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

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.

Trial registration: ClinicalTrials.gov NCT02465060.

FIG 1.

Gene alterations observed in National Cancer Institute Molecular Analysis for Therapy Choice trial. A genomic waterfall plot displaying the top 15 most frequently mutated genes ranked by their rate of mutation and categorized by variant type—amplification, deletion, missense, nonsense, in-frame insertion, in-frame deletion, frameshift insertion, frameshift deletion, and fusion. The lower bar categorizes the alterations based on seven disease types and combines all others. For the purposes of this figure, negative PTEN expression by immunohistochemistry is assigned the deletion variant type.^,

FIG 2.

Co-occurring single nucleotide variants (SNVs) in the National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial and The Cancer Genome Atlas (TCGA). (A, B) Circle plots depict the co-occurrence of mutations across seven tumor types compared (cervical squamous carcinoma, colorectal adenocarcinoma, cholangiocarcinoma-pancreaticobiliary, invasive breast carcinoma, lung adenocarcinoma, prostate adenocarcinoma, and pancreatic carcinoma). Band thickness represents the fraction of co-occurrence within each of NCI-MATCH and TCGA. For the purposes of these figures, only mutations in gene pairs occurring in more than five patients have been plotted. BRCA gene co-occurrences in NCI-MATCH were present just below the applied threshold. (C) Circular figures represent the total number of patients versus patients with or without SNV co-occurrence. (*) Patient must have one of the top seven diseases.^,

FIG 3.

(A-F) Treatment assignments, actionable alterations, and gene alteration by disease cohort. (A) Number of patient assignments by agent/target and variant type for invasive breast cancer (inset displays patients assigned v not assigned in this cohort). (B) Number of observed actionable alterations by gene and variant type in patients with breast cancer; includes targetable gene mutations lacking a National Cancer Institute Molecular Analysis for Therapy Choice agent. (C) A genomic waterfall plot displaying the top 20 most frequently mutated genes ranked by their rate of mutation and categorized by variant type (amplification [amp], deletion [del], missense, nonsense, in-frame insertion [ins], in-frame deletion, frameshift insertion, frameshift deletion, and fusion) in patients with breast cancer. For the purposes of this figure, negative PTEN expression by immunohistochemistry (IHC) is assigned the deletion variant type. (continued on following page)

FIG 3.

(A-F) Treatment assignments, actionable alterations, and gene alteration by disease cohort. (A) Number of patient assignments by agent/target and variant type for invasive breast cancer (inset displays patients assigned v not assigned in this cohort). (B) Number of observed actionable alterations by gene and variant type in patients with breast cancer; includes targetable gene mutations lacking a National Cancer Institute Molecular Analysis for Therapy Choice agent. (C) A genomic waterfall plot displaying the top 20 most frequently mutated genes ranked by their rate of mutation and categorized by variant type (amplification [amp], deletion [del], missense, nonsense, in-frame insertion [ins], in-frame deletion, frameshift insertion, frameshift deletion, and fusion) in patients with breast cancer. For the purposes of this figure, negative PTEN expression by immunohistochemistry (IHC) is assigned the deletion variant type. (continued on following page)