Early tumor shrinkage and depth of response in patients with metastatic esophageal cancer treated with 2-weekly docetaxel combined with cisplatin plus fluorouracil: an exploratory analysis of the JCOG0807.

BACKGROUND: We herein investigated the association between early tumor shrinkage (ETS) and depth of response (DpR) and clinical outcomes in patients with metastatic esophageal cancer treated with 2-weekly docetaxel combined with cisplatin plus fluorouracil (bDCF) using data from the JCOG0807, a phase I/II trial of bDCF as first-line chemotherapy for metastatic esophageal cancer. METHODS: ETS was defined as a percent decrease in the sum of the target lesions' longest diameter after 8 weeks, whereas DpR was defined as a percentage of the maximal tumor shrinkage during the treatment course. Multivariable analyses were conducted to identify significant prognostic variables in progression-free survival (PFS) and overall survival (OS): one for ETS and covariates, and another for DpR and covariates. RESULTS: Among 53 patients, 35 patients with ETS ≥ 20% (66.0%) had longer PFS (7.5 vs. 3.4 months, hazard ratio [HR]: 0.26, 95% confidence interval [95% CI] 0.14-0.49), OS (13.8 vs. 6.1 months, HR 0.20, 95% CI 0.11-0.39), and PPS (6.4 vs. 2.8 months, HR 0.38, 95% CI 0.20-0.72) than those with ETS < 20%. In addition, 37 patients with DpR ≥ 30% (69.8%) had longer PFS (7.5 vs. 2.9 months, HR 0.17, 95% CI 0.08-0.34), OS (13.8 vs. 6.0 months, HR 0.14, 95% CI 0.07-0.27), and PPS (6.8 vs. 2.8 months, HR 0.30, 95% CI 0.15-0.58) than those with DpR < 30%. Multivariable analyses revealed that each ETS and DpR was an independent factor of longer PFS and OS. CONCLUSIONS: ETS and DpR might be associated with clinical outcomes in patients with metastatic esophageal cancer treated with bDCF.

Fibroblast growth factor receptor 2 (FGFR2) fusions in Japanese patients with intrahepatic cholangiocarcinoma.

OBJECTIVE: Fibroblast growth factor receptor gene alterations have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer that has a poor prognosis. This study evaluated the frequency of fibroblast growth factor receptor 2 fusions in clinical specimens from Japanese patients with iCCA. METHODS: This study enrolled 116 patients who had histologically or cytologically confirmed adenocarcinoma and been diagnosed as relapsing after resection or with unresectable intrahepatic cholangiocarcinoma. We evaluated the frequency of fibroblast growth factor receptor 2 fusions-positive cells in their specimens using break-apart fluorescent in situ hybridization 'for 114 patients who met the study protocol'. RESULTS: Of a total of 114 cases, six (5.3%) were identified as fibroblast growth factor receptor 2 fusions-positive with a high frequency (87% or more) of fibroblast growth factor receptor 2 fusions-positive tumour cells whereas the remainder, with the exception of three cases with indeterminate results, were identified as fibroblast growth factor receptor 2 fusions-negative. The patients' baseline characteristics as well as their objective response rates, disease control rates, times to progression, and times to treatment failure with previous or ongoing first-line chemotherapy did not have any obvious relationship to the proportion of fibroblast growth factor receptor 2 fusions-positive case. CONCLUSIONS: Further detailed elucidation of fibroblast growth factor receptor 2 fusion status is expected to contribute to the development of promising therapeutic options for patients suffering from recurrent or unresectable intrahepatic cholangiocarcinoma.

A triplet combination of FOLFOXIRI plus cetuximab as first-line treatment in RAS wild-type, metastatic colorectal cancer: a dose-escalation phase Ib study.

BACKGROUND: The triplet-agent (5-fluorouracil/leucovorin, oxaliplatin, and irinotecan; FOLFOXIRI) combined with an anti-epidermal growth factor receptor antibody as a first-line treatment of metastatic colorectal cancer (mCRC) has shown promising results in Western trials. This phase Ib study assessed the safety of FOLFOXIRI plus cetuximab in Japanese patients with RAS wild-type mCRC. METHODS: Patients with previously untreated RAS wild-type mCRC received weekly cetuximab (400 mg/m2 at week 1 and subsequently 250 mg/m2) plus FOLFOXIRI that consisted of irinotecan (100, 120, and 150 mg/m2 defined as dose levels 0, 1, and 2), followed by oxaliplatin 85 mg/m2 and l-leucovorin 200 mg/m2 and then 5-fluorouracil 2400 mg/m2. The dose level of irinotecan was escalated starting at dose level 1 in a 3 + 3 manner. The primary endpoint was to determine the maximum-tolerated dose (MTD) and the recommended phase-2 dose (RP2D). Secondary endpoints included safety, overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). RESULTS: Nine patients were enrolled. The MTD was not reached at dose level 2 and the RP2D was 150 mg/m2 irinotecan. The most frequent grade 3/4 adverse events were neutropenia (44%), fatigue (11%), paronychia (22%), and acneiform rash (11%). No dose-limiting toxicities occurred in any of the enrolled patients. No treatment-related death was observed. The ORR was 89% (95% confidence interval 52-100%). CONCLUSION: The safety profile of the combination of cetuximab and FOLFOXIRI was acceptable and promising anti-tumor activity was demonstrated, supporting further study in patients with RAS wild-type mCRC.

Five-year follow-up of nivolumab treatment in Japanese patients with esophageal squamous-cell carcinoma (ATTRACTION-1/ONO-4538-07).

BACKGROUND: In the phase II ATTRACTION-1 study, nivolumab demonstrated a promising antitumor activity among Japanese patients with treatment-refractory advanced esophageal cancer. Here, we report the follow-up results of ATTRACTION-1 of > 5 years. METHODS: We enrolled patients with esophageal cancer that was refractory or intolerant to a standard chemotherapy. Then, nivolumab (3 mg/kg) was administered every 2 weeks. The primary endpoint was a centrally assessed objective response rate. RESULTS: Nivolumab was administered to 65 patients with esophageal squamous-cell carcinoma (ESCC). The centrally assessed objective response rate was 17.2%. The overall survival rates at 3 and 5 years were 10.9% and 6.3%, respectively. Three-year survivors tended to have more reduced target lesions. A total of 63.1% of the patients exhibited treatment-related adverse events, and no new safety signal was observed. Patients with select adverse events tended to have better overall survival than those without. No apparent chronological order was observed between the first response and the onset of select adverse events. CONCLUSION: Our follow-up analysis of more than 5 years is currently the longest and is the first to demonstrate that nivolumab has long-term efficacy and safety for advanced ESCC.

Long-term efficacy and predictive correlates of response to nivolumab in Japanese patients with esophageal cancer.

The long-term efficacy of nivolumab in esophageal squamous cell carcinoma and its association with disease biomarkers are currently not well known. Therefore, we investigated the association in Japanese patients with treatment-refractory advanced esophageal cancer who participated in an open-label, single-arm, multicenter phase II study. Patients received nivolumab 3 mg/kg i.v. every 2 weeks until disease progression or unacceptable toxicity, and were followed up for 2 years after the initial dosing of the last patient. Archival tissue samples were collected before treatment and analyzed for programmed death ligand-1 (PD-L1) and CD8+ status of tumors and tumor-infiltrating lymphocytes (TILs) and human leukocyte antigen class 1. Efficacy end-points included objective response rate (ORR), overall survival (OS), progression-free survival (PFS), time to response, and duration of response. Of 65 enrolled patients (83% male), 64 were evaluable for efficacy and 41 (63%) for biomarkers. The ORR, median OS, and survival rate were 17.2%, 10.78 months, and 17.2%, respectively. Time to response was 1.45 months and duration of response was 11.17 months. The PD-L1 positivity of tumor cells was possibly associated with better PFS (2.04 vs 1.41 months, cut-off 1%) and OS (11.33 vs 6.24 months, cut-off 1%). Median OS was prolonged in patients with a median number of TILs greater than 63.75% vs 63.75% or less (11.33 vs 7.85 months). Nivolumab showed continued long-term efficacy, as seen by the stability of PFS and OS, in Japanese patients with esophageal squamous cell carcinoma. Further investigation of PD-L1 tumor expression and TILs as potential biomarkers for predicting patients likely to benefit from nivolumab therapy is warranted.

Phase I Study of Alternate-Day Administration of S-1, Oral Leucovorin, and Bevacizumab for Refractory Metastatic Colorectal Cancer.

LESSONS LEARNED: The recommended S-1 dose was 40 mg/m2 , twice daily on Monday, Wednesday, Friday, and Sunday, with oral leucovorin and bevacizumab. Compared with daily administration, the alternate-day administration of S-1 with oral leucovorin may reduce mucositis with promising antitumor activity in refractory metastatic colorectal cancer. BACKGROUND: Daily S-1 plus oral leucovorin administration in a 1-week-on/1-week-off schedule has promising efficacy in gastrointestinal cancer but is associated with high risk of mucositis and diarrhea. METHODS: This phase Ib, 3+3 dose-escalation trial included patients with chemorefractory metastatic colorectal cancer (mCRC) receiving S-1 (40 mg/m2 ) and leucovorin (25 mg) orally twice daily (level 1, even-numbered days; level 2, Monday, Wednesday, Friday, and Sunday) and intravenous bevacizumab (5 mg/kg) every 2 weeks. Enrollment continued at the recommended dose level in the expansion cohort. RESULTS: We enrolled 21 patients (3 and 18 patients in levels 1 and 2, respectively). Briefly, 12 and 9 patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0 and 1, respectively, and 8 and 13 patients had 1-3 and ≥4 prior treatment lines, respectively. Dose-limiting toxicity (DLT) was not observed, and level 2 was confirmed as the recommended dose. Common grade 3-4 adverse events at level 2 were anemia (22%), anorexia (6%), and diarrhea (6%). In the entire cohort, response rate, disease control rate, and median progression-free survival were 10%, 71%, and 4.2 months, respectively. CONCLUSION: The recommended S-1 dose was 40 mg/m2 , twice daily on Monday, Wednesday, Friday, and Sunday, with 25 mg oral leucovorin twice daily and 5 mg/kg bevacizumab every 2 weeks. Compared with the daily administration, alternate-day administration of S-1 plus leucovorin may reduce mucositis with promising antitumor activity in refractory mCRC.

A 3-Year Overall Survival Update From a Phase 2 Study of Chemoselection With DCF and Subsequent Conversion Surgery for Locally Advanced Unresectable Esophageal Cancer.

BACKGROUND: A multicenter phase 2 trial analysed chemoselection with docetaxel plus 5-fluorouracil and cisplatin (DCF) induction chemotherapy (ICT) and subsequent conversion surgery (CS) for locally advanced unresectable esophageal cancer. This study presents updated 3-year analyses to further characterize the impact of DCF-ICT followed by CS. METHODS: Esophageal cancer patients with clinical T4 disease, unresectable supraclavicular lymph node metastasis, or both were eligible for this study. The treatment starts with DCF-ICT, followed by CS if the cancer is resectable, or by concurrent chemoradiation if it is not resectable. This updated analysis presents 3-year overall survival (OS), 3-year progression-free survival (PFS), and pattern of relapse. RESULTS: The median follow-up period for the patients surviving without death was 39.3 months. The estimated 1-year OS was 66.7%, and the lower limit of the 80% confidence interval (CI) was 54.6%. The estimated 3-year OS was 46.6% (95% CI 34.2-63.5%). The OS for the patients who underwent R0 resection (n = 19) was significantly longer than for those who did not (3-year OS: 71.4% vs. 30.1%). The estimated 1-year PFS was 50.6%, and the 3-year PFS was 39.6%. The PFS for R0 was significantly longer than for non-R0 (3-year PFS: 61.3% vs 25.0%). Recurrence or progression at the primary site was observed in 31% of the non-R0 group. The rate of distant metastasis did not differ significantly between the non-R0 and R0 groups (21% vs 16%). CONCLUSIONS: Long-term follow-up evaluation confirmed that DCF chemoselection aimed at CS is feasible and promising in terms of survival for patients with locally advanced esophageal cancer.

The association of primary tumor site with acute adverse event and efficacy of definitive chemoradiotherapy for cStage II/III esophageal cancer: an exploratory analysis of JCOG0909.

BACKGROUND: JCOG0909 is a phase II trial of definitive chemoradiotherapy including salvage treatment for cStage II-III thoracic esophageal cancer; the radiation field for elective regional lymph node irradiation, which can affect patient outcome and adverse event, varied based on the primary tumor site, i.e., upper (Ut), middle (Mt), and lower thoracic (Lt) esophagus. The impact of different primary sites on the safety and efficacy of definitive chemoradiotherapy in JCOG0909 is not well characterized. METHODS: Patients were categorized into three groups (Ut, Mt, and Lt) according to the primary tumor location. We compared acute adverse events during definitive chemoradiotherapy, complete response (CR) rate, 3-year progression-free survival (PFS), and overall survival (OS) among the 3 groups. RESULTS: Out of the 96 patients enrolled in JCOG0909 between April 2010 and August 2014, 94 patients (16, 59, and 19 patients in the Ut, Mt, and Lt groups, respectively) were included in this exploratory analysis. The proportion of patients with cStage III was 25% in the Ut, 37% in the Mt, and 47% in the Lt group. Grade 3-4 leukopenia, neutropenia, and thrombocytopenia were more frequently observed in the Mt (66%, 54%, and 15%) and Lt groups (84%, 68%, and 16%) than in the Ut group (38%, 44%, and 0%). There was no significant between-group difference with respect to 3-year OS (73.3%, 77.9%, and 57.9%), 3-year PFS (60.0%, 59.3%, and 47.4%), or CR rate (62.5%, 62.7%, and 42.1%). CONCLUSIONS: In JCOG0909, the incidence of severe hematological toxicity had a trend toward higher in the Mt and Lt than the Ut esophageal cancer; however, no remarkable difference by primary sites was observed with respect to efficacy endpoints.

Exploration of potential prognostic biomarkers in aflibercept plus FOLFIRI in Japanese patients with metastatic colorectal cancer.

Aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) is a second-line treatment for metastatic colorectal cancer. This ancillary exploratory analysis of data in Japanese people was aimed at exploring the relationship between a set of potential prognostic biomarkers and efficacy endpoints following aflibercept plus FOLFIRI therapy. Sixty-two patients with metastatic colorectal cancer received aflibercept (4 mg/kg) plus FOLFIRI every 2 weeks. Seventy-eight potential protein biomarkers were chosen for analysis based on their roles in angiogenesis, tumor progression, and tumor-stroma interaction. Plasma levels of biomarkers at baseline and at pre-dose 3 (day 1 of treatment cycle 3) were measured in all patients by ELISA. Relationships between these levels and efficacy endpoints were assessed. Ten potential biomarkers had a ±30% change from baseline to pre-dose 3 (adjusted P < .001), with the greatest changes occurring in placental growth factor (median: +4716%) and vascular endothelial growth factor receptor 1 (+2171%). Baseline levels of eight potential biomarkers correlated with overall survival in a univariate Cox regression analysis: extracellular newly identified receptor for advanced glycation end-products binding protein, insulin-like growth factor-binding protein 1, interleukin-8, kallikrein 5, pulmonary surfactant-associated protein D, tissue inhibitor of metalloproteinases 1, tenascin-C, and tumor necrosis factor receptor 2. None correlated with progression-free survival or maximum tumor shrinkage. Pre-dose 3 levels did not correlate with any efficacy endpoints. Preliminary data show that these eight biomarkers could be associated with overall survival. ClinicalTrials.gov identifier: NCT01882868.

Phase II trial of aflibercept with FOLFIRI as a second-line treatment for Japanese patients with metastatic colorectal cancer.

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

Nimotuzumab combined with concurrent chemoradiotherapy in Japanese patients with esophageal cancer: A phase I study.

Nimotuzumab is a humanized anti-epidermal growth factor receptor IgG1 monoclonal antibody. This phase I study assessed the tolerability, safety, efficacy, and pharmacokinetics of nimotuzumab in combination with chemoradiotherapy in Japanese patients with esophageal cancer. Patients with stage II, III, and IV esophageal cancer were enrolled. Patients were planned to receive nimotuzumab (level 1: 200 mg/wk for 25 weeks; or level 2: 400 mg/wk in the chemoradiation period, 400 mg biweekly in an additional chemotherapy period [8 weeks after the chemoradiation period] and a maintenance therapy period [after chemotherapy to 25 weeks]) combined with cisplatin (75 mg/m2 on day 1) and fluorouracil (1000 mg/m2 on days 1-4) in the chemoradiation and additional chemotherapy periods. Radiotherapy was given concurrently at 50.4 Gy. A total of 10 patients were enrolled in level 1. Dose-limiting toxicities were observed in 2 patients (grade 3 infection and renal disorder). Maximum-tolerated dose was estimated to be at least 200 mg/wk and the dose was not escalated to level 2. The most common grade ≥3 toxicities were lymphopenia (90%), leukopenia (60%), neutropenia (50%), and febrile neutropenia, decreased appetite, hyponatremia, and radiation esophagitis (30% each). Neither treatment-related death nor grade ≥3 skin toxicity was observed in any patient. Complete response rate was 50%. Progression-free survival was 13.9 months. One- and 3-year survival rates were 75% and 37.5%, respectively. Immunogenicity was not reported in any patient. Nimotuzumab in combination with concurrent chemoradiotherapy was tolerable and effective for Japanese patients with esophageal cancer.

Salvage chemotherapy with the combination of oxaliplatin, leucovorin, and 5-fluorouracil in advanced gastric cancer refractory or intolerant to fluoropyrimidines, platinum, taxanes, and irinotecan.

BACKGROUND: Although nivolumab showed survival benefit in patients with advanced gastric cancer (AGC) progressing after standard chemotherapy, there is a lack of data regarding oxaliplatin-based chemotherapy in this clinical setting. METHODS: We retrospectively evaluated the efficacy and safety of oxaliplatin with l-leucovorin and bolus/continuous infusion of 5-fluorouracil as salvage treatment in patients with AGC refractory or intolerant to fluoropyrimidines, cisplatin, taxanes, and irinotecan. RESULTS: Overall, 50 patients treated between December 2009 and December 2013 were included in this analysis. The overall response rate (ORR) was 21.2% among 33 patients with measurable disease. The median time to treatment failure (TTF) and overall survival (OS) were 2.4 and 4.2 months. In multivariate analysis, factors associated with OS included poor performance status [hazard ratio (HR) 3.20; 95% confidence interval (CI) 1.55-6.60], shorter time from the start of first-line therapy (HR 2.20; 95% CI 1.18-4.12), and higher neutrophil/lymphocyte ratio value (HR 4.87; 95% CI 2.32-10.25). In patients (n = 35) with at most one risk factor, the ORR, median TTF, and OS were 26.1%, 3.6, and 6.7 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (30%), anemia (22%), febrile neutropenia (8%), and peripheral neuropathy (8%). Initial and subsequent dose reduction was performed in 18 (36%) and 23 (46%) patients. There was one treatment-related death caused by septic infection. CONCLUSIONS: Salvage chemotherapy with the combination of oxaliplatin, leucovorin, and 5-fluorouracil has a potential activity and is tolerable for heavily treated AGC with appropriate dose modification and patient selection.

Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial.

BACKGROUND: Nivolumab is a human monoclonal IgG4 antibody that inhibits programmed cell death protein 1 (PD-1) expressed on activated T cells. We investigated the safety and activity of nivolumab in patients with treatment-refractory oesophageal cancer. METHODS: We did an open-label, single-arm, multicentre phase 2 study. Eligible patients had advanced squamous-cell carcinoma, adenosquamous-cell carcinoma, or adenocarcinoma of the oesophagus refractory or intolerant to fluoropyrimidine-based, platinum-based, and taxane-based chemotherapy. Patients were treated with 3 mg/kg nivolumab given intravenously once every 2 weeks in 6-week cycles. The primary endpoint was centrally assessed objective response (the proportion of patients whose best response was complete or partial response), according to the Response Evaluation Criteria In Solid Tumors, version 1.1. Adverse events and treatment-related adverse events (defined as events for which a causal relation to nivolumab could not be ruled out) were monitored throughout the study. The safety analysis was done in patients who received at least one dose of nivolumab, and drug activity was assessed in patients who received at least one dose of nivolumab and had at least one central assessment of tumour response. This study is registered with clinicaltrials.jp, number ONO-4538-07/JapicCTI-No.142422. Follow-up of patients is ongoing. FINDINGS: Between Feb 25 and Nov 14, 2014, 65 patients were enrolled, all with squamous-cell carcinoma. 64 patients were assessable for the primary endpoint as one patient was excluded due to having multiple primary cancers; all patients were assessable for safety. Median follow-up was 10·8 months (IQR 4·9-14·3). 11 (17%, 95% CI 10-28) of 64 patients had a centrally assessed objective response. Of the 65 patients assessed for adverse events, the most common grade 3 or 4 events were grade 4 dyspnoea and hyponatraemia (one [2%) patient each), grade 3 lung infection (five [8%] patients), grade 3 decreased appetite (two [3%] patients), grade 3 increased blood creatinine phosphokinase (two [3%] patients), and grade 3 dehydration (two [3%] patients). Serious adverse events that occurred during the study were lung infection (four [6%] patients), dehydration (two [3%]), interstitial lung disease (two [3%]), and hyponatraemia, dyspnoea, fatigue, abnormal hepatic function, diarrhoea, bile duct stenosis, gastroenteritis, pneumonia, oedema, and back pain (one [2%] patient each). There were no treatment-related deaths. INTERPRETATION: Nivolumab showed promising activity with a manageable safety profile. This drug could offer a potential new treatment approach for patients with treatment-refractory advanced squamous-cell carcinoma. FUNDING: Ono Pharmaceutical, Bristol-Myers Squibb.

Efficacy of Second-Line Bevacizumab-Containing Chemotherapy for Patients with Metastatic Colorectal Cancer following First-Line Treatment with an Anti-Epidermal Growth Factor Receptor Antibody.

OBJECTIVE: Anti-epidermal growth factor receptor (EGFR) antibodies and bevacizumab are commonly used, sequentially, as palliative chemotherapies for patients with metastatic colorectal cancer. However, little is known about the efficacy of second-line treatments containing bevacizumab after first-line treatment with an anti-EGFR antibody. METHODS: We retrospectively reviewed 128 patients who received second-line bevacizumab-containing chemotherapy and evaluated the effect of prior use of anti-EGFR antibody on the efficacy of the second-line treatment. RESULTS: As first-line treatments, 35 of these patients received only cytotoxic chemotherapy (cohort A), 58 received bevacizumab-containing chemotherapy (cohort B), and 35 received anti-EGFR-containing chemotherapy (cohort C). The median progression-free survival (PFS) with the second-line bevacizumab-containing therapy was 8.3 months in cohort C, 6.9 months in cohort A (hazard ratio [HR], 1.43; 95% confidence interval [CI], 0.83-2.51), and 5.6 months in cohort B (HR, 1.95; 95% CI, 1.18-3.22). Multivariate analysis showed that PFS in cohort C was the same as that in cohort A, but better than that in cohort B. The overall response rate in cohort C (25.7%) was also similar to that in cohort A (20.0%), but better than that in cohort B (10.3%). CONCLUSIONS: Prior use of anti-EGFR antibody did not adversely affect the efficacy of subsequent bevacizumab-containing chemotherapy.

Serum CA19-9 Response Is an Early Predictive Marker of Efficacy of Regorafenib in Refractory Metastatic Colorectal Cancer.

PURPOSE: Regorafenib improves survival in chemorefractory metastatic colorectal cancer (mCRC) patients. However, regorafenib induces various adverse events (AEs) that often impair patients' quality of life. Identification of early predictive markers of the efficacy is warranted. METHODS: We retrospectively examined 146 consecutive mCRC patients who received regorafenib. Clinical parameters, including patient background, AEs, and changes in biochemical parameters until day 28, were evaluated to identify efficacy predictors. RESULTS: Median progression-free survival (PFS) was 2.1 months, and median overall survival was 6.6 months. Major AEs in all cycles were hand-foot skin reaction, hypertension, and increased aspartate transaminase. We extracted 121 patients for prognostic analysis. In univariate analysis, decreased carcinoembryonic antigen (HR: 0.570, p = 0.012) and decreased carbohydrate antigen 19-9 (CA19-9) (HR: 0.422, p = 0.0012) were identified as prognostic markers of PFS. Patients in whom serum CA19-9 decreased after regorafenib exhibited significantly better PFS (median 3.7 vs. 2.0 months, p = 0.004) than those in whom serum CA19-9 did not decrease. Multivariate analysis revealed early CA19-9 decrease as an independent predictive factor (HR: 0.415, 95% CI: 0.210-0.818, p = 0.011). CONCLUSION: Early response of CA19-9 may predict the efficacy of regorafenib. Additional studies are needed for external validation.

Association between ABCG2 and SLCO1B1 polymorphisms and adverse drug reactions to regorafenib: a preliminary study
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OBJECTIVE: Due to the occurrence of severe adverse drug reactions to regorafenib, a drug used in cancer therapy, the identification of a predictive marker(s) is needed to increase the therapeutic applicability of this compound. We therefore investigated whether polymorphisms in the ABCG2 and SLCO1B genes are associated with adverse drug reactions to regorafenib. METHODS: For these analyses, 37 Japanese cancer patients were treated with regorafenib, genotyped for polymorphisms in ABCG2 and SLCO1B, and evaluated for drug-related adverse drug reactions. RESULTS: There was no association between the ABCG2 421C>A variant and adverse drug reactions to regorafenib. After treatment, the incidences of increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) as well as increased total bilirubin (grade ≥ 2) were 8%, 4%, and 12%, and 42%, 25%, and 25% among SLCO1B1*1b carriers and non-carriers, respectively. There were no significant associations between elevated ALT and bilirubin and the SLCO1B1*1b allele. However, there were significantly lower incidences of increased AST (8% vs. 42%) and anemia (16% vs. 50%) in SLCO1B1*1b carriers than in non-carriers. CONCLUSIONS: The absence of SLCO1B1*1b allele appears to be associated with the development of adverse drug reactions to regorafenib; however, further studies involving larger test groups and other populations are needed to confirm these findings.
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Phase II study of chemoselection with docetaxel plus cisplatin and 5-fluorouracil induction chemotherapy and subsequent conversion surgery for locally advanced unresectable oesophageal cancer.

BACKGROUND: The standard treatment for locally advanced unresectable squamous cell carcinoma (SCC) of the oesophagus is chemoradiation with cisplatin and 5-fluorouracil (CF-RT). This multicentre phase II trial assessed the safety and efficacy of chemoselection with docetaxel plus cisplatin and 5-fluorouracil (DCF) induction chemotherapy (ICT) and subsequent conversion surgery (CS) for initially unresectable locally advanced SCC of the oesophagus. METHODS: Patients with clinical T4 and/or unresectable supraclavicular lymph node metastasis were eligible. Treatment started with three cycles of DCF-ICT, followed by CS if resectable, or by CF-RT if unresectable. The resectability was re-evaluated at 30-40 Gy of CF-RT, followed by CS if resectable, or by completion of 60 Gy of CF-RT. If resectable after CF-RT, CS was performed. The primary end point was 1-year overall survival (OS). RESULTS: From April 2013 to July 2014, 48 patients were enrolled. CS was performed in 41.7% (n=20), including DCF-CS (n=18), DCF-CF-RT40Gy-CS (n=1), and DCF-CF-RT60Gy-CS (n=1). R0 resection was confirmed in 19 patients (39.6%). Grade ⩾3 postoperative complications included one event each of recurrent laryngeal nerve palsy, lung infection, wound infection, pulmonary fistula, and dysphagia; but no serious postoperative complications were observed in patients undergoing CS. Clinical complete response after CF-RT was confirmed in 4 patients (8.3%). The estimated 1-year OS was 67.9% and lower limit of 80% confidence interval was 59.7%. There was one treatment-related death in patient receiving DCF-CF-RT60Gy. CONCLUSIONS: Chemoselection with DCF-ICT followed by CS as a multidisciplinary treatment strategy showed promising signs of tolerability and efficacy in patients with locally advanced unresectable SCC of the oesophagus.

Phase 1 study of ombrabulin in combination with cisplatin (CDDP) in Japanese patients with advanced solid tumors.

OBJECTIVE: In clinical studies in Western countries, the recommended dose of combination ombrabulin a vascular disrupting agent, with cisplatin is 25 mg/m2 ombrabulin with 75 mg/m2 cisplatin every 3 weeks. Here, we report the first Phase 1 study of this treatment regimen in Japanese patients with advanced solid tumors. METHODS: This was an open-label, multicenter, sequential cohort, dose-escalation Phase 1 study of ombrabulin with cisplatin administered once every 3 weeks. The study used a 3 + 3 design without intrapatient dose escalation. The investigated dose levels of ombrabulin were 15.5 and 25 mg/m2 combined with cisplatin 75 mg/m2. The latter dose level was regarded as the maximum administered dose if more than one patient experienced dose-limiting toxicities. RESULTS: Ten patients were treated, but no dose-limiting toxicity was observed at both dose levels. Ombrabulin 25 mg/m2 with cisplatin 75 mg/m2 was the maximum administered dose and regarded as the recommended dose in the combination regimen for Japanese patients with cancer. The most frequently reported drug-related adverse events were neutropenia, decreased appetite, constipation, nausea and fatigue. One partial response and five cases of stable disease were reported as the best overall responses. Pharmacokinetic parameters of ombrabulin and cisplatin were comparable with those in non-Japanese patients. CONCLUSIONS: Ombrabulin 25 mg/m2 with cisplatin 75 mg/m2 once every 3 weeks was well tolerated and established as the recommended dose in Japanese patients with advanced solid tumors. The safety and pharmacokinetic profiles were comparable between Japanese and Caucasian patients.

A short interval between bevacizumab and anti-epithelial growth factor receptor therapy interferes with efficacy of subsequent anti-EGFR therapy for refractory colorectal cancer.

BACKGROUND: Both bevacizumab and anti-epithelial growth factor receptor (EGFR) agents (e.g. cetuximab and panitumumab) are sequentially used for metastatic colorectal cancer (mCRC). Their co-administration as a first-line treatment does not improve outcome, indicating that there are negative interactions between these agents. A long-term pharmacokinetics study demonstrated serum persistence of bevacizumab following termination of bevacizumab 6 months after the last administration. This prompted us to investigate the impact of short intervals between bevacizumab and anti-EGFR antibody on the efficacy of subsequent anti-EGFR therapy. METHODS: We retrospectively reviewed consecutive patients with KRAS exon 2 wild-type mCRC who underwent anti-EGFR therapy after the failure of fluoropyrimidines, oxaliplatin and irinotecan. We divided patients into two groups (Group A: the interval between bevacizumab and anti-EGFR agent< 6 months; Group B: the interval >6 months). RESULTS: Of the 114 included patients (median age, 63 years), 78 (68%) were male. Most patients (88%) were treated with cetuximab plus irinotecan. Groups A and B consisted of 74 and 40 patients, respectively. There were no significant differences in patient characteristics. Group B patients had significantly longer progression-free survival (4.2 vs. 6.6 months; HR, 0.65; 95% CI, 0.43-0.98; P = 0.038) and longer overall survival (11.6 vs. 14.3 months; HR, 0.63; 95% CI, 0.41-0.98, P = 0.039). The response rate was 24.3% in Group A and 47.5% in Group B (P = 0.012). CONCLUSION: A short interval between bevacizumab and anti-EGFR antibody treatment may interfere with the efficacy of subsequent anti-EGFR therapy.