A recent phase II study published in Nature explores the efficacy and safety of combining irinotecan with trifluridine/tipiracil (TAS-102), commonly known as Lonsurf, plus bevacizumab in patients with heavily pretreated metastatic colorectal cancer (mCRC). The study offers a potential new treatment strategy for patients who have exhausted other options.
The global burden of colorectal cancer is substantial, with over 1.9 million new cases and 935,000 deaths in 2020 alone. While treatments like fluoropyrimidines, oxaliplatin, irinotecan, and targeted therapies such as bevacizumab have improved outcomes, many patients eventually develop resistance, necessitating further treatment options.
Study Design and Key Findings
The phase II trial enrolled patients with mCRC who had progressed after multiple prior lines of therapy. Patients received irinotecan, trifluridine/tipiracil (TAS-102), and bevacizumab. The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall survival (OS), objective response rate (ORR), and safety.
The study reported a median PFS of 4.6 months and a median OS of 9.4 months. These results suggest a clinically meaningful benefit in a patient population with limited treatment alternatives. The objective response rate was 11.1%, indicating that a subset of patients experienced tumor shrinkage.
Safety and Tolerability
The most common adverse events were hematologic toxicities, including neutropenia, anemia, and febrile neutropenia. These side effects were generally manageable with dose modifications and supportive care. The safety profile is consistent with what has been observed in prior studies of these agents.
Mechanism of Action and Rationale
Trifluridine/tipiracil (TAS-102) is an oral fluoropyrimidine nucleoside analog that incorporates into DNA, inhibiting cell proliferation. Bevacizumab is a monoclonal antibody that targets VEGF, inhibiting angiogenesis. Irinotecan is a topoisomerase I inhibitor. The combination of these agents may provide synergistic antitumor activity by targeting different pathways involved in cancer growth and progression.
Implications for Clinical Practice
The results of this phase II study suggest that the combination of irinotecan, trifluridine/tipiracil (TAS-102), and bevacizumab could be a valuable option for patients with heavily pretreated mCRC. Further studies are needed to confirm these findings and to identify predictive biomarkers that may help to select patients most likely to benefit from this regimen.
