Background: Previous preclinical study reported that a combination of PANI with FTD/TPI demonstrated synergistic antitumor activity (Baba, 2017); however, no clinical study has been reported in this combination yet. Therefore, we conducted a phase I/II study to evaluate the efficacy and safety of this combination in pts with RAS wt mCRC. Here, we report the results of final analysis, including follow-up. Methods: Eligible pts had RAS wt mCRC refractory or intolerant to fluoropyrimidines, irinotecan, oxaliplatin, or angiogenesis inhibitors, and had never been treated with anti-EGFR antibodies, FTD/TPI, or regorafenib (REG).Pts received four-week cycles of PANI (every two weeks) and FTD/TPI (twice daily, days 1 to 5 and 8 to 12). The primary endpoint was frequency of dose-limiting toxicity (DLT) in phase I and progression-free survival (PFS) rate at 6 months (M) in phase II. With a PFS rate at 6 M of 48% deemed promising and 29% judged unacceptable, and assuming a one-sided significance level of 5%, the necessary sample size to achieve a power of 80% was estimated to be 47 pts (target sample size, 52 pts). Results: Since no DLT occurred in phase I, the recommended dose was determined to be 6 mg/kg for PANI and 35 mg/m² for FTD/TPI. In phase II with a median follow-up of 16.5 M, the PFS rate at 6 M (n = 54) was 33.3% (90% CI: 22.8–45.3; p = 0.24), and median PFS and overall survival were 5.8 M (95% CI: 4.5–6.5) and 14.1 M (95% CI: 12.2–19.3), respectively. The response rate and disease control rate were 37.0% and 81.4%, respectively. The most common grade 3 or higher adverse events (n = 55) were neutropenia (10.9%), febrile neutropenia (9.1%), stomatitis (9.1%), and dermatitis acneiform (9.1%). Subsequent therapy was given to 39 pts (72.2%), including 25 pts (46.3%) treated with REG. Subgroup analyses stratified by age, PS, and primary lesion will be reported at the time of conference presentation. Conclusions: PANI combined with FTD/TPI showed favorable antitumor activity with an acceptable safety profile for previously treated RAS wt mCRC, although the primary endpoint of PFS rate at 6 M did not meet the prespecified threshold. Clinical trial information: NCT02613221