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

Author:

Flaherty Keith T.1ORCID,Gray Robert J.2,Chen Alice P.3ORCID,Li Shuli2,McShane Lisa M.3ORCID,Patton David4ORCID,Hamilton Stanley R.5ORCID,Williams P. Mickey6,Iafrate A. John17,Sklar Jeffrey8,Mitchell Edith P.9,Harris Lyndsay N.3,Takebe Naoko3,Sims David J.6,Coffey Brent10,Fu Tony6,Routbort Mark5ORCID,Zwiebel James A.3ORCID,Rubinstein Larry V.3ORCID,Little Richard F.3,Arteaga Carlos L.11,Comis Robert1213,Abrams Jeffrey S.3ORCID,O’Dwyer Peter J.3,Conley Barbara A.3,

Affiliation:

1. Massachusetts General Hospital, Boston, MA

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

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

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

5. University of Texas MD Anderson Cancer Center, Houston, TX

6. Frederick National Laboratory for Cancer Research, Frederick, MD

7. Harvard University, Boston, MA

8. Yale University, New Haven, CT

9. Thomas Jefferson University Hospital, Philadelphia, PA

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

11. University of Texas Southwestern Simmons Cancer Center, Dallas, TX

12. ECOG-ACRIN Cancer Research Group, Philadelphia, PA

13. Deceased.

Abstract

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.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

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