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

Autor:	Flaherty KT; Massachusetts General Hospital, Boston, MA., Gray RJ; ECOG-ACRIN Cancer Research Group Biostatistics Center, Dana Farber Cancer Institute Boston, MA., Chen AP; Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD., Li S; ECOG-ACRIN Cancer Research Group Biostatistics Center, Dana Farber Cancer Institute Boston, MA., McShane LM; Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD., Patton D; Center for Biomedical Informatics and Information Technology, NCI, NIH, Bethesda, MD., Hamilton SR; University of Texas MD Anderson Cancer Center, Houston, TX., Williams PM; Frederick National Laboratory for Cancer Research, Frederick, MD., Iafrate AJ; Massachusetts General Hospital, Boston, MA.; Harvard University, Boston, MA., Sklar J; Yale University, New Haven, CT., Mitchell EP; Thomas Jefferson University Hospital, Philadelphia, PA., Harris LN; Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD., Takebe N; Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD., Sims DJ; Frederick National Laboratory for Cancer Research, Frederick, MD., Coffey B; Center for Biomedical Informatics and Information Technology, Frederick National Laboratory for Cancer Research, Frederick, MD., Fu T; Frederick National Laboratory for Cancer Research, Frederick, MD., Routbort M; University of Texas MD Anderson Cancer Center, Houston, TX., Zwiebel JA; Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD., Rubinstein LV; Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD., Little RF; Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD., Arteaga CL; University of Texas Southwestern Simmons Cancer Center, Dallas, TX., Comis R; ECOG-ACRIN Cancer Research Group, Philadelphia, PA.; Deceased., Abrams JS; Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD., O'Dwyer PJ; Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD., Conley BA; Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD.
Jazyk:	angličtina
Zdroj:	Journal of clinical oncology : official journal of the American Society of Clinical Oncology [J Clin Oncol] 2020 Nov 20; Vol. 38 (33), pp. 3883-3894. Date of Electronic Publication: 2020 Oct 13.
DOI:	10.1200/JCO.19.03010
Abstrakt:	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.
Databáze:	MEDLINE
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