Baseline soluble MICA levels act as a predictive biomarker for the efficacy of regorafenib treatment in colorectal cancer.

BACKGROUND: To evaluate the effect of regorafenib on soluble MHC class I polypeptide-related sequence A (MICA) (sMICA) level in vitro. In addition, we clinically examined whether its plasma levels were associated with regorafenib activity in terms of progression-free survival (PFS) in patients with CRC. METHODS: Human CRC cell line HCT116 and HT29 cells were treated with regorafenib and its pharmacologically active metabolites, M2 or M5 at the same concentrations as those in sera of patients. We also examined the sMICA levels and the area under the plasma concentration-time curve of regorafenib, M2 and M5. RESULTS: Regorafenib, M2, and M5 significantly suppressed shedding of MICA in human CRC cells without toxicity. This resulted in the reduced production of sMICA. In the clinical examination, patients with CRC who showed long median PFS (3.7 months) had significantly lower sMICA levels than those with shorter median PFS (1.2 months) (p = 0.045). CONCLUSIONS: MICA is an attractive agent for manipulating the immunological control of CRC and baseline sMICA levels could be a predictive biomarker for the efficacy of regorafenib treatment.

Final report on plasma ctDNA T790M monitoring during EGFR-TKI treatment in patients with EGFR mutant non-small cell lung cancer (JP-CLEAR trial).

Osimertinib is active against T790M-positive epidermal growth factor receptor mutant non-small cell lung cancer. We enrolled 122 sensitive epidermal growth factor receptor mutant non-small cell lung cancer patients who were planned to receive or were receiving first-/second-generation epidermal growth factor receptor tyrosine kinase inhibitors without disease progression and monitored plasma T790M every 1-2 months using the cobas® EGFR Mutation Test v2. We previously reported the concordance between T790M status in plasma and tissue. This is the final report on the sensitivity of plasma T790M and the efficacy of sequential osimertinib. The sensitivity was 21.1% (95% confidence interval: 6.1-45.6%). The best overall response was 25.0% (95% confidence interval: 9.8-46.7) in the plasma T790M-positive group and 28.6% (95% confidence interval: 8.4-58.1) in the plasma T790M-negative but tissue T790M-positive group. Median progression-free survival was 7.9 months (95% confidence interval: 4.7-17.5) for the former and 4.4 months (95% confidence interval: 3.0-N.E.) for the latter, with no statistically significant difference (P = 0.74).

Pharmacokinetics of gefitinib in elderly patients with EGFR-mutated advanced non-small cell lung cancer: a prospective study.

BACKGROUND: Gefitinib is recommended as a first-line treatment option for elderly patients with non-small cell lung cancer (NSCLC). Because no pharmacokinetics of gefitinib have been examined, we prospectively assessed the pharmacokinetics of gefitinib in patients with epidermal growth factor receptor gene-mutated advanced NSCLC who were 75 years or older. METHODS: Gefitinib was orally administered once daily at a dose of 250 mg. The concentrations of gefitinib and its major metabolite O-desmethyl gefitinib in plasma were measured by high-performance liquid chromatography. The area under the plasma concentration-time curve from time 0 to 48 h (AUC0-48) was calculated. Polymorphisms in CYP3A5, CYP2D6, ABCG2, ABCB1, and OATP1B1 were analyzed by direct sequencing. RESULTS: Eighteen patients with a median age of 80.5 years (range, 75-89) with adequate liver and kidney functions were examined. AUC0-48 values of gefitinib and O-desmethyl gefitinib in this population were 9.49 ± 3.5 and 10.6 ± 14 µM h, respectively. Compared to the gefitinib pharmacokinetics observed in a previous phase I study in Japan, systemic exposure to gefitinib in elderly patients was slightly higher than that in younger patients. Three patients experienced grade 3 diarrhea, increases in alanine aminotransferase, and aspartate aminotransferase levels 30 days after starting gefitinib treatment. The CYP2D6 genotype was associated with CYP2D6-mediated metabolism of gefitinib to O-desmethyl gefitinib. CONCLUSIONS: We demonstrated for the first time the systemic exposure to gefitinib in elderly patients with NSCLC. TRIAL REGISTRATION: The study was registered with the University Hospital Medical Information Network-Clinical Trials Registry Japan (UMIN000026409) on November 8, 2013.

Alteration in the Plasma Concentrations of Endogenous Organic Anion-Transporting Polypeptide 1B Biomarkers in Patients with Non-Small Cell Lung Cancer Treated with Paclitaxel.

Paclitaxel has been considered to cause OATP1B-mediated drug-drug interactions at therapeutic doses; however, its clinical relevance has not been demonstrated. This study aimed to elucidate in vivo inhibition potency of paclitaxel against OATP1B1 and OATP1B3 using endogenous OATP1B biomarkers. Paclitaxel is an inhibitor of OATP1B1 and OATP1B3, with Ki of 0.579 ± 0.107 and 5.29 ± 3.87 µM, respectively. Preincubation potentiated its inhibitory effect on both OATP1B1 and OATP1B3, with Ki of 0.154 ± 0.031 and 0.624 ± 0.183 µM, respectively. Ten patients with non-small cell lung cancer who received 200 mg/m2 of paclitaxel by a 3-hour infusion were recruited. Plasma concentrations of 10 endogenous OATP1B biomarkers-namely, coproporphyrin I, coproporphyrin III, glycochenodeoxycholate-3-sulfate, glycochenodeoxycholate-3-glucuronide, glycodeoxycholate-3-sulfate, glycodeoxycholate-3-glucuronide, lithocholate-3-sulfate, glycolithocholate-3-sulfate, taurolithocholate-3-sulfate, and chenodeoxycholate-24-glucuronide-were determined in the patients with non-small cell lung cancer on the day before paclitaxel administration and after the end of paclitaxel infusion for 7 hours. Paclitaxel increased the area under the plasma concentration-time curve (AUC) of the endogenous biomarkers 2- to 4-fold, although a few patients did not show any increment in the AUC ratios of lithocholate-3-sulfate, glycolithocholate-3-sulfate, and taurolithocholate-3-sulfate. Therapeutic doses of paclitaxel for the treatment of non-small cell lung cancer (200 mg/m2) will cause significant OATP1B1 inhibition during and at the end of the infusion. This is the first demonstration that endogenous OATP1B biomarkers could serve as surrogate biomarkers in patients. SIGNIFICANCE STATEMENT: Endogenous biomarkers can address practical and ethical issues in elucidating transporter-mediated drug-drug interaction (DDI) risks of anticancer drugs clinically. We could elucidate a significant increment of the plasma concentrations of endogenous OATP1B biomarkers after a 3-hour infusion (200 mg/m2) of paclitaxel, a time-dependent inhibitor of OATP1B, in patients with non-small cell lung cancer. The endogenous OATP1B biomarkers are useful to assess the possibility of OATP1B-mediated DDIs in patients and help in appropriately designing a dosing schedule to avoid the DDIs.

High-throughput method to analyze tegafur and 5-fluorouracil in human tears and plasma using hydrophilic interaction liquid chromatography/tandem mass spectrometry.

RATIONALE: We developed a new high-throughput method to analyze tegafur (FT) and 5-fluorouracil (5-FU) in tear and plasma samples using hydrophilic interaction liquid chromatography (HILIC)/tandem mass spectrometry (MS/MS). METHODS: The tear samples (10 µL) spiked with FT, 5-FU, and 5-chlorouracil (internal standard) were diluted using 40 µL of 2 M ammonium acetate and 250 µL of acetonitrile with 2% formic acid; 20 µL of plasma spiked with the two drugs and internal standard was diluted with 80 µL of 2 M ammonium acetate and 500 µL of acetonitrile with 2% formic acid. After centrifugation, the clear supernatant extract (15 µL) was directly injected into the HILIC/MS/MS instrument, and each drug was separated on a Unison UK-Amino column (50 mm × 3 mm i.d., 3 µm particle size) with a linear gradient elution system composed of 10 mM ammonium acetate (pH 6.8) and acetonitrile at a flow rate of 0.7 mL/min. We performed quantification by multiple reaction monitoring (MRM) with negative-ion atmospheric-pressure chemical ionization. RESULTS: Distinct peaks were observed for the drugs on each MRM channel within 2 min. The regression equations showed good linearity within the range 0.04-4.0 µg/mL for the tear and plasma samples with detection limits at 0.02-0.04 µg/mL. Recoveries for target analytes (FT and 5-FU) for the tear and plasma samples were in the 94-128% and 94-104% ranges, respectively. The intra- and inter-day coefficients of variation for the two drugs were lower than 10.8%. The accuracies of quantitation were 97-115% for both samples. CONCLUSIONS: We established a high-throughput, reproducible, and practical procedure for analyzing FT and 5-FU in human tear and plasma samples using HILIC/MS/MS analysis with an aminopropyl-bonded mixed-mode separation column. This method can be applied to the high-throughput routines used in clinical analyses.

Plasma ctDNA monitoring during epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor treatment in patients with EGFR-mutant non-small cell lung cancer (JP-CLEAR trial).

BACKGROUND: Osimertinib, a third generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), is active against EGFR-mutant non-small cell lung cancer (NSCLC) resistant to first-/second-generation EGFR-TKIs with the T790M mutation. T790M monitoring in plasma circulating tumor DNA (ctDNA) in patients receiving EGFR-TKIs is less invasive than re-biopsy and could provide valuable clinical information. METHODS: Patients with advanced or postoperative recurrent NSCLC with sensitizing EGFR mutations who were planned to receive or were receiving first-/second-generation EGFR-TKI treatment without disease progression were eligible for enrollment. Plasma samples at baseline and every 1-2 months thereafter were analyzed for EGFR mutation status using the cobas®EGFR Mutation Test v2. RESULTS: Between September 2016 and March 2017, 122 patients at 15 Japanese institutions were enrolled. In August 2018, 1291 plasma samples from 121 patients were analyzed for EGFR mutation status. At baseline, a sensitizing EGFR mutation was detected in 29 (23.9%) of 121 patients and T790M mutation was detected in three (2.5%). At follow-up, 66 (54.5%) patients experienced disease progression and 64 (52.9%) discontinued first-line EGFR-TKI treatment. Twenty-two (18.2%) patients showed T790M in plasma ctDNA, of which 15(68.2%) received osimertinib. Although 31 patients received re-biopsy to examine EGFR status at disease progression, T790M was detected in only nine (22.0%) patients, of which 7 (77.8%) received osimertinib. CONCLUSIONS: ctDNA monitoring during EGFR-TKI treatment is useful for detecting T790M mutation. The efficacy of osimertinib treatment based on T790M status in plasma ctDNA remains to be established, warranting further research.

Coadministration of cytotoxic chemotherapeutic agents with irinotecan is a risk factor for irinotecan-induced cholinergic syndrome in Japanese patients with cancer.

BACKGROUND: Cholinergic syndrome is an acute adverse event frequently observed in patients administered irinotecan, and can sometimes negatively affect their quality of life. In some manifestations of the syndrome such as bradycardia, careful monitoring of patients is advised. In this study, we retrospectively investigated the risk factors associated with irinotecan-induced cholinergic syndrome in Japanese patients with cancer. METHODS: Patients who received irinotecan-based chemotherapy between April 2014 and June 2018 were examined. Patient backgrounds and clinical data during the first cycle of an irinotecan-containing regimen, including cholinergic syndrome manifestation within 24 h after the start of treatment, were collected from medical records. Univariate and multivariate analyses were performed to assess the risk of irinotecan-induced cholinergic syndrome. RESULTS: Among 179 patients administered an irinotecan-containing regimen, 51 experienced cholinergic syndrome after the initiation of treatment. The most common symptom was sweating followed by diarrhea, abdominal pain, lacrimation, and nasal discharge. 42 patients developed symptoms of cholinergic syndrome during their first treatment with irinotecan. Multivariate analyses revealed that the incidences of cholinergic syndrome in patients administered 2 or 3 chemotherapeutic agents; i.e., irinotecan plus 1 or 2 other cytotoxic anticancer drug(s), were significantly higher than that in patients administered irinotecan alone [odds ratio (OR) 4.35, 95% confidence interval (CI) 1.5-12, p = 0.0053 and OR 4.50, 95% CI 1.5-14, p = 0.0093, respectively]. The addition of a molecularly targeted drug did not affect the incidence of cholinergic syndrome. CONCLUSION: The incidence rate of irinotecan-induced cholinergic syndrome increased concomitantly with the addition of cytotoxic chemotherapeutic agents administered.

Lack of correlation between the costs of anticancer drugs and clinical benefits in Japan.

Both overall survival (OS) and progression-free survival (PFS) are primary endpoints of phase III studies of new anticancer drugs. Medical care expenditures, especially oncology drug prices, are rapidly increasing; however, the impact of oncology drug prices on OS and PFS is unclear. We analyzed the relationship between oncology drug prices and clinical outcomes in Japan. The costs of a full course or 1 year of treatment were estimated on the basis of the latest National Health Insurance Drug Price Standards, and the relationship between costs and improvements in OS or PFS obtained with each drug were analyzed. Cost-effectiveness was compared between new-class drugs and next-in-class drugs. We then developed a simple model for estimating the costs required to prolong OS and PFS by 1 day and used this model to compare cost-effectiveness. Drug costs were not significantly related to treatment outcomes in terms of PFS or OS. There was no significant difference in the median cost between novel drugs and the next-in-class drugs (P = 0.39). The oncology drug cost required to prolong PFS by 1 day was more expensive than the drug cost required for prolong OS by 1 day. Prices of oncology drugs should be decided on the basis of actual clinical benefits for cancer patients, and the drug price evaluation process should be disclosed in Japan.

Organic Cation Transporter 1 Is Responsible for Hepatocellular Uptake of the Tyrosine Kinase Inhibitor Pazopanib.

Pazopanib is an orally active tyrosine kinase inhibitor that exhibits hepatotoxicity in some patients. Despite the clinical importance of its hepatic distribution, the transporter(s) responsible for hepatic uptake of pazopanib in humans remain undetermined. To characterize its hepatic uptake mechanism, we screened the effects of several transporter inhibitors, including tetrapentylammonium (TPeA) for organic cation transporters (OCTs) and cyclosporin A (CsA) for organic anion-transporting polypeptides (OATPs), on both plasma disappearance and hepatic distribution of pazopanib in mice after its i.v. administration. Among the inhibitors, TPeA largely reduced hepatic distribution and plasma clearance of pazopanib, whereas CsA showed only partial reduction. Pazopanib uptake by isolated mouse hepatocytes was similarly reduced by these inhibitors, suggesting that OCTs play a major role in the overall hepatic uptake of pazopanib in mice. In human embryonic kidney cell line HEK293 cells stably transfected with human OCT1, pazopanib uptake was significantly higher than that in vector-transfected cells. Moreover, pazopanib uptake by OCT1 became saturated and was inhibited by TPeA, but not by CsA, confirming that pazopanib is also a substrate of human OCT1. Importantly, OCT1-mediated uptake of a typical OCT1 substrate metformin was inhibited by pazopanib with an IC50 value of 0.253 µM, indicating that pazopanib has the potential for clinically relevant inhibition of human OCT1. Finally, pazopanib was taken up by cryopreserved human pooled hepatocytes in a time-dependent manner, and this uptake was largely reduced by TPeA but only partially reduced by CsA. Thus, the present findings suggest that OCT1 is responsible for hepatocellular uptake of pazopanib.

A phase I study of farletuzumab, a humanized anti-folate receptor α monoclonal antibody, in patients with solid tumors.

Farletuzumab is a humanized monoclonal antibody against folate receptor α (FRA). The purpose of the study is to assess safety and tolerability, the pharmacokinetic (PK) profile, and preliminary antitumor effect. Patients with ovarian cancer (OC) or FRA-expressing solid tumors who are resistant to standard treatments were eligible for the study. After single-dose administration for PK assessment, farletuzumab was administered by intravenous injection, repeating every week until disease progression. Dose-limiting toxicities (DLTs) were defined as grade 4 hematological and grade 3/4 nonhematological toxicities. Dose escalation was planned in 4 cohorts (50, 100, 200, and 400 mg/m(2)). Fourteen patients with OC and two patients with gastric cancer (GC) received farletuzumab infusion. Neither DLTs nor grade 3/4 toxicities were reported in all cohorts. Major adverse events, including grade 1/2 infusion related reaction (15 patients, 93.8%), headache (seven patients, 43.8%), and nausea and decreased appetite (five patients each, 31.3%), were observed and medically managed. AUC and Cmax increased dose-dependently and linear PK profiles were observed. No tumor shrinkage was recorded, but long-term disease stabilization for 25 and 20 months was observed in one patient with clear cell OC (100 mg/m(2)) and one patient with GC (400 mg/m(2)), respectively. No cumulative toxicity occurred in any patient. Farletuzumab was well tolerated in Japanese patients with a similar PK profile as compared with the US population. Long-term disease stabilization was observed in a subpopulation of clear cell OC and GC; both of them were resistant and progressive after standard chemotherapies (ClinicalTrials.gov Identifier: NCT01049061).

Association of VEGFA and CCL4L2 polymorphisms with hand-foot skin reaction and survival of regorafenib in Japanese patients with colorectal cancer.

PURPOSE: Treatment with regorafenib, which inhibits vascular endothelial growth factor (VEGF) receptor, frequently results in hand-foot skin reaction (HFSR), requiring treatment discontinuation or dose reduction. In our prospective study of regorafenib on patients with metastatic colorectal cancer, 17% of patients developed grade 3 HFSR. Herein, we retrospectively examined genetic polymorphisms associated with regorafenib-induced severe HFSR. METHODS: To identify associated polymorphisms, exploratory whole-exome sequencing focusing on factors related to VEGF-mediated signaling pathways was first performed in seven patients each, with grade 3 HFSR and without HFSR. The identified HFSR-associated polymorphisms were analyzed in all the 40 patients. RESULTS: The genotype frequency of rs3025009 G/A or A/A in the gene encoding VEGF-A (VEGFA) in patients with ≥ grade 2 HFSR was significantly higher than in other patients (P = 0.0257, Pc = 0.0771 [Bonferroni correction]). The frequency of C-C motif of chemokine ligand 4-like 2 (CCL4L2) rs3744596 A/T or T/T in patients with grade 3 HFSR was significantly lower than in others (P = 0.00894, Pc = 0.0268). The combination of the risk genotypes VEGFA rs3025009 G/A or A/A and CCL4L2 rs3744596 A/A was significantly associated with a higher incidence of grade 3 (P = 0.000614, Pc = 0.00246) and a longer median progression-free survival (P = 0.0234) than others. CONCLUSIONS: These VEGF-related polymorphisms were found to be associated with HFSR and the survival benefits of regorafenib treatment. TRIAL REGISTRATION NUMBER AND DATE: UMIN000013939, registered on May 12, 2014, when 6 months after the approval by the Institutional Review Board of Showa University.

Concomitant polypharmacy is associated with irinotecan-related adverse drug reactions in patients with cancer.

BACKGROUND: Patients with cancer often receive chemotherapeutic agents concurrently with other medications to treat comorbidity. The practical effects of concomitant medications, especially polypharmacy, on adverse drug reactions related to irinotecan-based chemotherapy are not well documented. METHODS: Associations of adverse drug reactions related to irinotecan monotherapy or a combination of irinotecan, 5-fluorouracil, and L-leucovorin (FOLFIRI) with concomitant medicines used to treat comorbidity were retrospectively investigated in Japanese patients with cancer. RESULTS: Of the 172 patients, 118 received concomitant medications. Twenty-one patients had grade 4 neutropenia and/or grade 3 or 4 diarrhea. Univariate and multivariate analyses revealed that concomitant medications were significantly associated with irinotecan-related severe neutropenia and/or diarrhea (P = 0.023 and 0.044). Multiple concomitant medications were significantly related to severe irinotecan-related toxicity in patients given monotherapy or FOLFIRI (P = 0.01). The incidence of severe irinotecan-related toxicities increased in parallel with the number of concomitant medications. CONCLUSION: We found that multiple concomitant medicines were significantly associated with severe irinotecan-related toxicity, indicating that polypharmacy must be effectively managed to decrease the risk of adverse drug reactions in patients with cancer who received irinotecan-based chemotherapy.

Associations of HLA-C*01:02 and HLA-B*46:01 with regorafenib-induced erythema multiforme in Japanese patients with metastatic colorectal cancer.

Regorafenib improves the survival of patients with metastatic colorectal cancer (mCRC); however, it is also characterized by detrimental dermal side effects that may require treatment cessation or modified dosing. In our previous prospective pharmacokinetic, pharmacodynamic, and pharmacogenetic studies, 17.5% (7/40) of the patients with mCRC had grade 3 erythema multiforme (EM) that caused treatment discontinuation. Haplotypes in genes encoding human leukocyte antigen (HLA) are associated with EM following the administration of drugs, such as allopurinol. This study examined the association between HLA haplotypes and regorafenib-induced EM. Regorafenib was administered orally at 160 mg/body once daily for weeks 1-3 of each 4-week cycle. To determine the HLA haplotypes, we used the WAKFlow HLA Typing Kit HLA-A, -B, or -C. The carrier frequency of HLA-C*01:02 in patients with EM (6/7) was higher than that in tolerant controls (8/33; odds ratio [OR] = 18.8, 95% confidence interval [CI] = 1.95-180, p = 0.00437). HLA-B*46:01 was also associated with EM (OR = 11.6, 95% CI = 1.47-92.1, p = 0.0299). These associations were no longer significant after Bonferroni correction for multiple testing. Therefore, regorafenib-induced EM in Japanese patients appears to be associated with specific HLA haplotypes but further validation is needed.

A polymorphism in ABCA2 is associated with neutropenia induced by capecitabine in Japanese patients with colorectal cancer.

PURPOSE: Capecitabine is a prodrug that converts to 5-fluorouracil (5-FU) in three steps. A previous study showed that ABCA2 rs2271862 (C > T) and ABCG5 rs6720173 were associated with increased clearance of 5-FU and 5'-deoxy-5-fluorouridine, respectively, in Spanish patients with colorectal cancer (CRC) (Br J Clin Pharmacol 2021) and reported that ABCA2 rs2271862 was associated with decreased risk of capecitabine-induced neutropenia. Other studies have reported that ABCB1 rs1128503, rs2032592, and rs1045642 were associated with capecitabine-induced toxicity in Spanish CRC patients (Oncotarget 2015, Phamacogenomics 2010). Here, we prospectively examined the effects of ABC transporter genes polymorphisms on capecitabine pharmacokinetics and toxicity. METHODS: We enrolled patients with postoperative CRC treated with adjuvant capecitabine plus oxaliplatin (CapeOX) and patients with metastatic CRC receiving CapeOX. Pharmacokinetic analysis of the first capecitabine dose (1000 mg/m2) was performed on day 1. We analyzed plasma concentrations of capecitabine and its three metabolites by high-performance liquid chromatography and ABC transporter genes polymorphisms using direct sequencing. RESULTS: Patients with ABCA2 rs2271862 T/T genotype had significantly lower area under the plasma concentration-time curve of capecitabine, but not of its metabolites, which were divided by the dose of the parent drug, than patients with C/C or C/T genotype (P = 0.0238). Frequency of ≥ grade 2 neutropenia was significantly lower in patients with ABCA2 rs2271862 T/T genotype (P = 0.00915). Polymorphisms in ABCG5 and ABCB1 were not associated with capecitabine pharmacokinetics and toxicity. CONCLUSIONS: We found that ABCA2 polymorphism was significantly associated with systemic exposure to capecitabine and capecitabine-induced neutropenia in Japanese patients with CRC.

A phase I study of infusional 5-fluorouracil, leucovorin, oxaliplatin and irinotecan in Japanese patients with advanced colorectal cancer who harbor UGT1A1*1/*1,*1/*6 or *1/*28.

OBJECTIVE: To evaluate the safety and efficacy of combination chemotherapy with 5-fluorouracil (5-FU), leucovorin, irinotecan and oxaliplatin (FOLFOXIRI) in Japanese patients with advanced colorectal cancer. METHODS: This phase I dose-finding study was designed to determine the maximum tolerated dose (MTD), recommended dose (RD) or both of FOLFOXIRI. Patients with UDP-glucuronosyltransferase (UGT) 1A1*6/*6, *28/*28 and *6/*28 genotypes were excluded, because these UGT1A1 genotypes are linked to severe neutropenia in Japanese. RESULTS: A total of 10 Japanese patients with advanced colorectal cancer were studied. The MTD of FOLFOXIRI in these Japanese patients was 165 mg/m(2) irinotecan, 85 mg/m(2) oxaliplatin and 2,400 mg/m(2) 5-FU. Accordingly, the RD of FOLFOXIRI was determined to be 150 mg/m(2) irinotecan, 85 mg/m(2) oxaliplatin and 2,400 mg/m(2) 5-FU. Toxic effects, evaluated until the completion of 4 cycles, were manageable. Grade 3-4 neutropenia occurred in 27% of cycles, but there was no febrile neutropenia. Among the 9 assessable patients, the objective response rate was 89%. CONCLUSIONS: We thus determined the RD of FOLFOXIRI in Japanese patients with advanced colorectal cancer who do not have UGT1A1*28/*28, *6/*6 or *6/*28 genotypes. Our results indicate that FOLFOXIRI is a well-tolerated regimen for these Japanese patients.

Relationship of circulating tumor cells to the effectiveness of cytotoxic chemotherapy in patients with metastatic non-small-cell lung cancer.

The aim of this study was to investigate the relationship of the number of circulating tumor cells (CTCs) with the effectiveness of cytotoxic chemotherapy in patients with metastatic non-small-cell lung cancer (NSCLC). We prospectively evaluated CTCs in the peripheral blood of patients with previously untreated metastatic NSCLC. From May 2008 through August 2010, 33 patients (23 men and 10 women; median age, 64 years; range, 46-74 years) were enrolled. All patients received combination chemotherapy with gemcitabine and carboplatin. The CTCs were captured from samples of peripheral blood with a semiautomated system using an antibody against epithelial cell adhesion molecule. Blood samples with one or more CTC per 7.5 ml were defined as positive. Of total 33 patients, 12 (36.4%) had positive CTCs and 5 (15.2%) had five or more CTCs before chemotherapy. There were no differences in response rates to cytotoxic chemotherapy between CTC-positive patients and CTC-negative patients. On the other hand, the rate of progressive disease in cytotoxic chemotherapy was significantly higher in CTC-positive patients (66.7%) than in CTC-negative patients (23.8%, p = 0.02). In conclusion, the number of CTCs could be a useful predictive factor for the effectiveness of cytotoxic chemotherapy in patients with metastatic NSCLC.

A case of bronchial asthma as an immune-related adverse event of pembrolizumab treatment for bladder cancer: A case report.

RATIONALE: Bladder cancer is one of the most common cancers worldwide. The anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab, which is an immune checkpoint inhibitor (ICI), has improved survival in bladder cancer. We report a case of bladder cancer that had a high antitumor effect with anti-programmed cell death PD-1 antibody pembrolizumab, an ICI, but asthma occurred an immune-related adverse event (irAE). PATIENT CONCERNS: A 70-year-old female patient was diagnosed as unresectable bladder cancer who was indicated for ICI treatment. DIAGNOSIS: After ICI administration as a treatment for bladder cancer, the patient had a grade 3 asthma attack. Cytotoxic T lymphocyte antigen 4 (CTLA-4) in CD4+ FOX3+ T cells was upregulated in the early phase before the development of asthma attacks. Moreover, T-cell immunoglobulin and mucin domain 3 (TIM-3) was upregulated in all memory T cells among CD4+ T cells. However, no change in the expression of TIM-3 was observed in any CD8+ T-cell subtype. In contrast, the proportion of CD161- T helper 17 cell (Th17) cells increased. INTERVENTIONS: The patient was treated with betamethasone, montelukast, salbutamol nebulization, and a combination of salmeterol (50 µg) and fluticasone (500 µg) (SFC). OUTCOMES: The patient's wheezing resolved, and her peak flow rate reached 100% of the predicted value; therefore, the patient continued treatment with SFC and montelukast and was discharged from the hospital. CONCLUSION: Increases in CTLA-4 and TIM-3 expression in CD4+ T cells (not CD8+), as well as an increase in Th17 cells, may reflect asthma-related inflammation activity. Immune-related adverse events during immune checkpoint inhibitor administration may be predictive markers of antitumor efficacy.

Prospective analysis of factors precluding the initiation of durvalumab from an interim analysis of a phase II trial of S-1 and cisplatin with concurrent thoracic radiotherapy followed by durvalumab for unresectable, locally advanced non-small cell lung cancer in Japan (SAMURAI study).

Background: The standard of care for unresectable, locally advanced non-small cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT) followed by durvalumab, based on the PACIFIC trial. Disease progression and pneumonitis were reported as the main reasons to preclude the initiation of durvalumab in multiple retrospective studies. However, the transition rate and the reasons for failure to proceed to consolidation therapy with durvalumab after CRT were not evaluated prospectively. Although phase II studies in Japan have shown high efficacy and tolerability of CRT with cisplatin + S-1 (SP), no prospective study using durvalumab after SP-based CRT has yet been reported. We therefore conducted a phase II study to verify the efficacy and safety of durvalumab following SP-based CRT. In this interim analysis, we report the transition rate and the reasons for its failure. Methods: In treatment-naïve LA-NSCLC, cisplatin (60 mg/m2, day 1) and S-1 (80-120 mg/body, days 1-14) were administered with two 4-week cycles with concurrent thoracic radiotherapy (60 Gy) followed by durvalumab every 2 weeks for up to 12 months. The primary endpoint was 12 month progression-free survival rate. Results: Fifty-nine patients were enrolled, of whom 86.4% (51/59) proceeded to durvalumab. All of them initiated durvalumab within 42 days after CRT [median 18 days (range: 3-38)], including 27.5% (14/51) in <14 days. Common reasons for failure to proceed to durvalumab were disease progression (2/59, 3.4%) and adverse events (6/59, 10.2%). Among the latter cases, four resumed treatment and proceeded to durvalumab within 42 days on off-protocol. The objective response rate and the disease control rate were 62.7% and 93.2%, respectively. The incidences of ⩾grade 3 pneumonitis, febrile neutropenia, and esophagitis were 0%, 8.5%, and 3.4%, respectively. Conclusion: Regarding durvalumab after CRT, this interim analysis of the SAMURAI study clarified the high transition rate, early introduction, and reasons for failure to proceed to consolidation therapy, which were not determined in the PACIFIC trial. Trial registration: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127.

A phase II study of S-1 and cisplatin with concurrent thoracic radiotherapy followed by durvalumab for unresectable, locally advanced non-small-cell lung cancer in Japan (SAMURAI study): primary analysis.

Background: The standard of care for unresectable, locally advanced non-small-cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT) followed by durvalumab, based on the PACIFIC study. Although multiple Japanese phase II studies have shown high efficacy and tolerability of CRT with cisplatin plus S-1 (SP), no prospective study using durvalumab after SP-based CRT has been reported. Objectives: We conducted a multicenter phase II study of this approach, the interim analysis of which showed a high transition rate to durvalumab consolidation therapy. Here, we report the primary analysis results. Design: In treatment-naïve LA-NSCLC, cisplatin (60 mg/m2, day 1) and S-1 (80-120 mg/body, days 1-14) were administered with two 4-week cycles with concurrent thoracic radiotherapy (60 Gy) followed by durvalumab (10 mg/kg) every 2 weeks for up to 1 year. Methods: The primary endpoint was 1-year progression-free survival (PFS). The expected 1-year PFS and its lower limit of the 80% confidence interval (CI) were set as 63% and 47%, respectively, based on the results of TORG1018 study. Results: In all, 59 patients were enrolled, with 51 (86.4%) proceeding to durvalumab. The objective response rate throughout the study was 72.9% (95% CI: 59.7-83.6%). After median follow-up of 21.9 months, neither median PFS nor OS was reached. The 1-year PFS was 72.5% (80% CI: 64.2-79.2%, 95% CI: 59.1-82.2%), while the 1-year overall survival was 91.5% (95% CI: 80.8-96.4%). No grade 5 adverse events were observed throughout the study. The most common adverse event during the consolidation phase was pneumonitis (any grade, 78.4%; grade ⩾3, 2.0%). Eventually, 52.5% of patients completed 1-year durvalumab consolidation therapy from CRT initiation. Conclusion: This study of durvalumab after SP-based CRT met its primary endpoint and found a 1-year PFS of 73% from CRT initiation. This study provides the first prospective data on the prognosis and tolerability of durvalumab consolidation from the initiation of CRT. Trial registration: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127.

Delayed elimination of SN-38 in cancer patients with severe renal failure.

This prospective study is designed to examine the effects of severe renal failure on the pharmacokinetics of irinotecan. The pharmacokinetics of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), and SN-38 glucuronide (SN-38G) in three cancer patients with severe renal failure [creatinine clearance (Ccr) ≤ 20 ml/min] who were undergoing dialysis and received 100 mg/m(2) irinotecan as monotherapy were prospectively compared with those in five cancer patients with normal renal function (Ccr ≥ 60 ml/min). To ensure that the subjects had similar genetic backgrounds of UDP-glucuronosyltransferase (UGT) 1A1, patients with UGT1A1*1/*1, *1/*6, or *1/*28 were enrolled. The estimated terminal elimination rate constant of SN-38 in patients undergoing dialysis was approximately one tenth of that in patients with normal renal function (P = 0.025). Approximately 50% of SN-38 was dialyzed with a 2.1-m(2) dialysis membrane, whereas 27% was dialyzed with a 1.5-m(2) membrane. Our results showed that the elimination of SN-38 was significantly delayed in patients with severe renal failure compared with patients with normal renal function. We demonstrated that SN-38 was partly dialyzed.