TAS-102, Irinotecan, and Bevacizumab in Pre-treated Metastatic Colorectal Cancer (TABAsCO), A Phase II Clinical Trial. ClinicalTrials.gov NCT04109924

Background: The efficacy of FOLFIRI plus an antiangiogenesis biologic agent as 2nd line therapy for metastatic colorectal adenocarcinoma is limited. TAS-102 is a novel oral antimetabolite with a distinct mechanism of action from fluoropyrimidines. We evaluated the antitumor efficacy of TAS-102, irinotecan and bevacizumab in patients with pre-treated, advanced colorectal adenocarcinoma in a multicenter, phase II, single-arm study. Methods: Patients with advanced colorectal adenocarcinoma who had progressed after oxaliplatin and fluoropyrimidine and were eligible for treatment with bevacizumab were treated with irinotecan, bevacizumab, and TAS-102 in 28-day cycles. The primary endpoint was progression-free survival (PFS). Results: We enrolled 35 evaluable patients. The study was positive. The median PFS was 7.9 (90% CI 6.2-11.8) months (vs. 6 months in historical control, p=0.018). The median overall survival was 16.5 (90% CI 9.8-17.5) months. Sixty-seven percent of patients experienced grade 3 or higher treatment-related adverse events. The most common toxicities were hematological (neutropenia) and gastrointestinal (diarrhea, nausea, and vomiting). Conclusions: Irinotecan, TAS-102 and bevacizumab is an active 2nd line therapy for patients with metastatic colorectal adenocarcinoma. Neutropenia is common and can affect dose density/intensity mandating use of G-CSF. A randomized study versus standard of care therapy is warranted. Overall design: We evaluated the significance of expression of genes involved in different types of DNA repair, trifluorothymidine metabolism, cell cycle control, and replication in treatment outcomes. We identified 12 patients treated at Roswell Park with available archival tumor tissue. Under a separate de-identified protocol (BDR 155422), we extracted RNA from these tumors for whole transcriptome sequencing (see Supplementary Methods). Additionally, we identified 21 patients treated with TAS-102 monotherapy with available archival tumor samples for similar analyses to be used as controls (BDR 151721). Genes of interest were grouped in the following categories: HR, BER, MMR, nucleotide excision repair (NER), proofreading polymerases, non-homologous end joining (NHEJ), DNA damage response, cell cycle checkpoints, replication, and trifluorothymidine/nucleotide metabolism. Clinical data for samples is available from authers by request.