Trifluridine/tipiracil and bevacizumab combination gives a prolonged PFS compared to trifluridine/tipiracil monotherapy in mCRC

Prof Hironaga Satake - Kochi Medical School, Kochi, Japan

Trifluridine/tipiracil, FTD/TPI, also known as TAS-102, has been widely used as one of the standard treatments in the late-line treatment for patients with metastatic colorectal cancer. The efficacy of the FTD/TPI plus bevacizumab combination was also recently reported in the SUNLIGHT trial. But the previously reported standard schedule for the combination of FTD/TPI – five days on, two says off for two weeks then two weeks off – plus bevacizumab combination every two weeks is complicated by severe haematological toxicities and difficult schedules.

Several phase II studies suggested that modifying the FTD/TPI schedule in combination with bevacizumab from four week intervals to bi-weekly dosing, one week on, one week off, reduced haematological toxicities without reducing efficacy. So we conducted a phase III trial to confirm the superiority of bi-weekly FTD/TPI plus bevacizumab to four-week interval FTD/TPI monotherapy.

What was the study design?

JCOG2014 (ROBiTS) is our open-label multicentre phase III trial conducted in the Colorectal Cancer Study Group of Japan Clinical Oncology Group, JCOG. Patients with metastatic colorectal cancer who were refractory or intolerant to standard chemotherapy were randomised in a 1:1 ratio. Arm A received four-week interval FTD/TPI monotherapy and arm B received bi-weekly FTD/TPI plus bevacizumab.

The primary endpoint was overall survival. Secondary endpoints were progression free survival, response rate, disease control rate and safety.

What were the results of this study?

In consideration of the results of the SUNLIGHT trial, this study was prematurely terminated. Patient backgrounds were well balanced. With a median follow-up of 8 months the overall survival was comparable in both groups but PFS was better in the bi-weekly FTD/TPI plus bevacizumab. The median PFS was 2.4 months in the control arm group and 4.0 months in the bi-weekly FTD/TPI plus bevacizumab combination arm. The hazard ratio was 0.607.

The response rate and disease control rate also tended to be better in the bi-weekly FTD/TPI plus bevacizumab arm. The most common grade 3 or higher adverse events in each group were neutropenia and anaemia, both were mild in the bi-weekly FTD/TPI plus bevacizumab arm. Febrile neutropenia was observed in four cases in the control arm group but not in the bi-weekly FTD/TPI plus bevacizumab arm.

What is the clinical impact of these results?

JCOG2014 (ROBiTS) demonstrates that the bi-weekly FTD/TPI plus bevacizumab combination in late-line chemotherapy for patients with metastatic colorectal cancer resulted in prolonged PFS and reduced haematological toxicity compared to four-week interval FTD/TPI monotherapy. In the late-line chemotherapy for metastatic colorectal cancer, not only treatment efficacy but also impact on quality of life due to adverse events should be considered. Also this study was unfortunately terminated early. The bi-weekly FTD/TPI plus bevacizumab combination may be considered as a treatment option for late-line chemotherapy of metastatic colorectal cancer patients.

Is there anything else you would like to add?

Now we are going in Japan a prospective observational study is already underway to evaluate the outcome of the bi-weekly FTD/TPI plus bevacizumab combination regimen versus four-week interval FTD/TPI plus bevacizumab combination, the SUNLIGHT trial, SUNRISE regimen, is now ongoing.