A phase 1b expansion study of TAS‐102 with oxaliplatin for refractory metastatic colorectal cancer

Abstract

Background TAS‐102, a novel antimetabolite, is approved for treatment of refractory metastatic colorectal cancer (CRC). This study sought to determine whether the addition of TAS‐102 to oxaliplatin (TAS‐OX) was safe and effective in metastatic CRC previously treated with oxaliplatin. Methods This investigator‐initiated, open‐label, single‐arm phase 1b study enrolled patients with metastatic CRC previously treated with 5‐fluorouracil, irinotecan, and oxaliplatin. In dose escalation, TAS‐102 was given at 3 dose levels: 25, 30, and 35 mg/m2 twice daily on day 1 to day 5 with 85 mg/m2 oxaliplatin on day 1 in 14‐day cycles. The primary endpoint of dose escalation was the recommended dose for expansion, and in dose expansion, the primary endpoint was overall response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Results Forty‐one patients were treated with TAS‐OX. No dose‐limiting toxicities were observed in the 11 patients treated in escalation. The recommended dose for expansion was 35 mg/m2 TAS‐102 twice daily on day 1 to day 5 in combination with 85 mg/m2 oxaliplatin on day 1 in 14‐day cycles. In the intention‐to‐treat population, the ORR was 2.4% (95% CI, 0%‐12.9%) with 1 of 41 patients having a partial response, although 12 (29%) had tumor shrinkage. The median progression‐free survival was 2.7 months (95% CI, 2.4‐4.8 months) and median overall survival was 6.8 months (95% CI, 5.7‐10 months). Conclusions TAS‐OX is safe with no unexpected toxicities at standard doses of each agent. The combination did not result in a clinically meaningful ORR, although progression‐free survival and overall survival were encouraging in this heavily pretreated population. Lay Summary For metastatic colorectal cancer, the treatment combination of TAS‐102 and oxaliplatin was found to be well‐tolerated and revealed no unexpected side effects. Twelve of 41 patients had reductions in the size of their tumor, and the study treatment delayed the time to tumor growth as opposed to what would be expected.

Revisiting Temozolomide's role in solid tumors: Old is gold?

“…Cechini et al discovered that the combination of temozolomide and Olaparib was well tolerated by patients suffering from colorectal cancer, and that it did demonstrate anticancer effectiveness in a subgroup of patients whose tumors showed MGMT promoter hypermethylation, reduced MGMT protein expression, and enhanced CD8+ effector TILs. [152]. O6-methylguanine (O6MeG), one of the several methyl adducts produced when exposed to temozolomide, makes up a small percentage of these adducts but is the main cytotoxic lesion that seriously hinders DNA replication because thymine is inserted in opposition to methylguanine [153,154].…”

Research progress of traditional Chinese medicine as sensitizer in reversing chemoresistance of colorectal cancer

“…The dual nature of TP also affects chemical resistance. TAS-102 is an oral FU preparation composed of trifluoropyridine (TFT) and thymidine phosphorylation inhibitor (TPI) ( 104 ). TFT can inhibit TS from hindering DNA synthesis, but it can also induce DNA damage and demonstrate a cytotoxic effect by doping its metabolites into DNA.…”

Metastatic colorectal cancer: Advances in the folate-fluoropyrimidine chemotherapy backbone

“…In a pivotal phase 3 study in patients with refractory colorectal cancer, TAS-102 was associated with an improvement in median OS (7.1 months compared with 5.3 months with placebo) [76]. Subsequent studies have explored the use of TAS-102 in combination with other therapies such as bevacizumab [77] and oxaliplatin [78]. Preliminary evidence also suggests that high expression of thymidine kinase 1, the enzyme required for trifluridine phosphorylation, may be a predictive factor of TAS-102 efficacy [79].…”