Phase IB/II first line panitumumab, irinotecan, trifluridine/tipiracil in RAS wild-type patients with metastatic colorectal cancer: PIT study.

Abstract

e15532 Background: Trifluridine/tipiracil (TT) is an oral fluoropyrimidine (FP) currently used in later line therapy. Preclinical data have demonstrated synergistic activity when panitumumab (Pmab) or irinotecan (Ir) are combined with TT supporting use in combination schedules in early line protocols. PIT was a phase IB/II study determining the maximum tolerated dose (MTD), safety and tolerability of substituting FP with TT, combined with Pmab and Ir in RAS wild-type mCRC. Methods: Phase IB 3+3 design dose escalation study (Dose level 1: TT 20mg/m2 oral BD, Ir 150mg/m2 IV, Pmab 6mg/m2). Primary objective was MTD of the combination in RAS WT mCRC patients, either 1st or 2nd line. Treatment was administered in 14-day cycles. Pmab and Ir were administered intravenously on day 1 with TT dosed orally, bid, days 1-5. Once MTD was established the phase II expansion study was to enrol 50 previously untreated mCRC patients. Primary endpoint was modified to toxicity. Results: The study closed due to slow recruitment. 14 patients were enrolled from 6/18 to 10/21. Med follow up 23 months. Med age 59 yrs (range 37-74yrs). 60% were male. One patient each was BRAF MT and right sided. ECOG 0/1 50%/50%. Thirteen patients had PIT as first line, 57% had prior adjuvant therapy. There was one DLT in first 3 patients however based on additional toxicity data (Clin Cancer Res. 2020 Apr 1:1555) a decision was made to not dose escalate beyond level 1 and commence phase II. Overall Gd 3 toxicity: Acne/rash 46%, Diarrhoea 31%, Fatigue 8%, neutropenia 15%, hypomagnesaemia 23%. One patient had Gd 4 neutropenia and there was one treatment related death (neutropenic sepsis). 12 patients had evaluable disease, 58% PR, 42% SD. Survival: Med PFS 14.1 mths, Med OS 40.6mths and 12 mth OS 64%. Conclusions: The MTD was deemed TT 20mg/m2, irinotecan 150mg/m2 and panitumumab 6mg/kg. Toxicity was manageable however significant grade 3 diarrhoea and rash was seen. There was one toxic death contributed to therapy. Small numbers do make interpretation difficult however there is a signal of activity. The slow recruitment illustrates difficulty in exploring novel combinations in early lines and potentially the reluctance to consider first line anti-EGFR therapy. Clinical trial information: ACTRN12617001190392.