Initial report of a phase I/II study of S-1 and irinotecan (IRIS) in combination with cetuximab in patients with wild-type RAS metastatic colorectal cancer
Authors: E. Oki, H. Samura, H. Okumura, T. Ohchi, H. Orita, K. Kobayashi, T. Kinjo, S. Mori, T. Touyama, K. Ohgaki, H. Kawanaka, A. Makiyama, N. Ureshino, M. Kotaka, T. Shimose, H. Saeki, T. Nishimaki, H. Baba, Y. Maehara
Journal: Annals of Oncology (2018)

Background: Combination therapy with oral fluoropyrimidine and irinotecan with cetuximab has not yet been established as first-line treatment of metastatic colorectal cancer (mCRC). This study was designed to assess the tolerability of different doses of tri-weekly intravenous infusion of irinotecan in combination with S-1 (IRIS) and weekly cetuximab (phase I) and explore the efficacy and safety of the IRIS in combination with cetuximab in patients with mCRC (phase II). Methods: Main eligibility was RAS (exon 2) wild-type mCRC and without any prior chemotherapy except for adjuvant therapy. S-1 was given orally at a dose of 40 mg/m2 (40-60mg) twice for 2 weeks, followed by a 1-week rest. Irinotecan (150mg/m2) was given on days 1. Cetuximab was administered on days 1 (400 mg/ m2), 8 (250 mg/ m2) and 15 (250 mg/ m2), followed by every week (250 mg/ m2) thereafter. A standard 3 + 3 phase I dose de-escalation design was utilized to decide maximum tolerant dose (MTD) and recommend dose (RD) of irinotecan. Primary endpoint of Phase II part was overall response rate (ORR). We set the expected and threshold RRs at 60% and 40%, respectively. ORR was assessed by central office according to RECIST version 1.1 criteria. Results: Between December 2014 and September 2017, 58 patients were enrolled. Seven patients were excluded owing to ineligibility. No dose limiting toxicity was observed in phase I part and RD irinotecan was decided at 150mg/m2. In phase II part, the treatment response with confirmation was complete response (CR) in 1, and partial response (PR) in 28, stable disease (SD) in 15, progressive disease (PD) in 6, not evaluated (NE) in 1, final response rate was 56.9% (90 %; CI 44.4 – 68.7 %, p = 0.011). The safety profile revealed the common Grade 3/4 adverse events to be neutropenia (31.4%), appetite loss (27.5%), hypokalemia (11.8%) and diarrhea (11.8%). Grade 3/4 HFS occurred in 9 patients (9.8%). Conclusions: This study showed the efficacy and safely was comparable to other first line treatment regimens. The results support IRIS/cetuximab is more convenient and provide treatment flexibility in first line treatment with metastatic colorectal cancers. Clinical trial identification: UMIN000015835. Legal entity responsible for the study: This work was supported by CReS Kyushu with funding from Merck Serono, Japan, under a research contract. Funding: Merck Serono. Disclosure: E. Oki: Honoraria for lecturing: Bayer Yakuhin, Ltd, Japan; Eli Lilly Japan K.K.; Taiho Pharmaceutical Co., Ltd.; Yakult Honsha Co., Ltd.; Merck Serono Co., Ltd.; Takeda Pharmaceutical Co., Ltd.; Johnson & Johnson K.K.; and Chugai Pharmaceutical Co., Ltd. M. Kotaka: Honoraria lecturing: Chugai Pharmaceutical Co., Ltd. H. Baba, Y. Maehara: Lecture fees: Taiho Pharm; Grant research funding: Taiho Pharm, Merck Serono, Yakult Honsha, Japan. All other authors have declared no conflicts of interest.