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Aflibercept plus 5‐fluorouracil/levofolinate/irinotecan (FOLFIRI) is a second‐line treatment for metastatic colorectal cancer. This ancillary exploratory analysis of data in Japanese people was aimed at exploring the relationship between a set of potential prognostic biomarkers and efficacy endpoints following aflibercept plus FOLFIRI therapy. Sixty‐two patients with metastatic colorectal cancer received aflibercept (4 mg/kg) plus FOLFIRI every 2 weeks. Seventy‐eight potential protein biomarkers were chosen for analysis based on their roles in angiogenesis, tumor progression, and tumor‐stroma interaction. Plasma levels of biomarkers at baseline and at pre‐dose 3 (day 1 of treatment cycle 3) were measured in all patients by ELISA. Relationships between these levels and efficacy endpoints were assessed. Ten potential biomarkers had a ±30% change from baseline to pre‐dose 3 (adjusted P

Aflibercept targets vascular endothelial growth factor. The present study involved assessing the efficacy, safety and pharmacokinetics of aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) as a second-line treatment for metastatic colorectal cancer (mCRC) in Japanese patients. Aflibercept (4 mg/kg) plus FOLFIRI was administered every 2 weeks in 62 patients with mCRC until disease progression, unacceptable toxicity or patient withdrawal. Tumors were imaged every 6 weeks. The primary endpoint was objective response rate (ORR); secondary endpoints were progression-free survival, overall survival, safety, and pharmacokinetics of aflibercept, irinotecan and 5-fluorouracil. A total of 60 patients were evaluated for ORR; 50 had received prior bevacizumab. The ORR was 8.3% (95% confidence interval [CI]: 1.3%-15.3%), and the disease control rate (DCR) was 80.0% (69.9%-90.1%). The median progression-free survival was 5.42 months (4.14-6.70 months) and the median overall survival was 15.59 months (11.20-19.81 months). No treatment-related deaths were observed, and no significant drug-drug interactions were found. The most common treatment-emergent adverse events were neutropenia and decreased appetite. Free aflibercept had a mean maximum concentration (coefficient of variation) of 73.2 μg/mL (15%), clearance of 0.805 L/d (22%) and volume of distribution of 6.2 L (18%); aflibercept bound with vascular endothelial growth factor had a clearance of 0.162 L/d (9%) (N = 62). Aflibercept did not significantly affect the pharmacokinetics of irinotecan or 5-fluorouracil: The clearance was 11.1 L/h/m2 (28%) for irinotecan and, at steady state, 72.6 L/h/m2 (56%) for 5-fluorouracil (N = 10). Adding aflibercept to FOLFIRI was shown to be beneficial and well-tolerated in Japanese patients with mCRC. ClinicalTrials.gov Identifier: NCT01882868.

Pharmacogenetic testing for UDP-glucuronosyltransferase (UGT) 1A1*28, a promoter variant of the UGT1A1 gene, is now carried out clinically to estimate the risk of irinotecan-associated toxicity. We studied the clinical significance of UGT1A1*6 and UGT1A1*27, two variants in exon 1 of the UGT1A1 gene that are found mainly in Asians. The study group comprised 46 Japanese patients who received various regimens of chemotherapy including irinotecan at doses from 50 to 180 mg/m(2). Pharmacogenetic relationships were explored between the UGT1A1 genotype and the ratio of the area under the plasma concentration-time curve (AUC) of the active metabolite of irinotecan (SN-38) to that of SN-38 glucuronide (SN-38G), used as a surrogate for UGT1A1 activity (AUC(SN-38)/AUC(SN-38G)). No patient was homozygous for UGT1A1*28, and none had UGT1A1*27. Two were heterozygous for UGT1A1*28. Two were homozygous and 15 heterozygous for UGT1A1*6, all of whom were wild type with respect to UGT1A1*28. Two patients were simultaneously heterozygous for UGT1A1*28 and UGT1A1*6, present on different chromosomes. The other 25 patients had none of the variants studied. The two patients simultaneously heterozygous for UGT1A1*28 and UGT1A1*6 and the two patients homozygous for UGT1A1*6 had significantly higher AUC(SN-38)/AUC(SN-38G) ratios than the others (P = 0.0039). Concurrence of UGT1A1*28 and UGT1A1*6, even when heterozygous, altered the disposition of irinotecan remarkably, potentially increasing susceptibility to toxicity. Patients homozygous for UGT1A1*6 should also be carefully monitored. UGT1A1 polymorphisms in the coding region of the UGT1A1 gene should be genotyped in addition to testing for UGT1A1*28 to more accurately predict irinotecan-related toxicity, at least in Asian patients.

S-1 is an oral anticancer agent composed of tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate. CDHP is added to prevent degradation of 5-fluorouracil (5-FU) by inhibiting dihydropyrimidine dehydrogenase. CYP2A6 is involved in the biotransformation of FT to 5-FU. Thus, we prospectively analyzed the effects of the CYP2A6 genotype, plasma level of CDHP, and patient characteristics on the pharmacokinetic (PK) variability of FT and 5-FU. Fifty-four Japanese patients with metastatic or recurrent cancers who received S-1 were enrolled. The CYP2A6 polymorphisms (*4A, *7, and *9) with deficient or reduced activity were analyzed. All subjects were classified into three groups according to their CYP2A6 genotype: wild type (*1/*1), one-variant allele (*1/any), or two-variant alleles (combination other than *1). The PK of FT, 5-FU, and CDHP were measured on day 1 of treatment. Multivariate regression analysis revealed that oral clearance of FT was associated with the CYP2A6 genotype (analysis of variance [ANOVA], P = 0.000838). The oral clearance of FT seen in patients with the two-variant alleles was significantly lower than those in wild type and the one-variant allele (95% confidence intervals 0.75-2.41 and 0.41-1.82, respectively; Tukey-Kramer test). The area under the time-concentration curve (AUC) of 5-FU was significantly correlated with the AUC of CDHP (ANOVA, P = 0.00126). The AUC of 5-FU and CDHP were inversely correlated with creatinine clearance (ANOVA, P = 0.0164 and P = 0.000762, respectively). Although the CYP2A6 variants are the cause of the PK variability of FT, the AUC of CDHP affected by renal function is the key determinant of the variability in the PK of 5-FU.