Assessment, Analysis, and Discussion
PPTD, DLTs, diarrhea, toxicities, perforation, proteinurea, myelotoxicity, anorexia
EVENTS, HYPERTENSION, METASTATIC GASTRIC CANCER, ANOREXIA
This phase Ib study indicated that combining IRI and BEV with biweekly FTD/TPI is safe for mCRC treatment. In Japanese mCRC patients pretreated with fluoropyrimidine and oxaliplatin, this regimen showed modest efficacy in this pilot study. To the best of our knowledge, this is the first study to evaluate such a triple combination with biweekly administration of FTD/TPI in Asian patients.Five DLTs occurred in the dose escalation part of the study. We determined that the RP2D could be defined as FTD/TPI 35 mg/mThe triple drug combination was tolerable, and no drug-related AE was observed other than those that might be expected. Most drug-related AEs were grade 3-4 hematological events that could be managed by delay in the treatment schedule, dose reduction, and basic supportive care. Gastrointestinal toxicities such as anorexia and diarrhea were mainly grade 1 or 2 and related to FTD/TPI and IRI, which was also within our expectations. In addition, grade 3 hypertension, proteinurea, and perforation related to BEV were observed in <10% of our patients. AEs were managed using dose reduction and dose delay, with only 2 treatment-related AEs resulting in treatment discontinuation. Thus, the overall safety profile of this regimen is consistent with the expected toxicities of the individual agents, with no unanticipated safety issue.The preliminary efficacy results showed modest antitumor activity in this trial. We reported an ORR of 19% and PFS of 7.1 months in the RP2D population, which is numerically better compared to previous trials of those for other conventional chemotherapies, including FOLFIRI in combination with anti-VEGF as second-line therapy.The limitation of this study is that it was a nonrandomized prospective trial with a small sample size. In particular, because the PPTD population consisted of only 16 patients, it was difficult to accurately assess efficacy in such a heterogeneous group with various prognostic factors such as RAS status and previous treatment with biologics. Given the study design, it was also difficult to determine the most appropriate IRI dose between 150 mg/mIn conclusion, this dose escalation/expansion study indicated that treatment with a triple combination of FTD/TPI, IRI, and BEV has moderate antitumor activity with severe but manageable myelotoxicity for mCRC after failed standard first-line therapy with fluoropyrimidines and oxaliplatin. Continued investigation of this regimen may be possible in other patient populations such as metastatic gastric cancer.