Background: Trifluridine/tipiracil (TT) is an oral fluoropyrimidine (FP) currently utilised in later-line therapy for metastatic colorectal cancer, with a unique mechanism of action and clinical activity in patients with prior FP failure. Preclinical data demonstrates synergistic activity with panitumumab or irinotecan, providing rationale for its use in earlier lines of treatment. PIT was a non-randomised, phase IB/II study determining the safety and tolerability of TT combined with panitumumab and irinotecan for first- or second-line management of RAS wildtype metastatic colorectal cancer. Methods: The part IB dose escalation study enrolled 3 patients before the MTD was determined from other published work. TT was dosed orally, BID 25 mg/m2 on days 1–5, with 6 mg/kg panitumumab and 180 mg/m2 irinotecan administered intravenously on day 1 of 14-day cycles. The phase II expansion study aimed to enrol 50 patients, with the primary endpoint modified to toxicity. Results: This study closed early due to slow recruitment, with the enrolment of 14 patients. Thirteen received PIT as first-line therapy for metastatic disease. A total of 64% experienced grade 3 toxicity (predominantly rash, electrolyte disturbances, diarrhoea, and neutropenia). One patient experienced grade 4 neutropenia, and there was one treatment-related death (neutropenic sepsis). At a median follow-up of 36 months, 12 patients had evaluable disease (PR: 58%; SD: 42%), with a 6-month PFS of 91%, a median PFS of 18.2 months, a median OS of 41.3 months, and a 12-month OS of 57%. Conclusions: The toxicity profile was notable for high rates of grade 3 rash and diarrhoea. Whilst the small patient numbers limit interpretation, there is a significant signal of activity for this combination, supporting this concept for future trials (ANZCTR number: ACTRN12617001190392, 2017 Aug 15).
Blanc et al. (Tue,) studied this question.
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