Abstract A079: National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH): A successful precision medicine signal-seeking trial in patients (pts) with rare variants and refractory malignancies

Abstract

Abstract Introduction: NCI-MATCH, developed by ECOG-ACRIN & NCI, is the largest precision medicine study for pts with refractory malignancy. Over 1100 clinical sites in the National Clinical Trials Network enrolled pts. The purpose of the study is to identify potentially beneficial targeted treatments across tumor types with similar molecular abnormalities. Methods: The NCI Central IRB approved NCI-MATCH. Pts with refractory/no treatment available solid tumors, lymphomas or myelomas had a fresh biopsy profiled by next generation sequencing (143 genes, > 4000 single nucleotide variants, indels, amplifications & targeted fusions). Pts are assigned by a defined algorithm to treatments with evidence of activity against tumors with the relevant molecular alteration. Pts are excluded if a treatment is FDA approved or known to be ineffective for their malignancy. After successfully sequencing fresh biopsies from 5540 pts, subprotocols with extremely rare variants lacked sufficient accrual. To address actionable variants with a prevalence of < 1.5%, we decided to accept clinical sequencing results from 30 commercial and academic laboratories vetted by NCI-MATCH to address relevant variants. These labs notify clinicians participating in NCI-MATCH if their pt’s tumor contains an actionable variant. Treatment continues until tumors became refractory, pt intolerance or withdrawal of consent. An objective response rate (ORR by RECIST) of > 16% among 31 eligible patients is considered a positive signal. Results: After screening 5540 pts, 37.6% had an actionable variant. After histology and treatment-specific exclusions, 17.8% were assigned and 69.5% enrolled on the assigned subprotocol. 11 of the initial 30 subprotocols reached completion with adequate follow-up. Of the first 11 evaluable subprotocols, 3 addressing rare variants had a positive signal: Nivolumab in pts with loss of expression of MLH1 or MSH2 (ORR 36%), capivasertib in pts with AKT mutations (ORR 23%), and dabrafenib + trametinib in pts with BRAF V600 mutations (ORR 33%). These molecular variants were found in 2%, 1.2% and 1.9% respectively, of screened pts. Two other subprotcocols (afatinib in ERBB2 mutations and AZD4547 in FGFR abnormalities) showed responses in rare tumors or specific variant subsets, respectively. As of July 15, 2019, an additional 378 of 432 (88%) pts have been assigned to a treatment with a clinical sequencing assay; 83% of these pts enrolled to 1 of 24 subprotocols, allowing completion of an additional 9 of the original 30 subprotocols and complete accrual to 2 of 5 recently added subprotocols. Four of 35 subprotocols closed for lack of accrual, 10 continue accruing and 4 are planned. Conclusions: Platform precision medicine trials can identify potentially useful targeted treatments for diverse malignancies in pts with uncommon tumors & rare actionable variants, an unmet need. In a population of pts with refractory cancers, lymphomas and myelomas, 30-40% will have an actionable variant for targeted treatment (investigational or standard). Of the first 11 subprotocols with adequate follow-up, 3 (27%) showed a positive signal and an additional 2 showed responses in rare tumors or in a molecular subset, suggesting that the NCI-MATCH trial approach identifies useful targets for further exploration. Citation Format: Lyndsay N Harris, Robert J Gray, Barbara A Conley, Alice P Chen, Keith T Flaherty, Stanley R Hamilton, Paul M Williams, Chris Karlovich, David Patton, Shuli Li, Lisa M McShane, Larry V Rubinstein, Edith P Mitchell, James V Tricoli, Richard F Little, Carlos L Arteaga, Peter J O'Dwyer, NCI-MATCH team. National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH): A successful precision medicine signal-seeking trial in patients (pts) with rare variants and refractory malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A079. doi:10.1158/1535-7163.TARG-19-A079