SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 147,950 new cases of CRC will be diagnosed in the United States in 2020 and about 53,200 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23. Approximately 15-25% of the patients with CRC present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with CRC will develop metastatic disease during the course of their illness. Patients with metastatic CRC, whose disease has progressed after treatment with standard therapies, have limited therapeutic options available, to treat their disease.
LONSURF® is a combination of two agents – a novel oral nucleoside, Trifluridine and a thymidine phosphorylase inhibitor, Tipiracil hydrochloride. This combination has a unique mechanism of action. Trifluridine, the active ingredient of LONSURF® incorporates into DNA resulting in DNA damage. Degradation of Trifluridine which occurs when taken orally is prevented by Tipiracil hydrochloride. In a pivotal, global, Phase III trial (RECOURSE), LONSURF® significantly improved Overall Survival (OS) compared to placebo, with a 32% reduction in the risk of death, among patients with chemo-refractory metastatic CRC. AVASTIN® (Bevacizumab) is a humanized anti-VEGF monoclonal IgG1 antibody that directly binds Vascular Endothelial Growth Factor (VEGF) to inhibit angiogenesis.
In a previously published multicenter Phase I/II study (C-TASK FORCE), the combination of LONSURF® in combination with AVASTIN® showed promising antitumor activity with acceptable toxicity among patients with metastatic CRC. Based on the encouraging results of this study, the authors conducted an open-label, randomized, Phase II study in which the efficacy of LONSURF® plus AVASTIN® was compared with LONSURF® monotherapy in patients with refractory metastatic CRC. This study enrolled and randomly assigned 93 patients in 1:1 ratio to LONSURF® plus AVASTIN® (N=46) or LONSURF® alone (N=47). The main inclusion criteria were histopathologically confirmed metastatic CRC, refractory or intolerant to a Fluoropyrimidine (5-FU), Irinotecan (CAMPTOSAR®), Oxaliplatin (ELOXATIN®), and Cetuximab (ERBITUX®) or Panitumumab (VECTIBIX®), with the latter two agents offered only for RAS wild-type tumors. Patients had a WHO performance status of 0 or 1 and previous therapy with AVASTIN®, ZALTRAP® (Aflibercept), CYRAMZA® (Ramucirumab), or STIVARGA® (Regorafenib) was allowed. Randomized patients received LONSURF® 35 mg/m2 orally twice daily on days 1-5 and 8-12 every 28 days alone, or in combination with AVASTIN® 5 mg/kg IV on days 1 and 15 of each treatment cycle, until disease progression or unacceptable toxicity. Patients were stratified by institution and RAS mutation status. The Primary endpoint was Progression Free Survival (PFS).
After a median follow up of 10.0 months, the median PFS was 4.6 months in the LONSURF® plus AVASTIN® group versus 2.6 months in the LONSURF® monotherapy group (HR=0.45; P=0.0015). This represented a 55% reduction in the risk of progression or death. This benefit remained significant when analysis was adjusted for the stratification factors of study center and RAS mutation status (HR = 0.47, P =0.0015). The median Overall Survival was 9.4 months versus 6.7 months (HR=0.55, P =0.03) and Disease Control Rates were 67% versus 51% (P=0.14), in favor of the combination therapy. The most common treatment-related Grade 3 or more adverse events in the combination group were neutropenia and diarrhea.
It was concluded that among patients with chemo-refractory metastatic CRC, a combination of LONSURF® and AVASTIN® was associated with a significant and clinically relevant improvement in Progression Free Survival with tolerable toxicity, compared with LONSURF® monotherapy. The authors added that this could be a new treatment option and practice-changing development for patients with refractory metastatic CRC. TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Pfeiffer P, Yilmaz M, Möller S, et al. THE LANCET Oncology. Published:January 27, 2020DOI:https://doi.org/10.1016/S1470-2045(19)30827-7
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