P. M., Iafrate, A. J., Sklar, J., Mitchell, E. P., Harris, L. N., Takebe, N., Sims, D. J., Coffey, B., Fu, T., Routbort, M., Zwiebel, J. A., Rubinstein, L. V., Little, R. F., Arteaga, C. L., Comis, R., Abrams, J. S., O’Dwyer, P. J., Conley, B. A., & for the NCI-MATCH team
- Affiliations
- Massachusetts General Hospital (US)
- Dana-Farber Cancer Institute (US)
- National Institutes of Health (US)
- The University of Texas MD Anderson Cancer Center (US)
- Frederick National Laboratory for Cancer Research (US)
- Harvard University (US)
- Yale University (US)
- Thomas Jefferson University Hospital (US)
- Harold C. Simmons Comprehensive Cancer Center (US)
- ECOG-ACRIN Cancer Research Group (US)
- Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD
- Corresponding author
- Flaherty, Keith T.
- ORCID
- Flaherty, Keith T.
- Gray, Robert J.
- Chen, Alice P.
- Li, Shuli
- McShane, Lisa M.
- Patton, David
- Hamilton, Stanley R.
- Williams, P. Mickey
- Iafrate, A. John
- Sklar, Jeffrey
- Mitchell, Edith P.
- Harris, Lyndsay N.
- Takebe, Naoko
- Coffey, Brent
- Routbort, Mark
- Zwiebel, James A.
- Rubinstein, Larry V.
- Little, Richard F.
- Arteaga, Carlos L.
- Abrams, Jeffrey S.
- Conley, Barbara A.
- Venue
- Journal of Clinical Oncology
- Published
- 2020-11-20
- Volume
- 38
- Issue
- 33
- Pages
- 3883-3894
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC7676882
- OpenAlex
- W3092241364
- Cited by
- 294
- References
- 27
- Citations by year
- 2026: 35 · 2025: 41 · 2024: 51 · 2023: 68 · 2022: 55 · 2021: 41 · 2020: 3
- FWCI
- 14.31
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Journal of Clinical Oncology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- The Medicine Forum (submittedVersion, cc-by)
- Funders
- National Cancer Institute (U10CA180820, UG1CA233337, UG1CA233329, UG1CA233180, UG1CA233341, U10CA180794, UG1CA233302, U24CA196172)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Keywords
- NCI-MATCH trial, actionable molecular alterations, targeted therapy, molecular profiling, next-generation sequencing, resistance mutations, combination targeted therapy, refractory cancer, urothelial carcinoma, pancreatic cancer, small cell lung cancer
- MeSH terms
- Adolescent, Adult, Aged, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Biopsy, Female, Humans, Male, Middle Aged, Neoplasms, Disease Progression, Young Adult, High-Throughput Nucleotide Sequencing
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