Abstract
The NCI-MATCH was designed to characterize the efficacy of targeted therapies in histology-agnostic driver mutation-positive malignancies. Sub-protocols F and G were developed to evaluate the role of crizotinib in rare tumors that harbored either ALK or ROS1 rearrangements. Patients with malignancies that progressed following at least one prior systemic therapy were accrued to the NCI-MATCH for molecular profiling, and those with actionable ALK or ROS1 rearrangements were offered participation in sub-protocols F or G, respectively. There were five patients who enrolled on Arm F (ALK) and four patients on Arm G (ROS1). Few grade 3 or 4 toxicities were noted, including liver test abnormalities, and acute kidney injury. For sub-protocol F (ALK), the response rate was 50% (90% CI 9.8–90.2%) with one complete response among the 4 eligible patients. The median PFS was 3.8 months, and median OS was 4.3 months. For sub-protocol G (ROS1) the response rate was 25% (90% CI 1.3–75.1%). The median PFS was 4.3 months, and median OS 6.2 months. Data from 3 commercial vendors showed that the prevalence of ALK and ROS1 rearrangements in histologies other than non-small cell lung cancer and lymphoma was rare (0.1% and 0.4% respectively). We observed responses to crizotinib which met the primary endpoint for ALK fusions, albeit in a small number of patients. Despite the limited accrual, some of the patients with these oncogenic fusions can respond to crizotinib which may have a therapeutic role in this setting.
Highlights
The NCI MATCH trial is an expansive National Clinical Trials Network/NCI Community Oncology Research Program effort, developed and implemented with the goal of providing a largescale platform for the study of targeted agents in molecularly defined malignancies
Patient characteristics A total of 5 patients enrolled on sub-protocol F (ALK), with the first patient enrolled on November 24, 2015, and the last on April 24, 2019
Accrual to sub-protocols F and G was limited, reducing our ability to assess the efficacy of treatment with any precision
Summary
The NCI MATCH trial is an expansive National Clinical Trials Network/NCI Community Oncology Research Program effort, developed and implemented with the goal of providing a largescale platform for the study of targeted agents in molecularly defined malignancies. With the availability of molecular testing and drugs designed to target actionable mutations, this effort has been one of the largest to provide access to treatment based on driver mutation status, rather than histology or primary site of disease. The chimeric proteins that result from gene fusions involving ALK or ROS1 are both therapeutic targets of the tyrosine kinase inhibitor crizotinib. The kinase domains of ALK and ROS1 share significant amino homology within the ATP-binding sites, resulting in high-affinity binding of crizotinib in cell-based assays. This, in turn, results in activation of downstream signaling involving the MAPK, PI3K, and JAK/STAT pathways, thereby promoting increased cell growth and proliferation[1]
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