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Simple Summary: The treatment strategies and prognoses of patients with metastatic colorectal cancer differ according to the sidedness of the primary tumor. The aim of this study was to evaluate the sidedness-dependent prognostic impact of gene alterations in metastatic colorectal cancer. Among patients diagnosed with metastatic colorectal cancer enrolled from April 2017 to March 2019, 531 patients who underwent complete gene sequencing were assessed. TP53 gain-of-function and KRAS variants were poor prognostic factors, while the NOTCH3 sole variant was a favorable prognostic factor for left-sided metastatic colorectal cancer. The TP53 non-gain-of-function variant, BRAF V600E, and MYC amplification were poor prognostic factors for right-sided metastatic colon cancer. Prognostic gene alterations in metastatic colorectal cancer differed according to the sidedness of the primary tumor. The treatment strategies and prognoses of patients with metastatic colorectal cancer (CRC) differ according to the sidedness of the primary tumor. TP53 gain-of-function (GOF) and non-GOF variants have been reported to be differentially associated with prognosis by sidedness. We aimed to evaluate the sidedness-dependent prognostic impact of gene alterations in metastatic CRC. Patients enrolled between April 2017 and March 2019 were included in this study. Those excluded were individuals whose tumor tissues were obtained after chemotherapy and those who were enrolled in the study more than six months after starting first-line chemotherapy. Finally, we assessed 531 patients who underwent complete gene sequencing. The study revealed a significant difference in overall survival between individuals with left-sided CRC (n = 355) and right-sided colon cancer (CC) (n = 176) when considering the TP53 non-GOF variant, KRAS wild-type, NOTCH1 wild-type, NOTCH1 covariant, NOTCH3 sole variant, and MYC amplification. Multivariate analysis on each side revealed that the TP53 GOF and KRAS variants were independent poor prognostic factors for left-sided CRC (p = 0.03 and p < 0.01, respectively), and the TP53 non-GOF variant, BRAF V600E, and MYC amplification for right-sided CC (p < 0.05, p < 0.01, and p = 0.02, respectively). The NOTCH3 sole variant was an independent and favorable prognostic factor for left-sided CRC (p < 0.01). The prognostic significance of gene alterations differed between left-sided CRC and right-sided CC. [ABSTRACT FROM AUTHOR]

Purpose: Activated Notch receptor signaling has been implicated in tumor growth and progression in colorectal cancer (CRC). However, the pathogenic relevance of NOTCH gene alterations remains unclear. The aim of this study was to clarify mutational landscapes and assess their clinical significance in patients with metastatic CRC. Methods: Pre-chemotherapy tumor tissues obtained from 1154 metastatic CRC patients in the Nationwide Cancer Genome Screening Project in Japan between April 2017 and March 2019 were studied using the Oncomine Comprehensive Assay. Results: The frequencies of NOTCH1, NOTCH2, and NOTCH3 nonsynonymous sequence variants were 11.5%, 4.4%, and 10.4%, respectively. The majority of variants were missense of unknown significance that were distributed across all domains of all three NOTCH genes. The gain-of-function mutations in NOTCH reported in multiple malignancies were not identified. The NOTCH amplification rate was less than 1%. No NOTCH fusions were detected. In patients who were registered before, or within 1 year of, first-line chemotherapy, overall survival for 51 patients with only NOTCH3 variants was significantly longer than for 540 patients with no NOTCH variants (median, 40.2 months vs 27.7 months; P = 0.04). Multivariate analysis revealed that variant NOTCH3 was an independent prognostic factor for increased survival (hazard ratio 0.61, 95% confidence interval, 0.39–0.94; P = 0.03) besides poor prognostic factors associated with mutant TP53, KRAS, and BRAF, as well as amplified MYC. Conclusion: NOTCH genes are unlikely to harbor driver mutations and amplifications in patients with metastatic CRC. NOTCH3 variant should be further investigated as a favorable prognostic marker. [ABSTRACT FROM AUTHOR]

PURPOSE: ERBB2 copy number (CN), measured using next-generation sequencing, is a predictive biomarker for trastuzumab efficacy in human epidermal growth factor receptor 2 (HER2)–positive advanced esophagogastric and gastric cancer (AGC). We aimed to investigate the association of ERBB2 amplification and gene coalterations with response and resistance to trastuzumab-combined chemotherapy. METHODS: The SCRUM-Japan GI-SCREEN was a comprehensive genomic profiling project of GI cancer tissues using Oncomine Cancer Research Panel and Oncomine Comprehensive Assay. From 885 patients with AGC who successfully underwent gene profiling, 74 with ERBB2 amplification (CN ≥ 4.0) and who received first-line trastuzumab-combined chemotherapy were selected, and ERBB2 CN and gene coalterations were assessed. RESULTS: ERBB2 CN did not differ in tumor response to trastuzumab-combined chemotherapy (one-way analysis of variance test, P =.37). Multivariate analysis using the Cox proportional hazard model revealed that ERBB2 CN (continuous log2-converted CN, hazard ratio, 0.76; 95% CI, 0.62 to 0.93; P <.01) and receptor/oncogene amplifications in the HER2 signaling pathway (hazard ratio, 2.5; 95% CI, 1.2 to 5.3; P =.01) were significant predictors for progression-free survival (PFS). ERBB2 variants coexisted in five patients (7%) and were missense mutations. Two patients with low variant allele frequencies (VAFs; 8%, 12%) showed high ERBB2 CN (55, 80) and durable response (≥ 20 months), whereas three patients with high VAFs (66%–90%) showed low ERBB2 CN (8-11) and no response with short PFS (1-10 months). CONCLUSION: ERBB2 CN and gene coamplification in the HER2 signaling pathway were positive and negative predictors of PFS in trastuzumab-treated HER2-positive AGC patients, respectively. HER2-positive AGC patients with a high VAF of ERBB2 showed poor outcomes and may need HER2 tyrosine kinase inhibitors and trastuzumab deruxtecan. ERBB2 CN and gene coamplification on the HER2 pathway in gastric cancer are predictors for trastuzumab response. [ABSTRACT FROM AUTHOR]

Background: We investigated early tumor shrinkage (ETS) and depth of response (DpR) using data from the G-SOX study comparing S-1 plus oxaliplatin with S-1 plus cisplatin as the first-line treatment for advanced gastric cancer (AGC).Methods: ETS was determined as % decrease in the sum of the longest diameters of the target lesions at the first evaluation of week 6 compared to baseline. DpR was the maximum % shrinkage during the study treatment. The impact of ETS (cutoff value 20%) and DpR (continuous value) on progression-free survival (PFS) and overall survival (OS) were assessed by the log-rank test and Cox regression analysis including prognostic factors obtained in the G-SOX study; ECOG performance status, baseline sum of tumor diameters, disease status (recurrent/unresectable), and histology (diffuse/intestinal).Results: Among 685 patients enrolled in the G-SOX study, 632 patients who had the first tumor evaluation were analyzed. Patients with ETS ≥ 20% had longer PFS (median 4.5 vs. 2.8 months, p < 0.0001) and OS (median 14.8 vs. 10.5 months, p < 0.0001) than those with ETS < 20%. Adjusted hazard ratios of ETS < 20 vs. ≥ 20% were 0.606 (95% confidence interval (CI) 0.506-0.725) for PFS and 0.589 (95% CI 0.492-0.704) for OS. DpR was also significantly associated with PFS and OS (both p < 0.0001). These results were similar between the SOX and CS groups.Conclusions: In AGC patients receiving the first-line therapy, ETS and DpR might be predictors for PFS and OS. [ABSTRACT FROM AUTHOR]

Background: In patients with heavily treated metastatic colorectal cancer, TAS-102-a combination of trifluridine and tipiracil-has shown a significant overall survival benefit compared with placebo. In preclinical models, TAS-102 plus bevacizumab has shown enhanced activity against colorectal cancer xenografts compared with that for either drug alone. In this phase 1/2 study, we assessed the activity and safety of TAS-102 plus bevacizumab.Methods: We did this investigator-initiated, open-label, single-arm, multicentre, phase 1/2 trial of TAS-102 plus bevacizumab in four cancer centres in Japan. Eligible patients were aged 20 years or older; had histologically confirmed unresectable, metastatic colorectal adenocarcinoma; were refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (for tumours with wild-type KRAS); and had no previous treatment with regorafenib. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1. Using a dose de-escalation design in phase 1, the recommended phase 2 dose (RP2D) was determined for TAS-102 (35 mg/m2 given orally twice daily on days 1-5 and 8-12 in a 28-day cycle for level 1) plus bevacizumab (5 mg/kg, administered by intravenous infusion for 30 min every 2 weeks). In phase 2, patients received the RP2D. The primary endpoint was centrally assessed progression-free survival at 16 weeks, analysed in the first 21 patients to be enrolled and treated with the RP2D who had at least one imaging assessment. This study is completed and registered with the University Hospital Medical Information Network, number UMIN000012883.Findings: Between Feb 25, 2014, and July 23, 2014, we enrolled 25 patients with metastatic colorectal cancer: six patients in phase 1 and 19 patients in phase 2. The six patients who received TAS-102 at level 1 experienced no dose-limiting toxicities and this was deemed the RP2D. Nine of 21 patients who received the RP2D did not have a centrally assessed progression event; 16-week progression-free survival was 42·9% (80% CI 27·8-59·0). The most common grade 3 or worse adverse events as assessed in all 25 patients were neutropenia (18 [72%] patients), leucopenia (11 [44%]), anaemia (four [16%]), febrile neutropenia (four [16%]), and thrombocytopenia (three [12%]). Treatment-related serious adverse events were reported in three (12%) patients. No treatment-related deaths occurred.Interpretation: TAS-102 plus bevacizumab has promising activity with manageable safety, suggesting that this combination might become a potential treatment option for patients with metastatic colorectal cancer in a refractory setting.Funding: Taiho Pharmaceutical. [ABSTRACT FROM AUTHOR]

Background: This randomized phase II study compared weekly administration of paclitaxel (wPTX) with the best available 5-fluorouracil (5-FU) regimen as second-line treatment for advanced gastric cancer patients with severe peritoneal metastasis refractory to fluoropyrimidine. Methods: In the best available 5-FU arm, continuous infusion of 5-FU (800 mg/m/day, days 1-5, every 4 weeks) was given to patients with prior chemotherapy including bolus 5-FU, and methotrexate and 5-FU sequential bolus injection (methotrexate at 100 mg/m followed by bolus 5-FU at 600 mg/m with leucovorin, weekly) was given to those who had previously received continuous infusion of 5-FU or oral administration of fluoropyrimidine. In the wPTX arm, paclitaxel (80 mg/m) was administered on days 1, 8, and 15, every 4 weeks. This study adopted a screening design (one-sided α = 30 %) with the primary end point of overall survival. Results: One hundred patients were randomized to the 5-FU arm ( n = 49) or the wPTX arm ( n = 51). Although the median survival time was 7.7 months in both arms, the 2-year survival rates were 2.9 % in the 5-FU arm and 9.1 % in the wPTX arm [hazard ratio 0.89 (95 % confidence interval 0.57-1.38), one-sided p = 0.298}. The median progression-free survival was longer with wPTX than with 5-FU [3.7 months vs 2.4 months; hazard ratio 0.58 (95 % confidence interval 0.38-0.88), one-sided p = 0.005]. The incidences of grade 4 neutropenia, grade 3/4 febrile neutropenia, diarrhea, and treatment-related death were 6 %, 4 %, 10 %, and 2 %, respectively, in the 5-FU arm and 2 %, 0 %, 0 %, and 0 %, respectively, in the wPTX arm. Conclusions: As second-line chemotherapy, wPTX appears feasible and promising. This regimen can be included in a test arm in future phase III trials for treatment of advanced gastric cancer with severe peritoneal metastasis. [ABSTRACT FROM AUTHOR]

Purpose: Adding leucovorin to fluorouracil is known to improve response rate and overall survival in first-line chemotherapy for metastatic colorectal cancer (mCRC). The present multicenter phase II study evaluated the efficacy and safety of S-1, oxaliplatin, oral leucovorin, and bevacizumab combination therapy (SOLA). Methods: Patients with unresectable and untreated mCRC received S-1 (40-60 mg bid) plus leucovorin (25 mg bid) orally for 1 week, and oxaliplatin (85 mg/m) and bevacizumab (5 mg/kg) intravenously on day 1, every 2 weeks. Efficacy endpoints, including the response rate (the primary endpoint) and progression-free survival, were assessed by an independent review committee. Results: Of the 29 eligible patients, 25 patients (86 %) had a partial response [95 % confidence interval (CI) 68-96 %] and the remaining four patients showed stable disease with a trend toward tumor shrinkage. The median progression-free survival was 15 months (95 % CI 10-26 months). The median overall survival was not reached after a median follow-up time of 34 months. The 3-year survival rate was 54 %. Curative resections of metastatic lesions were performed in eight patients (28 %). Common grade 3 or 4 adverse events were neutropenia (20 %), hypertension (23 %), anorexia (20 %), fatigue (17 %), diarrhea (10 %), and peripheral sensory neuropathy (53 %). Conclusions: The SOLA therapy showed excellent efficacy and tolerable toxicities except for peripheral sensory neuropathy in patients with mCRC. Since oxaliplatin-induced neuropathy can be alleviated by modifying its administration, SOLA is a promising candidate regimen to be compared with FOLFOX plus bevacizumab in a future phase III trial. Clinical trial number: JapicCTI-090881. [ABSTRACT FROM AUTHOR]

Background: Oral uracil-tegafur and leucovorin (UFT/LV) therapy for elderly patients with metastatic colorectal cancer (mCRC) requires careful handling in Western countries because of a high incidence (≥20 %) of grade 3 diarrhea. However, its efficacy and safety for elderly Asian patients have not been investigated. Methods: In this multicenter cooperative phase II study, the eligibility criteria were: age of 75 years or older, no prior chemotherapy, and histologically confirmed colorectal cancer with one or more measurable lesions. UFT 300 mg/m/day and LV 75 mg/day were administered orally for 28 days followed by a 7-day rest period. Results: Twenty-one patients were enrolled in this study (prior to study termination after approval of bevacizumab), and all patients were eligible for efficacy and safety analysis. The median age was 79 years (range, 75-83 years). The majority of patients (95 %) had ECOG Performance Status 0 or 1. The overall response rate was 33 % (95 % confidence interval [CI], 18-53 %). The median progression-free and overall survivals were 5.3 months (95 % CI 4.0-7.9 months) and 18 months (95 % CI 13-21 months), respectively. Grade 3 or greater adverse events included anorexia (10 %), diarrhea (10 %), and leukopenia (5 %). These results were compatible with those seen in Japanese patients in a previous bridging study between Japan and the US, in which patients under 75 years old were evaluated. Conclusions: UFT/LV therapy was safe and feasible in elderly Japanese patients with mCRC, and further study of UFT/LV therapy in combination with bevacizumab is warranted. [ABSTRACT FROM AUTHOR]

Objective: Chemoradiotherapy (CRT) is a possible alternative to surgery for esophageal cancer. As complete response (CR) to CRT is essential for a good prognosis, potential biomarkers predictive of CR were explored. Methods: Endoscopic tumor biopsies were obtained from 41 patients with stage II–III esophageal squamous cell carcinoma before 5-fluorouracil/cisplatin-based definitive CRT. cDNA was derived from RNA isolated from microdissected tumor cells. mRNA expression levels of 10 genes involved in CRT or tumor biology were measured using quantitative real-time RT-PCR. Results: Expression levels of orotate phosphoribosyltransferase (OPRT) and dihydrofolate reductase mRNA were significantly higher in the CR group compared with the non-CR group (p = 0.0206 and 0.0191, respectively). Matrix metalloproteinase 9 mRNA expression was significantly lower in the CR group (p = 0.0436). CR rates were significantly higher in patients with node-negative disease and high expression levels of OPRT and dihydrofolate reductase genes (p = 0.0448, 0.0104 and 0.0104, respectively). No significant difference in CR rates was observed for other variables. Multivariate analysis revealed that high OPRT gene expression was an independent predictive factor of CR (p = 0.0192). It was also significantly associated with good prognosis (p = 0.0450). Conclusion: High OPRT gene expression may be a predictive factor of CR to 5-fluorouracil/cisplatin-based CRT in esophageal cancer. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The aim of this work was to determine whether intratumour contents of thymidine phosphorylase (TP), which converts 5′-deoxy-5-fluorouridine (5′-DFUR) to 5-fluorouracil, and dihydropyrimidine dehydrogenase (DPD), which degrades 5-fluorouracil to inactive molecules, could be useful in predicting the response of patients with metastatic gastric cancer to chemotherapy using 5′-DFUR. Endoscopic biopsy specimens for the measurement of TP and DPD were obtained from the primary lesions before the start of combination chemotherapy, in which 5′-DFUR, cisplatin and mitomycin C were administered. TP and DPD were measured by enzyme-linked immunosorbent assays after the objective responses to chemotherapy had been confirmed. Twenty five patients were enrolled in this study and data for 22 patients in whom responses were confirmed were analysed. The median levels (ranges) of TP and DPD were 80 (4.9–360) and 44 (15–82) U/mg protein, respectively. The median value (range) of TP to DPD ratios was 1.9 (0.25–5.1). Eight patients with a complete or partial response to chemotherapy had significantly higher TP to DPD ratios than did the remaining patients with stable or progressive disease (P=0.014). When a cut-off level of TP to DPD ratio was defined as the median value, the high-ratio group (n=11) showed a significantly higher response rate (64% vs. 9.1%, P=0.024) than the low-ratio group (n=11). Overall survival of the high-ratio group was significantly longer than that of the low-ratio group (the median survival time; 300 days vs. 183 days, P=0.047). The efficacy of 5′-DFUR could be optimised by preselecting patients with high TP/ DPD ratios in their tumour tissues, and this would be applicable to the treatment with capecitabine. [Copyright &y& Elsevier]

Background: Although nivolumab has a high efficacy, reliable biomarkers are needed to predict the efficacy. We evaluated the nivolumab efficacy according to the TP53 mutation in advanced gastric cancer patients enrolled in the GI-SCREEN project. Methods: Sequence data of tumour specimens and clinicopathological information of 913 patients with advanced gastric cancer who were enrolled between April 2015 and March 2017 were obtained from the GI-SCREEN database. The follow-up information of 266 patients treated with nivolumab was also provided. Results: Among 266 patients treated with nivolumab, the objective response rate (ORR) of TP53 wild type (wt) patients (24.6%) was higher than that of TP53 mutant patients (14.8%). Among TP53 mutant patients, the ORR of the frameshift type tended to be higher than the transition and transversion type (23.1%, 13.6%, and 13.0%, respectively). The median progression-free survival (PFS) was statistically longer in TP53 wt patients than in mutant patients (3.3 vs 2.1 months, HR 1.4, 95% CI 1.1–1.9). Among TP53 mutant patients, PFS was statistically longer in the frameshift type than in the transversion type. Conclusion: Nivolumab showed better efficacy in TP53 wt patients than in mutant patients. Among TP53 mutant patients, the frameshift type may have efficacy from nivolumab treatment. [ABSTRACT FROM AUTHOR]

Background: Several biomarkers have been established for metastatic colorectal cancer (mCRC). We investigated whether plasma angiogenesis factors could predict the efficacy of biologics combined with chemotherapy in first‐line (1L) treatment in patients with RAS wild‐type mCRC and the dynamics of plasma angiogenesis factors at progression during 1L treatment. Methods: In this multicenter prospective observational study, serial plasma samples were prospectively collected at pretreatment and progression stages; 17 plasma angiogenesis factors were analyzed using the multiplex assay with Luminex® technology. Interactions between the pretreatment measurements and treatment groups on progression‐free survival (PFS) and overall survival (OS) in patients with RAS wild‐type were assessed using the propensity‐score weighted Cox proportional hazards model. Results: From February 2018 to September 2020, 202 patients were enrolled in the 1L cohort; 133 patients had RAS wild‐type (chemotherapy plus bevacizumab [BEV group, n = 33] and plus anti‐epidermal growth factor receptor monoclonal antibodies [aEGFR group, n = 100]). A trend of strong interaction on PFS was observed for interleukin‐8 (IL‐8) (p = 0.0752) and soluble vascular cell adhesion molecule‐1 (sVCAM‐1) (p = 0.0156). Regarding OS, IL‐8 (p = 0.0283), soluble vascular endothelial growth factor‐receptor‐1 (sVEGFR‐1) (p = 0.0777) and sVCAM‐1 (p = 0.0011) tended to differentiate the treatment effect. In 112 patients, plasma samples were evaluable for dynamic analysis (57 and 55 from the BEV and aEGFR groups, respectively). In the BEV group, six factors significantly increased during progression, whereas two decreased. In the aEGFR group, three factors significantly increased, and six decreased. Conclusion: Pretreatment plasma IL‐8 and sVCAM‐1 levels could be predictive biomarkers to distinguish BEV and anti‐EGFR mAbs when combined with chemotherapy in the 1L treatment of RAS wild‐type mCRC. Several plasma angiogenesis factors showed significant change at progression in 1L chemotherapy plus biologics for RAS wild‐type mCRC, which are potential biomarkers for selecting an optimal angiogenesis inhibitor in second‐line treatment. [ABSTRACT FROM AUTHOR]

Background: To investigate the efficacy and safety of FOLFIRI plus bevacizumab regimen with irinotecan (180 mg/m(2)) in patients with advanced or recurrent colorectal cancer who were of the wild-type or heterozygous group for UGT1A1*28 and *6 polymorphisms and discontinued to oxaliplatin-based regimen, prospectively. Methods: The study population consisted of patients who had discontinued oxaliplatin-based regimen for any reason. The primary endpoint was the response rate. FOLFIRI and bevacizumab regimen [irinotecan: 180 mg/m(2), 5-fluorouracil infusion: 2400 mg/m(2), 5-fluorouracil bolus: 400 mg/m(2), levofolinate calcium: 200 mg/m(2), bevacizumab: 5 mg/kg] was repeated every 2 weeks for up to 24 cycles. Results: Ninety-four patients were enrolled; 93 patients were evaluated on safety, 94 patients on efficacy. The response rate was 10.1% (95% confidence interval (CI): 4.7-18.3%). The median time to treatment failure, progression-free survival, and overall survival were 4.1 months (95% CI: 2.8-4.8 months), 5.4 months (95% CI: 4.1-6.2 months), and 14.5 months (95% CI: 11.8-17.0 months), respectively. The treatment-related death was 1.1%, and the early death ≤30 days after the last study treatment was 1.1%. The incidence of grade 3 or higher adverse events was 60.2% for neutropenia, 23.7% for leukopenia, 9.7% for diarrhea, 6.5% for anorexia, and 5.4% for fatigue. All these adverse events and other adverse events were controllable. Conclusions: FOLFIRI plus bevacizumab regimen with an initial irinotecan dose of 180 mg/m(2) exhibited an adequate antitumor effect and was confirmed to be manageable and tolerable in Japanese patients with advanced or recurrent colorectal cancer, who had discontinued oxaliplatin-based regimen. Trial Registration: UMIN000001817 . [ABSTRACT FROM AUTHOR]

Background: We evaluated the safety, tolerability, pharmacokinetics, and tumor response of ramucirumab in combination with one of three platinum/fluoropyrimidine regimens in Japanese patients with chemotherapy-naïve metastatic gastric/gastroesophageal junction cancer. Methods: In this phase 1b study, patients received 8 mg/kg ramucirumab on days 1 and 8 every 3 weeks, following one of three regimens: capecitabine + cisplatin, XP; S-1 + cisplatin, SP; or S-1 + oxaliplatin, SOX. The primary objective was to assess safety and tolerability; the secondary objectives were to evaluate pharmacokinetics and tumor response. Results: Six patients were treated in each cohort. All regimens were generally well tolerated, although 1 patient in SOX was associated with grade 3 enterocolitis, which was considered a dose-limiting toxicity. Common grade 3 or higher adverse events included neutropenia (1 in XP, 3 in SP, and 2 in SOX), decreased appetite (1 in SP), and hypertension (2 in XP). The mean trough ramucirumab concentrations were consistent across all cohorts, and those of most patients exceeded target levels, which were estimated from previous studies of the approved ramucirumab dose (8 mg/kg every 2 weeks). Among the 11 patients with measurable disease, overall response rate and disease control rate were 45.5% and 100.0%, respectively. Median progression-free survival (95% CI) was 7.6 months (6.0 to not estimable). Conclusion: Ramucirumab 8 mg/kg on days 1 and 8 every 3 weeks in combination with XP, SP, or SOX was generally well tolerated and demonstrated preliminary anti-tumor activity in chemotherapy-naïve Japanese metastatic gastric/gastroesophageal junction cancer patients. [ABSTRACT FROM AUTHOR]

PURPOSE: Circulating tumor DNA (ctDNA) genotyping on the basis of next-generation sequencing (NGS) may guide targeted therapy for metastatic colorectal cancer (mCRC). However, the validity of NGS-based ctDNA genotyping for RAS/BRAF V600E mutation assessment and the efficacy of anti-EGFR and BRAF-targeted therapies on the basis of ctDNA results remains unclear. PATIENTS AND METHODS: The performance of NGS-based ctDNA genotyping for RAS/BRAF V600E mutation assessment was compared with that of a validated polymerase chain reaction–based tissue testing in patients with mCRC enrolled in the GOZILA study, a nationwide plasma genotyping study. The primary end points were concordance rate, sensitivity, and specificity. The efficacy of anti-EGFR and BRAF-targeted therapies on the basis of ctDNA were also evaluated. RESULTS: In 212 eligible patients, the concordance rate, sensitivity, and specificity were 92.9% (95% CI, 88.6 to 96.0), 88.7% (95% CI, 81.1 to 94.0), and 97.2% (95% CI, 92.0 to 99.4) for RAS and 96.2% (95% CI, 92.7 to 98.4), 88.0% (95% CI, 68.8 to 97.5), and 97.3% (95% CI, 93.9 to 99.1) for BRAF V600E, respectively. In patients with a ctDNA fraction of ≥1.0%, sensitivity rose to 97.5% (95% CI, 91.2 to 99.7) and 100% (95% CI, 80.5 to 100.0) for RAS and BRAF V600E mutations, respectively. In addition to a low ctDNA fraction, previous chemotherapy, lung and peritoneal metastases, and interval between dates of tissue and blood collection were associated with discordance. The progression-free survival of anti-EGFR therapy and BRAF-targeted treatment was 12.9 months (95% CI, 8.1 to 18.5) and 3.7 (95% CI, 1.3 to not evaluated) months, respectively, for matched patients with RAS/BRAF V600E results by ctDNA. CONCLUSION: ctDNA genotyping effectively detected RAS/BRAF mutations, especially with sufficient ctDNA shedding. Clinical outcomes support ctDNA genotyping for determining the use of anti-EGFR and BRAF-targeted therapies in patients with mCRC. Using a large-scale plasma genomic profiling program (SCRUM-Japan GOZILA), we validated ctDNA genotyping for RAS and BRAF V600E in metastatic colorectal cancer comparing with a validated tissue PCR-based testing. [ABSTRACT FROM AUTHOR]

Purpose: S-1 has shown a response rate of 35% in chemonaïve patients with metastatic colorectal cancer (mCRC). Leucovorin enhances the antitumor activity of 5-fluorouracil, and concurrent oral administration of S-1 and leucovorin may represent a more active treatment option for mCRC.Methods: S-1 (35 mg/m2) and leucovorin (25 mg/body) were orally administered twice daily to chemonaïve patients with mCRC. Predefined dose (schedule)-limiting toxicities (DLTs) during the first course and treatment continuity during the first two courses were evaluated during three periods of treatment with S-1 plus leucovorin (level 0, 2 weeks; level 1, 3 weeks; and level 2, 4 weeks), each followed by a 2-week rest. The pharmacokinetics (PK) of S-1 and leucovorin were studied on days 1 and 14 of the first course.Results: Fifteen patients were enrolled. All three patients had DLTs at level 2, and this level was considered the maximum tolerated schedule. Level 0 was designated as the recommended schedule based on the incidences of DLTs and treatment continuity. The main toxic effects were gastrointestinal, such as diarrhea and stomatitis. There was no grade 4 adverse event or treatment-related death. The overall response rate was 67% (95% confidence interval, 38-88%). The PK profiles of S-1 plus leucovorin were similar to those in previous studies.Conclusions: The recommended schedule was 2 weeks of S-1 plus leucovorin followed by a 2-week rest. The increased response and gastrointestinal toxicities of S-1 plus leucovorin as compared with S-1 monotherapy suggest that co-administration of leucovorin enhanced the activity of S-1. [ABSTRACT FROM AUTHOR]

Background: Oncogenic mutations in BRAF genes are found in approximately 5–10% of colorectal cancers. The majority of BRAF mutations are located within exons 11–15 of the catalytic kinase domains, with BRAF V600E accounting for more than 80% of the observed BRAF mutations. Sensitivity to BRAF- and mitogen-activated protein kinase (MEK) inhibitors varies depending on BRAF mutations and tumor cell types. Previously, we newly identified, BRAF L525R-mutation, in the activation segment of the kinase in colorectal cancer patient. Here, we characterized the function of the BRAF L525R mutation. Methods: HEK293 cells harboring a BRAF mutation (V600E or L525R) were first characterized and then treated with cetuximab, dabrafenib, and selumetinib. Cell viability was measured using WST-1 assay and the expression of proteins involved in the extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) signaling pathways was evaluated using western blot analysis. Results: The MEK inhibitor selumetinib effectively inhibited cell proliferation and ERK phosphorylation in BRAF L525R cells but not in BRAF V600E cells. Further studies revealed that AKT phosphorylation was reduced by selumetinib in BRAF L525R cells but not in BRAF V600E cells or selumetinib-resistant BRAF L525R cells. Moreover, the AKT inhibitor overcame the selumetinib resistance. Conclusions: We established a model system harboring BRAF L525R using HEK293 cells. BRAF L525R constitutively activated ERK. AKT phosphorylation caused sensitivity and resistance to selumetinib. Our results suggest that a comprehensive network analysis may provide insights to identify effective therapies. [ABSTRACT FROM AUTHOR]

PURPOSE: Low concordance between plasma-based and tissue-based tests for determining the RAS mutational status have been reported in some but not all patients with limited-extent metastatic colorectal cancer (mCRC). In this study, we investigated the relationship between metastatic site and circulating tumor DNA (ctDNA) detection using ctDNA genotyping, an alternative to tissue genotyping for precision oncology. MATERIALS AND METHODS: We investigated the relationship between metastatic site and ctDNA detection using Guardant360, a next-generation sequencing ctDNA assay, in mCRC patients with single-organ metastasis in the SCRUM-Japan GOZILA study (UMIN000029315). RESULTS: Of 1,187 patients with mCRC enrolled in GOZILA, 138 were eligible (49 with liver-only, 15 with lymph node-only, 27 with peritoneum-only, and 47 with lung-only metastases). The concordance of RAS / BRAF status between Guaradant360 and tissue in vitro diagnostic tests was 95.9% in patients with liver-only, 80.0% in lymph node-only, 56.0% in peritoneum-only, and 65.9% in lung-only metastases. ctDNA fraction, as measured by the median maximum variant allelic fraction (max VAF), and median number of detected variants were 23.1% and five in liver-only, 6.0% and five in lymph node-only, 0.4% and three in peritoneum-only, and 0.4% and three in lung-only metastases, respectively (all P <.001, Kruskal-Wallis test). Few patients with liver-only (2.0%) and lymph node-only metastasis (13.3%) had a max VAF < 0.2%, which is required to ensure a detection limit of 95%, but max VAF was more frequently < 0.2% in patients with lung-only (27.7%) or peritoneum-only metastasis (29.6%). CONCLUSION: Patients with lung-only and peritoneum-only metastatic disease have significantly lower levels of ctDNA, suggesting decreased clinical sensitivity for subclonal variants. This observation suggests that such patients may benefit from concurrent tissue and plasma testing to provide optimal genotyping for subsequent therapy selection. [ABSTRACT FROM AUTHOR]

Background: Although pre-emptive therapy with oral tetracycline, moisturizer, sunscreen, and topical corticosteroid is useful for preventing acneiform eruption (AfE) due to epidermal growth factor receptor (EGFR) inhibitors, no studies have examined the efficacy of topical corticosteroids themselves, or investigated the optimal potency of corticosteroid for treating facial AfE (FAfE).Patients and Methods: Screened patients with RAS wild-type colorectal cancer started pre-emptive therapy with oral minocycline and moisturizer on initiation of cetuximab or panitumumab therapy. Patients who developed grade 1 or 2 FAfE were randomly allocated to two groups: a ranking-down (RD) group that started with a very strong corticosteroid and serially ranked down every 2 weeks unless FAfE exacerbated; and a ranking-up (RU) group that started with a weak corticosteroid and serially ranked up at exacerbation. FAfE grade, patient quality of life, and adverse events (AEs) with topical corticosteroid were evaluated every 2 weeks. The primary endpoint was the total number of times grade 2 or higher FAfE was identified in the central review of the 8-week treatment period.Results: No significant differences in total numbers of grade 2 or higher FAfE or in AEs caused by topical corticosteroids were observed between groups during the 8 weeks. Incidence of grade 2 or higher FAfE tended to be lower in the RD group during the first 2 weeks.Conclusion: Considering the long-term care of FAfE, the RU regimen appears suitable and should be considered the standard treatment for FAfE due to EGFR inhibitor therapy.Trial Registration: UMIN Clinical Trials Registry (UMIN000024113). [ABSTRACT FROM AUTHOR]

Background: Paclitaxel plus ramucirumab (PTX + RAM) is the standard second-line chemotherapy for unresectable advanced or recurrent gastric cancer (AGC). Nanoparticle albumin-bound paclitaxel (nab-PTX) is an improved, more convenient form of PTX and is non-inferior to PTX. Although some retrospective and single-arm phase II studies regarding nab-PTX + RAM have been reported, comparative studies are lacking. Here, we compared the efficacy and toxicity of nab-PTX + RAM and PTX + RAM using propensity score matching. Methods: Clinical data of 265 patients treated for AGC with nab-PTX + RAM or PTX + RAM were retrospectively collected. Nab-PTX was administered at dosages of 100 mg/m2, replacing PTX in the standard PTX + RAM regimen. Progression-free survival (PFS), overall survival (OS), and toxicity were compared using 1:1 propensity score matching. Results: In total, 190 (72%) patients were matched. The median PFS was 5.3 [95% confidence interval (CI) 4.4–6.3] and 4.7 (95% CI 3.2–5.3) months in the nab-PTX + RAM and PTX + RAM groups, respectively [hazard ratio (HR) = 0.76, 95% CI 0.56–1.03, p = 0.07]. The median OS was 11.5 (95% CI 9.2–15.0) and 9.9 (95% CI 8.0–12.7) months, respectively (HR = 0.78, 95% CI 0.56–1.07, p = 0.12). Grade 3 and 4 neutropenia was observed more frequently in the nab-PTX + RAM group (72% vs. 56%, p = 0.03). No treatment-related deaths occurred. Conclusions: Nab-PTX + RAM exhibited more favorable trends in terms of PFS and OS but was more myelosuppressive than PTX + RAM. As neutropenia is commonly manageable toxicity, nab-PTX + RAM presents a treatment alternative for AGC. Further studies including randomized, controlled studies are warranted. [ABSTRACT FROM AUTHOR]

Purpose: Anti-tumor activity can often be enhanced with combination therapy in managing patients with metastatic cancer. However, dose sequence and schedule of delivery can alter the pharmacokinetics, toxicity, and anti-tumor response. Therefore, attention to drug-drug interactions which may be sequence or schedule-dependent are necessary. Docetaxel and topotecan are non-cross-resistance cytotoxic agents with activity in a variety of malignancies. The goal of this study was to determine the maximum tolerated dose of docetaxel and continuous infusion topotecan using two sequences of administration. Experimental design: Patients were randomized to schedule A or B and enrolled in four escalating-dose cohorts. On schedule A, docetaxel was administered over 1 h and followed by topotecan administered over 72 h. On schedule B, topotecan was given as a 72 h continuous infusion followed by a 1 h infusion of docetaxel. While the doses for the docetaxel and topotecan were the same for schedule A and schedule B, the toxicities, and thus the determination of maximum tolerated dose (MTD), were assessed independently. The plasma pharmacokinetic disposition of topotecan and docetaxel were evaluated during the first cycle of each sequence to assess drug interactions. Results: Thirty patients, 20 males and 10 females were evaluable for toxicity and response. Four patients were chemonaive. Mean number cycles given were 3. Grade 3/4 thrombocytopenia and neutropenia were comparable on both schedules, as was the dose-limiting toxicity (DLT) for both schedules. There were no apparent differences in absolute neutrophil count or platelet nadirs between schedules A and B for three of the four cohorts. The principal non-hematologic toxicity was nausea and vomiting. The time of overlap of topotecan lactone or total concentrations and docetaxel concentrations were greater on schedule A as compared with schedule B and was associated with reduced clearance of docetaxel on schedule A as compared to schedule B. However, the mean clearance for docetaxel (18∀16 L h-1 m-2 and 29∀28 L h-1 m-2 on schedules A and B, respectively, and topotecan 16∀10 L h-1 m-2 and 7∀6 L h-1 m-2 on schedules A and B, respectively) were not statistically different (P>0.05). Conclusions: The observed toxicity was not sequence-dependent, despite the observed change in kinetics. Docetaxel and topotecan can be administered with acceptable toxicity at the recommended phase-II dose of docetaxel 60 mg m-2 and topotecan 0.85 mg m-2 day-1×3 days. [ABSTRACT FROM AUTHOR]

PURPOSE: Circulating tumor DNA (ctDNA) genotyping may guide targeted therapy for patients with advanced GI cancers. However, no studies have validated ctDNA genotyping for microsatellite instability (MSI) assessment in comparison with a tissue-based standard. PATIENTS AND METHODS: The performance of plasma-based MSI assessment using Guardant360, a next-generation sequencing–based ctDNA assay, was compared with that of tissue-based MSI assessment using a validated polymerase chain reaction–based method in patients with advanced GI cancers enrolled in GOZILA study, a nationwide ctDNA profiling study. The primary end points were overall percent agreement, positive percent agreement (PPA), and negative percent agreement. The efficacy of immune checkpoint inhibitor therapy was also evaluated. RESULTS: In 658 patients with advanced GI cancers who underwent both plasma and tissue testing for MSI, the overall percent agreement, PPA, and negative percent agreement were 98.2% (95% CI, 96.8 to 99.1), 71.4% (95% CI, 47.8 to 88.7), and 99.1% (95% CI, 98.0 to 99.7), respectively. In patients whose plasma samples had a ctDNA fraction ≥ 1.0%, the PPA was 100.0% (15/15; 95% CI, 78.2 to 100.0). Three patients with MSI-high (MSI-H) tumors detected only by ctDNA genotyping achieved clinical benefits after receiving anti–programmed cell death 1 therapy with the progression-free survival ranging from 4.3 to 16.7 months. One patient with an aggressive cancer of an unknown primary site benefited from pembrolizumab after rapid detection of MSI-H by ctDNA genotyping. CONCLUSION: ctDNA genotyping was able to detect MSI with high concordance to validated tissue-based MSI testing, especially in patients with tumors that have sufficient ctDNA shedding. Furthermore, ctDNA genotyping enabled identification of patients with MSI-H tumors who benefited from immune checkpoint inhibitor treatment. [ABSTRACT FROM AUTHOR]

In the FUGA-BT trial (JCOG1113), gemcitabine plus S-1 (GS) showed non-inferiority to gemcitabine plus cisplatin (GC) in overall survival (OS) with good tolerance for patients with advanced biliary tract cancer (BTC). We performed a subgroup analysis focused on the elderly cohort of this trial. All 354 enrolled patients in JCOG1113 were classify into two groups; < 75 (non-elderly) and ≥ 75 years (elderly) group. We investigated the influence of age on the safety analysis, including the incidence of chemotherapeutic adverse events and the efficacy analysis, including OS. There were no remarkable differences in OS between the elderly (n = 60) and the non-elderly groups (n = 294). In the elderly group, median OS was 12.7 and 17.7 months for those who received GC (n = 20) and GS (n = 40), respectively. The prevalence of all-grade adverse events was similar between the elderly and the non-elderly groups. However, among the elderly group, Grade ≥ 3 hematological adverse events were more frequently observed in the GC arm than in the GS arm. The clinical outcomes of combination chemotherapy in elderly patients with advanced BTC were comparable to non-elderly patients. GS may be the more favorable treatment for elderly patients with advanced BTC. [ABSTRACT FROM AUTHOR]

A case of primary mucosa-associated lymphoid tissue lymphoma (MALToma) occurring in the transverse colon is reported. Endoscopic examination revealed a flat and oval-shaped submucosal tumor-like lesion, approximately 2 cm in diameter in the transverse colon. The tumor extracted by laparotomy showed proliferation of centrocyte-like cells positive for L26 immunostaining. The patient was diagnosed as having MALToma in the transverse colon. In this case, although the tumor invasion was limited to the submucosal layer, lymph node involvement was seen. Awareness of the clinical presentation and familiarization of colorectal MALToma are important. We emphasize that even if either antibiotic therapy or surgery is chosen for the therapy of colorectal MALToma, lymph node involvement should generally be taken into consideration, although the tumor invasion was limited to the submucosal layer. [ABSTRACT FROM AUTHOR]

Background: In the JCOG1108/WJOG7312G trial, a combination (FLTAX) of 5‐fluorouracil (FU) /leucovorin (FL) and paclitaxel (PTX) did not show superiority in overall survival (OS) to FL in untreated patients with severe peritoneal metastasis of gastric cancer (GC‐SPM), some of whom received second‐line chemotherapy with PTX after FL. This post hoc study aimed to investigate the clinical implications of using both FU and PTX either sequentially or in combination for patients with GC‐SPM. Methods: A total of 94 patients were enrolled and categorized into the following three subgroups: patients treated with (1) FL followed by PTX (FL/PTX, N = 25), (2) FL followed by best supportive care (BSC) (FL/BSC, N = 21), and (3) FLTAX (N = 48). OS was compared between the subgroups. By comparing baseline factors between the FL/PTX and FL/BSC subgroups, factors preventing the sequential use of PTX (SUP) were explored using logistic regression model. The efficacy of FL and FLTAX was compared according to the presence of risk factors preventing SUP. Results: The FL/PTX subgroup showed better and equivalent OS compared to the FL/BSC (median 7.8 vs. 2.0 months, p < 0.01) and FLTAX (median 7.8 vs. 8.0, p = 0.49) subgroups, respectively. Glasgow Prognostic Score 2 and initially unresectable disease were identified as risk factors preventing SUP. Absence of both risks predicted SUP with a sensitivity of 13% and a specificity of 100%, whereas absence of any risks predicted SUP with a sensitivity of 67% and a specificity of 62%. FLTAX showed better OS than FL in patients with one or two of these risks but worse OS in those with none. Conclusions: Although sequential use of FU and PTX showed equivalent survival to FLTAX in patients with GC‐SPM, FLTAX might be preferable given the difficulty in selecting patients likely to receive sequential use at the initiation of first‐line chemotherapy. [ABSTRACT FROM AUTHOR]

JCOG1113 is a randomized phase III trial in patients with advanced biliary tract cancers (BTCs) (UMIN000001685), and gemcitabine plus S-1 (GS) was not inferior to gemcitabine plus cisplatin (GC). However, poor renal function often results in high toxicity of S-1. Therefore, we examined whether GS can be recommended for patients with low creatinine clearance (CCr). Renal function was classified by CCr as calculated by the Cockcroft-Gault formula: high CCr (CCr ≥ 80 ml/min) and low CCr (80 > CCr ≥ 50 ml/min). Of 354 patients, 87 patients on GC and 91 on GS were included in the low CCr group, while there were 88 patients on GC and 88 patients on GS in the high CCr group. The HR of overall survival for GS compared with GC was 0.687 (95% CI 0.504–0.937) in the low CCr group. Although the total number of incidences of all Grade 3–4 non-haematological adverse reactions was higher (36.0% vs. 11.8%, p = 0.0002), the number of patients who discontinued treatment was not different (14.1% vs. 16.9%, p = 0.679) for GS compared with GC in the low CCr group. This study suggests that GS should be selected for the treatment of advanced BTC patients with reduced renal function. [ABSTRACT FROM AUTHOR]

Background: HER2 amplification has been identified in 2-3% of patients with colorectal cancer, although there are currently no approved HER2-targeted therapies for colorectal cancer. We aimed to study the antitumour activity and safety of trastuzumab deruxtecan (an antibody-drug conjugate of humanised anti-HER2 antibody with topoisomerase I inhibitor payloads) in patients with HER2-expressing metastatic colorectal cancer.Methods: DESTINY-CRC01 is an open-label, phase 2 study that recruited patients from 25 clinics and hospitals in Italy, Japan, Spain, the UK, and the USA. Eligible patients had centrally confirmed HER2-expressing metastatic colorectal cancer that had progressed on two or more previous regimens (HER2-targeted therapies other than trastuzumab deruxtecan permitted), were aged 18 years or older (≥20 years in Japan), had an Eastern Cooperative Oncology Group score of 0 or 1, and had RAS and BRAFV600E wild-type tumours. Patients were enrolled into one of three cohorts by HER2 expression level: cohort A (HER2-positive, immunohistochemistry [IHC] 3+ or IHC2+ and in-situ hybridisation [ISH]-positive), cohort B (IHC2+ and ISH-negative), or cohort C (IHC1+). Patients received 6·4 mg/kg trastuzumab deruxtecan intravenously every 3 weeks until disease progression, unacceptable adverse events, withdrawal of consent, or death. The primary endpoint was confirmed objective response rate in cohort A by independent central review which was assessed in the full analysis set and safety was assessed in the safety analysis set. Both the full analysis set and the safety analysis set included all patients who received one or more doses of trastuzumab deruxtecan. This ongoing trial is registered with ClinicalTrials.gov, number NCT03384940.Findings: Between Feb 23, 2018, and July 3, 2019, 78 patients were enrolled in the study (53 in cohort A, seven in cohort B, and 18 in cohort C), all of whom received at least one dose of study drug. For the 53 (68%) patients with HER2-positive tumours (cohort A), a confirmed objective response was reported in 24 (45·3%, 95% CI 31·6-59·6) patients after a median follow-up of 27·1 weeks (IQR 19·3-40·1). Grade 3 or worse treatment-emergent adverse events that occurred in at least 10% of all participants were decreased neutrophil count (17 [22%] of 78) and anaemia (11 [14%]). Five patients (6%) had adjudicated interstitial lung disease or pneumonitis (two grade 2; one grade 3; two grade 5, the only treatment-related deaths).Interpretation: Trastuzumab deruxtecan showed promising and durable activity in HER2-positive metastatic colorectal cancer refractory to standard treatment, with a safety profile consistent with that reported in previous trastuzumab deruxtecan trials. Interstitial lung disease and pneumonitis are important risks requiring careful monitoring and prompt intervention.Funding: Daiichi Sankyo. [ABSTRACT FROM AUTHOR]

Purpose: FOLFOXIRI plus bevacizumab is regarded as a first-line therapeutic option for selected patients with metastatic colorectal cancer (mCRC). Our aim was to assess the efficacy and safety of induction treatment with FOLFOXIRI plus bevacizumab in patients with untreated mCRC harboring UGT1A1 wild (*1/*1), or single-hetero (*1/*6 or *1/*28) genotypes. Methods: Twelve cycles of FOLFOXIRI plus bevacizumab were administered to patients with untreated mCRC. The primary endpoint was the overall response rate (ORR) assessed by central independent reviewers. Secondary endpoints included time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS), relative dose intensity (RDI), R0 resection rate, and safety. The exploratory objectives were early tumor shrinkage (ETS) and depth of response (DoR). Results: Of the 47 patients enrolled, 46 and 44 patients were eligible for the safety and efficacy analysis, respectively. The primary endpoint was met. The ORR was 63.6% (95% CI 47.8–77.6). At a median follow-up of 25.4 months, median TTF, PFS, and OS was 8.1, 15.5, and 34.4 months, respectively. The median RDI of 5-fluorouracil, irinotecan, oxaliplatin, and bevacizumab was 72, 69, 62, and 71%, respectively. R0 resection rate was 22.7%. Grade 3 or higher adverse events (≥ 10%) included neutropenia (65.2%), febrile neutropenia (26.1%), leukopenia (23.9%), anorexia (10.9%), nausea (10.9%), and diarrhoea (10.9%). No treatment-related deaths were observed. ETS and DoR were 70.5 and 45.4%, respectively. Conclusions: FOLFOXIRI plus bevacizumab induction treatment of Japanese patients was shown to be beneficial and manageable, although caution is required since the treatment causes febrile neutropenia. [ABSTRACT FROM AUTHOR]

Background and Objective: Gastric cancer has been associated with notable geographic heterogeneity in previous multi-regional studies. In particular, patients from Japan have better outcomes compared with patients from other regions. Here, we assess patient-focused outcomes for the subgroup of Japanese patients in the global RAINBOW study. Methods: Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (QLQ-C30) at baseline and 6-week intervals. Investigators assessed performance status before each 4-week cycle. Time-to-deterioration in each QLQ-C30 scale was defined as randomization to first worsening of ≥ 10 points (on a 100-point scale). Time-to-deterioration in performance status was defined as first worsening to ≥ 2. Hazard ratios were estimated using Cox proportional hazards models. Results: The Japan subgroup contained 140 patients (ramucirumab plus paclitaxel, n = 68; placebo plus paclitaxel, n = 72); baseline QoL data were available for all patients. At baseline, QLQ-C30 scores were similar between study arms. Of the 15 QLQ-C30 scales, nine had a hazard ratio < 1, indicating similar or numerically longer time-to-deterioration in QoL for ramucirumab plus paclitaxel; all 95% confidence intervals included 1. Best mean change from baseline numerically favored ramucirumab plus paclitaxel in most QoL scales. The hazard ratios for time-to-deterioration of performance status to ≥ 2 were 0.64 in the Japan subgroup and 0.88 in the non-Asian subgroup. The Japan subgroup had better QoL at baseline compared with the non-Asian subgroup. Conclusions: Treatment with ramucirumab plus paclitaxel maintained QoL and performance status over time compared with placebo plus paclitaxel in the Japan subgroup of the RAINBOW trial. These data suggest that the heterogeneity in gastric cancer between geographic regions includes multiple measures of QoL. Trial registration number: NCT01170663 (first submitted 21 July, 2010). [ABSTRACT FROM AUTHOR]

Cetuximab has been shown to be clinically active when given in combination with irinotecan in patients with irinotecan-refractory metastatic colorectal cancer (mCRC). However, it has remained unclear whether panitumumab is effective when combined with irinotecan. We compared efficacies of both regimens in this randomised phase II study. Patients with wild-type KRAS exon 2 mCRC previously treated with fluorouracil-, oxaliplatin- and irinotecan-based chemotherapies were randomised (1:1) to either panitumumab plus irinotecan (panitumumab arm) or cetuximab plus irinotecan (cetuximab arm). The primary end-point was progression-free survival (PFS). The planned sample size was 120, expecting a hazard ratio (HR) of 1.0 with non-inferiority margin of 1.3 (one-sided alpha error 0.2 and power 0.7). Major secondary end-points were overall survival (OS), response rate and safety. From December 2011 to September 2014, 121 patients were enrolled, and 61 and 59 patients were randomised to the panitumumab and cetuximab arms, respectively (1 patient excluded). Most patients (97%) had received prior chemotherapies containing bevacizumab. The median PFS was 5.42 months in the panitumumab arm and 4.27 months in the cetuximab arm (HR = 0.64, 95% confidence interval [CI] = 0.44–0.94, P < 0.001 for non-inferiority, P = 0.058 for superiority), and median OS was 14.85 and 11.53 months (HR = 0.66, 95% CI = 0.44–1.00, P = 0.050 for superiority), respectively. The incidence of grade 3 or 4 hypomagnesaemia was higher in the panitumumab arm than that in the cetuximab arm (17% vs. 7%). Panitumumab may be non-inferior to cetuximab in combination with irinotecan in survival of patients with irinotecan-refractory mCRC. • Panitumumab may be non-inferior to cetuximab, with irinotecan for metastatic colorectal cancer. • Favourable survival were shown in the panitumumab arm especially in subgroup after bevacizumab. • Hypomagnesemia was higher in the panitumumab arm. [ABSTRACT FROM AUTHOR]

Background: Oral fluoropyrimidine plus cisplatin is often not tolerated by patients with severe peritoneal metastases of gastric cancer. Combination of 5-fluorouracil (5-FU), l-leucovorin (l-LV), and paclitaxel (FLTAX) has promising activity for such patients. We conducted a phase II/III study comparing FLTAX with 5-FU/l-LV. Methods: Eligibility criteria included: unresectable or recurrent gastric adenocarcinoma; 20–75 years; performance status (PS) 0–2; peritoneal metastases + ; massive ascites and/or inadequate oral intake; no prior chemotherapy. Patients were randomly assigned to receive 5-FU/l-LV or FLTAX. The primary endpoint of phase III was overall survival: UMIN000010949. Results: We enrolled 101 patients. Early deaths occurred in patients with PS 2 having massive ascites and inadequate oral intake simultaneously; the protocol was amended to exclude such patients. Median survival times were 6.1 and 7.3 months for the 5-FU/l-LV and the FLTAX arms, respectively (HR 0.792; 80% CI 0.596–1.053; one-sided p = 0.1445). FLTAX arm had longer progression-free survival (PFS) [1.9 vs 5.4 months (HR 0.64; 95% CI, 0.43–0.96; p = 0.029)]. Grade 3/4 adverse events such as leucopenia and anorexia were more frequently observed in the 5-FU/l-LV arm. In the 5-FU/l-LV arm, two deaths were treatment-related. In the 5-FU/l-LV and FLTAX arms, 12 and 3 deaths occurred within 30 days after the last protocol treatment, respectively. Conclusions: Chemotherapy was indicated for patients with severe peritoneal metastases excluding patients with PS 2 having massive ascites and inadequate oral intake simultaneously. FLTAX did not confer a significant survival benefit but may be preferred because of longer PFS and acceptable toxicity. [ABSTRACT FROM AUTHOR]

The KEYNOTE-659 study evaluated the efficacy and safety of pembrolizumab in combination with chemotherapy as the first-line treatment in Japanese patients with advanced gastric/gastroesophageal junction (G/GEJ) cancer. In this paper, we report results from cohort 1 (S-1 plus oxaliplatin [SOX] with pembrolizumab). This was a non-randomised, multicentre, open-label phase IIb study in patients with advanced programmed death-ligand 1 (PD-L1)-positive, human epidermal growth factor receptor 2-negative G/GEJ tumours. The primary endpoint was the objective response rate (ORR) assessed by blinded independent central review (BICR). Secondary endpoints were duration of response (DOR), disease control rate (DCR), time to response (TTR), progression-free survival (PFS), overall survival (OS) and safety. Exploratory analyses were performed based on the PD-L1 combined positive score (CPS) status. Fifty-four patients were evaluated. The median follow-up was 10.1 months. ORR and DCR by BICR were 72.2% (95% confidence interval [CI] 58.4–83.5) and 96.3% (95% CI 87.3–99.5), respectively. Median DOR, TTR, PFS and OS were as follows: not reached, 1.5 months, 9.4 months and not reached. The ORR was 73.9% in patients with CPS ≥1 to <10 and 71.0% in those with CPS ≥10. Grade ≥3 treatment-related adverse events (TRAEs) were reported by 57.4% of patients. The most common grade ≥3 TRAEs were decreased platelet count (14.8%), decreased neutrophil count (13.0%), colitis (5.6%) and adrenal insufficiency (5.6%). SOX with pembrolizumab showed encouraging efficacy and a manageable safety profile for the first-line treatment of advanced G/GEJ cancer. NCT03382600/JapicCTI-183829. • This study was conducted for gastric/gastroesophageal junction (G/GEJ) cancer. • Efficacy and safety of S-1 + oxaliplatin (SOX) with pembrolizumab were assessed. • Overall response rate assessed by blinded independent central review was 72.2%. • No increase in treatment-related adverse events occurred with this combination. • First-line SOX with pembrolizumab warrants further evaluation for G/GEJ cancer. [ABSTRACT FROM AUTHOR]

Background: The phase III JACOB trial (NCT01774786) compared the efficacy and safety of pertuzumab and trastuzumab plus chemotherapy with placebo and trastuzumab plus chemotherapy in patients with previously untreated human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric or gastroesophageal junction cancer. We conducted a subgroup analysis in Japanese patients. Methods: Patients were randomized 1:1 to pertuzumab 840 mg or placebo, plus trastuzumab (loading dose, 8 mg/kg; maintenance dose, 6 mg/kg) and chemotherapy (cisplatin 80 mg/m2, and capecitabine 1000 mg/m2 twice daily for 28 doses or 5-fluorouracil 800 mg/m2 every 24 h for 120 h), every 3 weeks. Continuation of chemotherapy after 6 cycles was at the discretion of the patient and the treating physician. Results: A total of 40 Japanese patients were included in each arm. Median overall survival was 22.0 months (95% confidence interval [CI] 13.8–not evaluable) and 15.6 months (95% CI 9.7–19.2) in the pertuzumab and placebo arms, respectively (hazard ratio [HR] 0.64 [95% CI 0.37–1.10]). Median progression-free survival was 12.4 months (95% CI 6.1–14.1) in the pertuzumab arm and 6.3 months (95% CI 4.3–8.1) in the placebo arm (HR 0.50 [95% CI 0.30–0.82]). Grade ≥ 3 adverse events and serious adverse events were more frequent in the pertuzumab arm than the placebo arm. Conclusions: Results from this subgroup analysis of the JACOB trial suggest similar efficacy of pertuzumab in Japanese patients and patients in the overall population, encouraging continued investigation of new agents for gastric cancer in Japanese patients. [ABSTRACT FROM AUTHOR]

Aim: The phase II/III GATSBY study (NCT01641939) showed that trastuzumab emtansine did not have an efficacy benefit over taxane in patients with previously treated, human epidermal growth factor receptor 2 (HER2)‐positive advanced or metastatic gastric or gastroesophageal junction cancer. We evaluated patients from Japanese centers within GATSBY. Methods: In stage one, patients (randomized 2:2:1) received trastuzumab emtansine 3.6 mg/kg every 3 weeks, trastuzumab emtansine 2.4 mg/kg weekly, or physician's choice of taxane (docetaxel 75 mg/m² every 3 weeks or paclitaxel 80 mg/m² weekly). In stage two, patients (randomized 2:1) received trastuzumab emtansine 2.4 mg/kg weekly or taxane. Eligible patients had centrally assessed HER2‐positive disease and progression during or after first‐line therapy. Primary endpoint was overall survival. We present the 2.4 mg/kg weekly data. Results: Eighty‐two patients were randomized (intention‐to‐treat: 48 to trastuzumab emtansine 2.4 mg/kg weekly, 23 to taxane; September 2012‐August 2014) at 19 sites. Median overall survival was 11.8 months (95% confidence interval [CI], 9.3‐16.3) with trastuzumab emtansine 2.4 mg/kg weekly and 10.0 months (95% CI, 7.1‐18.2) with taxane (unstratified hazard ratio = 0.94, 95% CI, 0.52‐1.72). Trastuzumab emtansine 2.4 mg/kg weekly, versus taxane, was associated with fewer grade ≥3 adverse events (AEs; 52.1% vs 68.2%) and serious AEs (14.6% vs 18.2%). There were no fatal AEs. Conclusions: Efficacy in Japanese patients within GATSBY was consistent with the overall population; overall survival was not prolonged with trastuzumab emtansine 2.4 mg/kg weekly versus taxane. The safety profile of trastuzumab emtansine was similar to the overall population. [ABSTRACT FROM AUTHOR]

Background: Trastuzumab with cisplatin and fluoropyrimidines improves overall survival (OS) in patients with HER2-positive advanced gastric cancer (AGC). S-1 plus oxaliplatin (SOX) is one of the standard regimens for HER2-negative AGC in Japan. However, few studies have evaluated trastuzumab combined with SOX in patients with HER2-positive AGC. Methods: This was a multicenter, phase II study conducted at 10 institutions in Japan. Patients with HER2-positive AGC received S-1 twice a day on days 1–14 and oxaliplatin and trastuzumab on day 1 of a 21-day cycle. The primary endpoint was the confirmed overall response rate (ORR), and the secondary endpoints were OS, progression-free survival (PFS), and safety. The sample size was 75 to have 90% power with an alpha error of 0.1 (one-sided), expecting an ORR of 65% and threshold of 50%. Results: From June 2015 to January 2018, 75 patients were enrolled. The ORR was 70.7% [95% confidence interval (CI) 59.0–80.6]. The median OS and PFS were estimated as 18.1 months (95% CI 15.6–26.5) and 8.8 months (95% CI 7.4–12.2), respectively. The major grade 3 or 4 adverse events were sensory neuropathy (16.0%) and neutropenia (10.7%). Conclusions: Trastuzumab with SOX had promising activity with well-tolerated toxicities for patients with HER2-positive AGC. Clinical trial registration: UMIN000017602. [ABSTRACT FROM AUTHOR]

To enable the widespread application of genomic medicine, the extraction of genomic DNA from thin sections of archived formalin-fixed and paraffin-embedded (FFPE) tissue blocks for next-generation sequencing (NGS) is often necessary. However, there are currently no guidelines available on which specific regions of the microtome sections to use for macrodissection with respect to the histopathological factors observed under microscopic examination. The aim of this study was to clarify the relationship between histopathological factors and DNA quality, and to standardize the macrodissection method for more efficient implementation of NGS. FFPE tissue specimens of 218 patients from the Biomarker Research for Anti-EGFR Monoclonal Antibodies by Comprehensive Cancer Genomics study were used to investigate the relationship between 15 histopathological factors and the quantitative ratio of double-stranded DNA (dsDNA) to total nucleic acids, as well as the ∆ crossing point value of each tissue specimen. Multivariate logistic regression analysis revealed that specimen storage of ≥3 years was negatively associated with dsDNA quality (P=0.0007, OR: 4.30, 95% CI: 1.85-10.04). In contrast, the presence of a mucus pool was positively associated with dsDNA quality (P=0.0308, OR: 0.23, 95% CI: 0.06-0.87). Metastatic tumors and longer specimen storage periods were significantly associated with lower ∆Cp values (P=0.0007, OR: 4.43, 95% CI: 1.87-10.49; and P=0.0003, OR: 5.51, 95% CI: 2.18-13.95, respectively). Therefore, macrodissection should not be performed on specimens exhibiting histopathological factors associated with poor DNA quality. In particular, the use of tissue blocks with a storage period of <3 years allows the extraction of genomic DNA suitable for NGS. [ABSTRACT FROM AUTHOR]

Background: Alternate-day administration of S-1 is thought to reduce toxicities. This phase II study evaluated S-1 on alternate days combined with bevacizumab as first-line treatment for elderly patients with metastatic colorectal cancer. Patients and methods: Eligible patients had histologically proven colorectal adenocarcinoma, measurable metastatic lesions, age ≥ 75 years, Eastern Cooperative Oncology Group performance status ≤ 1, no previous chemotherapy, and refused oxaliplatin- or irinotecan-containing regimens. Patients received 40 mg, 50 mg, or 60 mg (body surface area ≤ 1.25 m2, > 1.25 to ≤ 1.50 m2, or > 1.50 m2, respectively) of S-1 twice orally on Sunday, Monday, Wednesday, and Friday every week. Bevacizumab (7.5 mg/kg) was administered every 3 weeks. The primary endpoint was progression-free survival. Results: Of 54 enrolled patients, 50 patients were evaluated for efficacy and 53 for safety. The median age was 79 years (range 75–88 years). The median progression-free survival was 8.1 months (95% confidence interval (CI) 6.7–9.5 months). The median overall survival was 23.1 months (95% CI 17.4–28.8 months). The response rate was 44% (95% CI 30.2–57.8%), and the disease control rate was 88% (95% CI 79.0–97.0%). Grade 3 or higher hematologic, non-hematologic, and bevacizumab-related adverse events occurred in 9%, 11%, and 25% of patients, respectively. The most common grade 3 and 4 treatment-related adverse events were hypertension (11%), nausea (6%), fatigue (6%), anemia (6%), and proteinuria (6%). Only 6 patients discontinued treatment due to adverse events. Conclusion: S-1 on alternate days combined with bevacizumab showed better tolerability and comparable survival compared with the results of similar studies. [ABSTRACT FROM AUTHOR]

Background: Avelumab is a human anti-PD-L1 IgG1 monoclonal antibody that has shown antitumor activity in several advanced cancers. We report results from JAVELIN Solid Tumor JPN, a phase 1 trial of avelumab in Japanese patients with advanced solid tumors with expansion in patients with advanced gastric cancer/gastroesophageal junction cancer. Methods: In the dose-escalation part, eligible patients had various previously treated metastatic or advanced solid tumors. In the dose-expansion part, patients had stage IV gastric cancer/gastroesophageal junction adenocarcinoma and disease progression after prior therapy that included a platinum and fluoropyrimidine agent. Patients received avelumab every 2 weeks intravenously at 3, 10, or 20 mg/kg during dose escalation and 10 mg/kg during dose expansion. Results: Among 17 patients who received avelumab in the dose-escalation part, no dose-limiting toxicities occurred, and the maximum tolerated dose was not reached. 40 patients were enrolled in the dose-expansion part, of whom 21 (52.5%) had received ≥ 3 prior lines of therapy for advanced disease. In these patients, the objective response rate was 10.0% (95% CI, 2.8–23.7%) and median overall survival was 9.1 months (95% CI, 7.2–11.2 months). Three of 40 patients (7.5%) had a grade 3 treatment-related adverse event (alanine aminotransferase increase, anemia, and hyponatremia), and no grade ≥ 4 treatment-related adverse events occurred. Five patients (12.5%) had an immune-related adverse event (all grade 1/2). Conclusions: Avelumab showed acceptable safety in Japanese patients with advanced solid tumors and clinical activity in patients with advanced gastric cancer/gastroesophageal junction cancer and disease progression after chemotherapy. [ABSTRACT FROM AUTHOR]

Background: OncoBEAMTM RAS CRC kit using BEAMing technology is a circulating tumour DNA (ctDNA) test for detecting plasma RAS mutational status in metastatic colorectal cancer (mCRC). We conducted a multicentre, prospective study to investigate the concordance of the RAS mutational status between plasma ctDNA and tumour tissue DNA.Methods: mCRC patients without prior anti-EGFR antibodies or regorafenib treatment were enroled. Plasma- and tissue-based RAS mutational status were determined by BEAMing, respectively.Results: A total of 280 patients from eight institutions were eligible. The overall agreement between plasma- and tissue-based analyses was 86.4%, with a positive percent agreement of 82.1% and negative percent agreement of 90.4%. From logistic regression analysis, lung metastasis alone indicated the most significant factor associated with discordance. The agreement between plasma- and tissue-based analyses was 64.5% in patients with lung metastasis alone (n = 31) indicating lower amount of ctDNA. Among the cases with lung metastasis alone, all plasma- and tissue-based analyses were perfectly concordant in cases with ≥20 mm of maximum lesion diameter or ≥10 lesions.Conclusion: The clinical validity of OncoBEAMTM RAS CRC kit was confirmed. Careful attention should be paid for mCRC patients with lung metastases alone having fewer metastases or smaller diameter lesions. [ABSTRACT FROM AUTHOR]

Background: Nivolumab, an anti-programmed death-1 agent, showed survival benefits in Asian patients, including Japanese, with gastric/gastro-esophageal junction (G/GEJ) cancer. We report the analysis of the Japanese subpopulation from ATTRACTION-2 that evaluated nivolumab versus placebo in unresectable advanced or recurrent G/GEJ cancer after ≥ 2 chemotherapy regimens.Methods: Data from the Japanese subpopulation in the randomized, double-blind, placebo-controlled, phase 3 trial were analyzed (data cutoff, February 25, 2017). Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and objective response rate (ORR).Results: Among the overall study population of 493 patients, 226 (nivolumab 152; placebo 74) were enrolled from 28 sites in Japan. In the Japanese subset, median OS was longer with nivolumab versus placebo (5.4 months, 95% CI 4.6-7.4 versus 3.6 months, 95% CI 2.8-5.0). The risk of death was lower in the nivolumab versus placebo group (hazard ratio 0.58, 95% CI 0.42-0.78; p = 0.0002). Incidences of serious adverse events were 23% (35/152) and 25% (18/72) in the nivolumab and placebo groups, respectively. In the Japanese ITT population, 22% of nivolumab-treated and 28% of placebo-treated patients received prior ramucirumab treatment. Overall, clinical activity of nivolumab was observed regardless of prior ramucirumab use. In the nivolumab group, ORR and PFS were numerically higher in patients with prior ramucirumab use than in those without.Conclusions: In the Japanese subpopulation, patients receiving nivolumab had longer OS, similar to the overall population, with a manageable safety profile. The interaction between nivolumab and ramucirumab will be clarified in ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Abstract Detection of RAS and BRAF mutations is essential to determine the optimal treatment strategy for metastatic colorectal cancer (CRC). We prospectively evaluated the MEBGEN RASKET-B KIT (RASKET-B), a novel multiplex kit, simultaneously detecting 48 types of RAS mutations and the BRAF V600E mutation using Luminex xMAP technology. The aim was to obtain market approval for RASKET-B as an in vitro diagnostic (IVD) option in Japan. Genomic DNA was extracted from 302 formalin-fixed paraffin-embedded tissues obtained from CRC patients. The primary endpoints were the concordance rate (CR) between the results from RASKET-B and the previously approved IVD kit (RASKET) for RAS mutations, and CR between the results from RASKET-B and direct sequencing (DS) for BRAF mutations. The secondary endpoints included the CR between RASKET-B and DS for RAS mutations and between RASKET-B and the pyrosequencing (PYRO) for the BRAF V600E mutation. Among the 302 samples, 142 RAS mutations (47%) and 18 BRAF V600E mutations (6.0%) were detected by RASKET-B. All mutations detected in the recruited patients were mutually exclusive. Both RAS and BRAF mutation rates were statistically higher in right-sided than left-sided CRC. The CR between RASKET-B and RASKET for RAS gene and RASKET-B and DS for BRAF V600E mutation was 100% for both (95% CI: 99%-100%). The results from RASKET-B were also highly concordant with DS for RAS (97.4%) and with PYRO for the BRAF (V600E) gene (99.7%). RASKET-B thus provides rapid, precise, and simultaneous detection of RAS and BRAF mutations in CRC. [ABSTRACT FROM AUTHOR]

Background: Ramucirumab, a monoclonal antibody vascular endothelial growth factor receptor-2 antagonist, given as monotherapy improved survival in a global phase 3 study (REGARD) of patients with gastric cancer. However, REGARD did not include Japanese patients. This study evaluated the efficacy and safety of ramucirumab monotherapy in Japanese patients with advanced gastric cancer.Methods: This multicenter, open-label, nonrandomized phase 2 study (Clinicaltrials.gov: NCT01983878) was performed at 16 Japanese sites. Patients with advanced gastric or gastroesophageal junction cancer after disease progression following first-line chemotherapy received intravenous ramucirumab 8 mg/kg every 2 weeks. Primary efficacy outcome: 12-week progression-free survival rate (PFS).Results: Thirty-six patients were enrolled. The 12-week PFS rate was 23.8% [90% confidence interval (CI) 12.4-37.2); the primary outcome was not met as the lower limit of the CI was outside the threshold of 16%. Median PFS was 6.6 weeks (90% CI 6.1-7.1). No patients achieved an objective response, and 11 (31%) patients achieved disease control. Median overall survival was 8.6 months (90% CI 5.7-10.7). The most frequent treatment-emergent adverse events (TEAEs) were diarrhea (9/36; 25%) and decreased appetite (8/36; 22%). Three patients reported Grade ≥ 3 ileus; all other Grade ≥ 3 TEAEs were reported by ≤ 2 patients. The most frequent adverse events of special interest (AESIs) were hypertension (10/36; 28%), bleeding/hemorrhage (7/36; 19%), and proteinuria (7/36; 19%). All Grade ≥ 3 AESIs were reported by ≤ 2 patients.Conclusions: These findings suggest that ramucirumab monotherapy has clinical activity and a manageable safety profile in Japanese patients with gastric cancer after disease progression following first-line chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract: Background: The principal antigen responsible for cetuximab‐induced anaphylaxis is galactose‐α‐1,3‐galactose (α‐gal), expressed on the Fab portion of the monoclonal antibody. Recent studies have shown that cetuximab allergy is associated with a history of tick bite. We explored factors predicting cetuximab‐induced anaphylaxis, focusing on the relationship thereof to a history of tick bite. Methods: Fifty‐two patients prescribed cetuximab at Ehime University Hospital or Shikoku Cancer Center were included in this study. We measured specific immunoglobulin E (IgE) levels targeting red meats, animal danders, and α‐gal using immunoCAP. Anti‐Rickettsia japonica antibody levels were assayed using an indirect immunoperoxidase test. Anticetuximab antibody was quantified by Western blotting and enzyme‐linked immunosorbent assay of serum samples. Results: Of the 52 patients, five exhibited anaphylactic reactions to cetuximab that were not associated with specific IgEs against beef, pork, or animal dander. IgE against α‐gal was detected at class 1 in the sera of two of the five patients. Anticetuximab IgE was detected in four of 52 patients, only one of whom had anaphylaxis to cetuximab. Only two of the 52 patients had a history of a tick bite, one of whom had cetuximab‐induced anaphylaxis. The patient without anaphylaxis was positive for anti‐ R. japonica antibody. Conclusions: The α‐gal‐specific IgE‐positivity can be used to identify those at risk of cetuximab‐induced anaphylaxis. The cutoff level should be set up the detection limit to predict cetuximab‐induced anaphylaxis, because the antibody levels are very low in our study. [ABSTRACT FROM AUTHOR]

Background: AVAGAST was an international, randomized, placebo-controlled phase III study of chemotherapy with or without bevacizumab as first-line therapy for patients with advanced gastric cancer. We performed exploratory analyses to evaluate regional differences observed in the trial.Methods: Analyses were performed in the placebo plus chemotherapy arm (intention-to-treat population). Chemotherapy was cisplatin 80 mg/m2 for six cycles plus capecitabine (1000 mg/m2 orally bid days 1-14) or 5-fluorouracil (800 mg/m2/day continuous IV infusion days 1-5) every 3 weeks until disease progression or unacceptable toxicity.Results: Overall, 387 patients were assigned to placebo plus chemotherapy (eastern Europe/South America, n = 118; USA/western Europe, n = 81; Korea/other Asia, n = 94; Japan, n = 94). At baseline, poor performance status, liver metastases, and larger tumors were most frequent in eastern Europe/South America and least frequent in Japan. Patients received subsequent chemotherapy after disease progression as follows: eastern Europe/South America (14%); USA/western Europe (37%); Korea/other Asia (61%); and Japan (77%). Hazard ratios for overall survival versus USA/western Europe were 1.47 (95% CI, 1.09-1.99) for eastern Europe/South America, 0.91 (95% CI, 0.67-1.25) for Korea/other Asia, and 0.87 (95% CI, 0.64-1.19) for Japan.Conclusions: Regional differences in the healthcare environment may have contributed to the differences in overall survival observed in the AVAGAST study. [ABSTRACT FROM AUTHOR]

Background Nanoparticle albumin-bound (nab)-paclitaxel was developed to improve paclitaxel solubility and does not need premedication to avoid infusion-related reactions associated with solvent-based (sb)-paclitaxel. We conducted a phase II trial to investigate the efficacy and safety of nab-paclitaxel plus ramucirumab combination therapy for previously treated advanced gastric cancer. Patients and methods Patients with unresectable advanced gastric cancer refractory to first-line chemotherapy were administered nab-paclitaxel 100 mg/m 2 intravenously on days 1, 8 and 15, plus ramucirumab 8 mg/kg intravenously on days 1 and 15 of a 28-day cycle. The primary end-point was Independent Review Committee (IRC)–assessed overall response rate (ORR). Secondary end-points were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), safety and quality of life (QOL). Results Forty-five patients were enrolled; 43 received the study treatment. The ORR assessed by the IRC was 54.8% (90% confidence interval [CI] 41.0–68.0) and the primary end-point was met. The DCR was 92.9% (95% CI 80.5–98.5). The IRC-assessed median PFS was 7.6 months (95% CI 5.4–8.1). The median OS was not reached at the data cutoff. The main treatment-related grade 3 or 4 adverse events were decreased neutrophil count (76.7%), decreased white blood cell count (27.9%), anaemia (11.6%), decreased appetite (7.0%), febrile neutropenia (4.7%), hypertension (4.7%) and proteinuria (4.7%). No treatment-related deaths occurred. No QOL deterioration was observed during study treatment. Conclusion Nab-paclitaxel plus ramucirumab combination therapy shows promising activity and manageable toxicities and could be a useful second-line treatment option for patients with previously treated advanced gastric cancer. [ABSTRACT FROM AUTHOR]

Background: Patients with BRAFV600E-mutated metastatic colorectal cancer (mCRC) have a poorer prognosis as well as resistance to anti-EGFR antibodies. However, it is unclear whether BRAF mutations other than BRAFV600E (BRAFnon-V600E mutations) contribute to anti-EGFR antibody resistance.Methods: This study was composed of exploratory and inference cohorts. Candidate biomarkers identified by whole exome sequencing from super-responders and nonresponders in the exploratory cohort were validated by targeted resequencing for patients who received anti-EGFR antibody in the inference cohort.Results: In the exploratory cohort, 31 candidate biomarkers, including KRAS/NRAS/BRAF mutations, were identified. Targeted resequencing of 150 patients in the inference cohort revealed 40 patients with RAS (26.7%), 9 patients with BRAFV600E (6.0%), and 7 patients with BRAFnon-V600E mutations (4.7%), respectively. The response rates in RAS, BRAFV600E, and BRAFnon-V600E were lower than those in RAS/BRAF wild-type (2.5%, 0%, and 0% vs 31.9%). The median PFS in BRAFnon-V600E mutations was 2.4 months, similar to that in RAS or BRAFV600E mutations (2.1 and 1.6 months) but significantly worse than that in wild-type RAS/BRAF (5.9 months).Conclusions: Although BRAFnon-V600E mutations identified were a rare and unestablished molecular subtype, certain BRAFnon-V600E mutations might contribute to a lesser benefit of anti-EGFR monoclonal antibody treatment. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant chemoradiotherapy following surgery has recently become a standard therapy. The purpose of the present study was to determine the effectiveness and toxicity of re-irradiation for oligo-recurrence in lymph nodes from esophageal cancer treated by definitive radiotherapy or by surgery with additional radiotherapy.Methods: We reviewed retrospectively 248 patients treated with (chemo)radiotherapy for oligo-recurrence in lymph nodes from esophageal cancer in five Japanese high-volume centers between 2000 and 2015. Thirty-three patients in whom re-irradiation was performed were enrolled in this study, and the results for patients in whom re-irradiation was performed were compared with the results for other patients.Results: Median maximum lymph node diameter was 22 mm. Median total radiation dose was 60 Gy. The median calculated biological effective dose using the LQ model with α/β = 10 Gy (BED10) in patients in whom re-irradiation was performed was significantly lower than the median BED10 in others. There was no different factor except for BED10, histology and irradiation field between patients with a past irradiation history and patients without a past irradiation history. The median observation period in surviving patients in whom re-irradiation was performed was 21.7 months. The 3-year overall survival rate in the 33 patients with a past irradiation history was 17.9%, with a median survival period of 16.0 months. Overall survival rate and local control rate in patients with a past irradiation history were significantly worse than those in patients without a past irradiation history (log-rank test, p = 0.016 and p = 0.0007, respectively). One patient in whom re-irradiation was performed died from treatment-related gastric hemorrhage.Conclusions: Results in the present study suggested that re-irradiation for oligo-recurrence in lymph nodes from esophageal cancer treated by definitive radiotherapy or by surgery with additional radiotherapy might be acceptable but unsatisfactory. [ABSTRACT FROM AUTHOR]

Background: The association between progression type and survival has been reported in breast cancer, but remains unclear in advanced gastric cancer (AGC). Here, this association was assessed using data obtained from an earlier randomized phase III study demonstrating the non-inferiority of S-1 plus oxaliplatin (SOX) to S-1 plus cisplatin (CS) on progression-free survival and overall survival (OS) in the first-line treatment of AGC. Methods: A Cox regression model including two time-dependent covariates, progression with new lesions and with no new lesions, was used to determine their effect on OS in each treatment group. When both types of progression were detected simultaneously, this was categorized as progression with new lesions. Results: Progression with and with no new lesions was identified in 91 and 167 patients, respectively, in the SOX group (333 patients) and 95 and 147 patients, respectively, in the CS group (330 patients). The association between progression type and OS was similar in both treatment groups; both progression types were strong poor prognostic factors, particularly progression with new lesions [hazard ratio (HR), 7.26; 95% confidence interval (CI), 4.89-10.80 in SOX and HR, 5.78; 95% CI, 4.13-8.08 in CS] compared to no new lesions (HR, 4.66; 95% CI, 3.21-6.77 in SOX and HR, 2.71; 95% CI, 1.95-3.75 in CS). Conclusions: Progression accompanied by new lesions had a strong negative impact on OS in patients treated with S-1 and platinum for AGC. [ABSTRACT FROM AUTHOR]

Background: This study evaluated the treatment results of lymph node (LN) oligo-recurrence in esophageal cancer patients treated with salvage radiotherapy (RT) in a multi-institutional retrospective study.Methods: Eligibility criteria for this retrospective analysis were: the primary lesion of esophageal cancer was controlled; from one to five LN recurrences; total RT dose ≥45 Gy to exclude palliative RT; without recurrence other than LN; and salvage RT for LN recurrence was given between January 2000 and April 2015. The median follow-up time for the 93 living patients was 29.6 months.Results: Two hundred thirty-seven patients were matched in five hospitals. The 3-year overall survival (OS) was 37%, local control was 45%, progression-free survival was 24%, and esophageal cancer-specific survival was 42%. On univariate analysis for OS, combined chemotherapy (p = 0.000055), disease-free interval (DFI) ≥12 months (p = 0.0013), LN max diameter ≤22 mm (p = 0.0052), and Karnofsky performance status ≥80% (p = 0.030) were associated with a significantly better prognosis. On multivariate analysis, significant differences were seen for combined chemotherapy (p = 0.000018), DFI (p = 0.0027), and LN max diameter (p = 0.018).Conclusions: LN oligo-recurrence following treatment for esophageal cancer was not a terminal-stage event. Moreover, cure may be possible by chemoradiation therapy with a long DFI (≥12 months) and small size (≤22 mm). [ABSTRACT FROM AUTHOR]

Background: The Randomized Phase III Study Comparing Oxaliplatin plus S-1 with Cisplatin plus S-1 in Chemotherapy-naïve Patients with Advanced Gastric Cancer (G-SOX) showed the noninferiority of S-1 (an oral fluoropyrimidine-derivative dihydropyrimidine dehydrogenase inhibitor) plus oxaliplatin combination therapy (SOX) to S-1 plus cisplatin therapy (CS) in overall survival [hazard ratio (HR) from proportional hazard model 0.958, 95 % confidence interval (CI) 0.803-1.142; noninferiority margin 1.15]. To further clarify the clinical position of SOX in advanced gastric cancer (AGC), a meta-analysis including information from other reported studies was conducted. Methods: In addition to G-SOX, Japanese phase III clinical trials including S-1 monotherapy were included in the analyses. Individual patient data for SOX (318 patients) and CS (324 patients) from G-SOX, as well as those for S-1 (160 patients) from the Randomized Phase III Study Comparing the Efficacy and Safety of Irinotecan plus S-1 with S-1 Alone as First-line Treatment for Advanced Gastric Cancer (GC0301/TOP-002), were available. Published clinical information for S-1 from other studies (total 705 patients) was also collected. A Weibull distribution was assumed for overall survival time, and parameters for SOX, CS, and S-1 were estimated parametrically. Posterior HR distributions were obtained with a Bayesian approach. Results: The HR of SOX to S-1 was 0.817 (95 % credible interval 0.704-0.939), and the probability of the HR <1.00 was 99.8 %. The HR of CS to S-1 was 0.871 (95 % credible interval; 0.754-0.998), and the probability of the HR <1.00 was 97.6 %. The HR of SOX to CS in G-SOX was 0.942 (95 % credible interval; 0.789-1.117), and the probability of HR <1.15 was 98.9 %. Conclusion: This meta-analysis indicates that SOX was superior to S-1 and noninferior to CS in AGC. [ABSTRACT FROM AUTHOR]