S. Morita

Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G)

BACKGROUNDnFOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab.nnnPATIENTS AND METHODSnWJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396.nnnRESULTSnAmong 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months.nnnCONCLUSIONnFOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC.nnnCLINICAL TRIALS NUMBERnUMIN000001396.

S-1 and irinotecan plus bevacizumab versus mFOLFOX6 or CapeOX plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer (TRICOLORE): a randomized, open-label, phase III, noninferiority trial

Abstract Background Combination therapy with oral fluoropyrimidine and irinotecan has not yet been established as first-line treatment of metastatic colorectal cancer (mCRC). We carried out a randomized, open-label, phase III trial to determine whether S-1 and irinotecan plus bevacizumab is noninferior to mFOLFOX6 or CapeOX plus bevacizumab in terms of progression-free survival (PFS). Patients and methods Patients from 53 institutions who had previously untreated mCRC were randomly assigned (1 : 1) to receive either mFOLFOX6 or CapeOX plus bevacizumab (control group) or S-1 and irinotecan plus bevacizumab (experimental group; a 3-week regimen: intravenous infusions of irinotecan 150u2009mg/m2 and bevacizumab 7.5u2009mg/kg on day 1, oral S-1 80u2009mg/m2 twice daily for 2u2009weeks, followed by a 1-week rest; or a 4-week regimen: irinotecan 100u2009mg/m2 and bevacizumab 5u2009mg/kg on days 1 and 15, S-1 80u2009mg/m2 twice daily for 2u2009weeks, followed by a 2-week rest). The primary end point was PFS. The noninferiority margin was 1.25; noninferiority would be established if the upper limit of the 95% confidence interval (CI) for the hazard ratio (HR) of the control group versus the experimental group was less than this margin. Result Between June 2012 and September 2014, 487 patients underwent randomization. Two hundred and forty-three patients assigned to the control group and 241 assigned to the experimental group were included in the primary analysis. Median PFS was 10.8u2009months (95% CI 9.6–11.6) in the control group and 14.0u2009months (95% CI 12.4–15.5) in the experimental group (HR 0.84, 95% CI 0.70–1.02; Pu2009<u20090.0001 for noninferiority, Pu2009=u20090.0815 for superiority). One hundred and fifty-seven patients (64.9%) in the control group and 140 (58.6%) in the experimental group had adverse events of grade 3 or higher. Conclusion S-1 and irinotecan plus bevacizumab is noninferior to mFOLFOX6 or CapeOX plus bevacizumab with respect to PFS as first-line treatment of mCRC and could be a new standard treatment. Clinical trials number UMIN000007834

Randomized controlled trial of S-1 versus docetaxel in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy (East Asia S-1 Trial in Lung Cancer)

Abstract Background Chemotherapy remains a viable option for the management of advanced non-small-cell lung cancer (NSCLC) despite recent advances in molecular targeted therapy and immunotherapy. We evaluated the efficacy of oral 5-fluorouracil-based S-1 as second- or third-line therapy compared with standard docetaxel therapy in patients with advanced NSCLC. Patients and methods Patients with advanced NSCLC previously treated withu2009≥1 platinum-based therapy were randomized 1 : 1 to docetaxel (60u2009mg/m2 in Japan, 75u2009mg/m2 at all other study sites; day 1 in a 3-week cycle) or S-1 (80–120u2009mg/day, depending on body surface area; days 1–28 in a 6-week cycle). The primary endpoint was overall survival. The non-inferiority margin was a hazard ratio (HR) of 1.2. Results A total of 1154 patients (577 in each arm) were enrolled, with balanced patient characteristics between the two arms. Median overall survival was 12.75 and 12.52u2009months in the S-1 and docetaxel arms, respectively [HR 0.945; 95% confidence interval (CI) 0.833–1.073; Pu2009=u20090.3818]. The upper limit of 95% CI of HR fell below 1.2, confirming non-inferiority of S-1 to docetaxel. Difference in progression-free survival between treatments was not significant (HR 1.033; 95% CI 0.913–1.168; Pu2009=u20090.6080). Response rate was 8.3% and 9.9% in the S-1 and docetaxel arms, respectively. Significant improvement was observed in the EORTC QLQ-C30 global health status over time points in the S-1 arm. The most common adverse drug reactions were decreased appetite (50.4%), nausea (36.4%), and diarrhea (35.9%) in the S-1 arm, and neutropenia (54.8%), leukocytopenia (43.9%), and alopecia (46.6%) in the docetaxel arm. Conclusion S-1 is equally as efficacious as docetaxel and offers a treatment option for patients with previously treated advanced NSCLC. Clinical trial number Japan Pharmaceutical Information Center, JapicCTI-101155.BACKGROUNDnChemotherapy remains a viable option for the management of advanced non-small-cell lung cancer (NSCLC) despite recent advances in molecular targeted therapy and immunotherapy. We evaluated the efficacy of oral 5-fluorouracil-based S-1 as second- or third-line therapy compared with standard docetaxel therapy in patients with advanced NSCLC.nnnPATIENTS AND METHODSnPatients with advanced NSCLC previously treated with≥1 platinum-based therapy were randomized 1xa0:xa01 to docetaxel (60mg/m2 in Japan, 75mg/m2 at all other study sites; day 1 in a 3-week cycle) or S-1 (80-120mg/day, depending on body surface area; days 1-28 in a 6-week cycle). The primary endpoint was overall survival. The non-inferiority margin was a hazard ratio (HR) of 1.2.nnnRESULTSnA total of 1154 patients (577 in each arm) were enrolled, with balanced patient characteristics between the two arms. Median overall survival was 12.75 and 12.52months in the S-1 and docetaxel arms, respectively [HR 0.945; 95% confidence interval (CI) 0.833-1.073; P = 0.3818]. The upper limit of 95% CI of HR fell below 1.2, confirming non-inferiority of S-1 to docetaxel. Difference in progression-free survival between treatments was not significant (HR 1.033; 95% CI 0.913-1.168; P = 0.6080). Response rate was 8.3% and 9.9% in the S-1 and docetaxel arms, respectively. Significant improvement was observed in the EORTC QLQ-C30 global health status over time points in the S-1 arm. The most common adverse drug reactions were decreased appetite (50.4%), nausea (36.4%), and diarrhea (35.9%) in the S-1 arm, and neutropenia (54.8%), leukocytopenia (43.9%), and alopecia (46.6%) in the docetaxel arm.nnnCONCLUSIONnS-1 is equally as efficacious as docetaxel and offers a treatment option for patients with previously treated advanced NSCLC.nnnCLINICAL TRIAL NUMBERnJapan Pharmaceutical Information Center, JapicCTI-101155.

Efficacy and safety of trastuzumab, lapatinib, and paclitaxel neoadjuvant treatment with or without prolonged exposure to anti-HER2 therapy, and with or without hormone therapy for HER2-positive primary breast cancer: a randomised, five-arm, multicentre, open-label phase II trial

BackgroundDual blockade of HER2 promises increased pathological complete response (pCR) rate compared with single blockade in the presence of chemotherapy for HER2-positive (+) primary breast cancer. Many questions remain regarding optimal duration of treatment and combination impact of endocrine therapy for luminal HER2 disease.MethodsWe designed a randomised phase II, five-arm study to evaluate the efficacy and safety of lapatinib and trastuzumab (6xa0weeks) followed by lapatinib and trastuzumab plus weekly paclitaxel (12xa0weeks) with/without prolongation of anti-HER2 therapy prior to chemotherapy (18 vs. 6xa0weeks), and with/without endocrine therapy in patients with HER2+ and/or oestrogen receptor (ER)+ disease. The primary endpoint was comprehensive pCR (CpCR) rate. Among the secondary endpoints, pCR (yT0-isyN0) rate, safety, and clinical response were evaluated.ResultsIn total, 215 patients were enrolled; 212 were included in the full analysis set (median age 53.0xa0years; tumour sizexa0=xa0T2, 65%; and tumour spreadxa0=xa0N0, 55%). CpCR was achieved in 101 (47.9%) patients and was significantly higher in ER− patients than in ER+ patients (ER− 63.0%, ER+ 36.1%; Pxa0=xa00.0034). pCR with pN0 was achieved in 42.2% of patients (ER− 57.6%, ER+ 30.3%). No significant difference was observed in pCR rate between prolonged exposure groups and standard groups. Better clinical response outcomes were obtained in the prolongation phase of the anti-HER2 therapy. No surplus was detected in pCR rate by adding endocrine treatment. No major safety concern was recognised by prolonging the anti-HER2 treatment or adding endocrine therapy.ConclusionsThis study confirmed the therapeutic impact of lapatinib, trastuzumab, and paclitaxel therapy for each ER− and ER+ subgroup of HER2+ patients. Development of further strategies and tools is required, particularly for luminal HER2 disease.

1271PRANDOMIZED PHASE III STUDY COMPARING GEFITINIB (G) WITH ERLOTINIB (E) IN PATIENTS (PTS) WITH PREVIOUSLY TREATED ADVANCED LUNG ADENOCARCINOMA (LA): WJOG 5108L

ABSTRACT Aim: A multicenter randomized phase III study designed to demonstrate non-inferiority of G to E was conducted. Methods: Eligible pts were those with pathologically proven LA with stage IIIB/IV (AJCC version 6) or recurrence, previously treated with at least one chemotherapy regimen, evaluable disease, age ≥20 years and ECOG PS 0-2. Pts were randomized 1:1 to E (150u2003mg, daily), or G (250mg, daily) according to gender, stage, EGFR mutation status, performance status, smoking history, CT line, and institution. Target sample size was 560 based on the assumption that G was not inferior to E in PFS (2 – 4 months, a =0.025 [one sided], b =0.80). Non-inferiority was to be concluded if the upper CI limit was Results: From 2009/7 to 2012/10, 561 pts were accrued, and 280 and 279 were randomly assigned to E and G, respectively, including 185 (66.1%, E) and 186 (66.7%, G) with EGFR mutated tumors. Other baseline factors were balanced between arms except PS: median age 67/68 years; % female 54/55; % PS = 0, 50/40; PS = 1, 43/54; % stage IV, 69/69; % 2nd line, 69/71, % smoker, 50/50; for E/G. Median PFS, TTF and OS for E/G were 7.5 m/6.5 m (p = 0.257, HR = 1.125, 95% CI: 0.940-1.347), 5.3 m/5.6 m (HR = 1.032, 95% CI: 0.866-1.231), and 24.5 m/22.8 m (HR = 1.038, 95% CI: 0.833-1.294), respectively. RR and DCR for E/G were 43.9%/46.1% and 75.0%/71.2%, respectively. Median PFS and OS in pts with EGFR mutation for E/G were 10.1 m/8.9 m (p = 0.532), and 32.0 m/26.6 m (p = 0.111), respectively. Exploratory subset analysis revealed the prolongation of PFS of E compared with that of G in pts aged Conclusions: Non-inferiority in PFS between E and G was not demonstrated according to predefined criteria; however, there was no statistically significant difference in PFS, OS, RR, DCR and TTF. Disclosure: S. Morita: other substantive relationships: Chugai, AstraZeneka; T. Seto: corporate-sponsored research: AstraZeneka other substantive relationships: AstraZeneka, Chugai; T. Hirashima: corporate-sponsored research: Astrazeneca, Chugai-pharm; M. Okada: corporate-sponsored research: AstraZeneka, Chugai, Roche other substantive relationships: AstraZeneka, Chugai, Roche; Y. Urata: other substantive relationships: Chugai, AstraZeneka; N. Yamamoto: other substantive relationships: AstraZeneka, Chugai; K. Nakagawa: corporate-sponsored research: AstraZeneka, Chugai other substantive relationships: AstraZeneka, Chugai; Y. Nakanishi: corporate-sponsored research: Chugai other substantive relationships: Chugai. All other authors have declared no conflicts of interest.

685PA MULTICENTER PHASE II STUDY OF SALVAGE PHOTODYNAMIC THERAPY USING TALAPORFIN SODIUM AND A DIODE LASER FOR LOCAL FAILURE OF ESOPHAGEAL CANCER AFTER CHEMORADIOTHERAPY

ABSTRACT Aim: We previously reported that photodynamic therapy (PDT) has a potential to cure local failure after chemoradiotherapy (CRT) for esophageal cancer (EC). However, first-generation PDT using porfimer sodium and an excimer dye laser has several problems: a high occurrence of skin phototoxicity, the requirement of a long light shielding period (6 weeks), and the need for an expensive and large laser generator. Talaporfin sodium (Laserphyrin®) is a second-generation photosensitizer that requires a shorter light shielding period (2 weeks) and induces less phototoxicity. We previously identified the optimum diode laser fluence (100 J/cm2) for PDT using talaporfin sodium in the phase I/IIA study. Therefore, in the present study, we conducted a multicenter phase IIB study to evaluate the efficacy and safety of PDT using talaporfin sodium as a salvage treatment for local failure after CRT or radiotherapy (RT) for EC. (UMIN000009184). Methods: Eligibility criteria were histologically proven local failure of ≤3u2003cm in diameter with a clinical depth limited within T2 after definitive CRT or RT (≥50u2003Gy) for EC. PDT commenced with intravenous administration of 40u2003mg/m2 of talaporfin sodium, followed by diode laser irradiation with a fluence of 100 J/cm2 and a fluence rate of 150 mW/cm2 4-6 h later. The primary endpoint was the local complete response (L-CR) rate, and the secondary endpoints were confirmed L-CR, local progression-free survival, progression-free survival, local time to treatment failure, and overall survival. The institutional review boards of all institutions approved the study protocol. Results: Between November 2012 and December 2013, a total of 26 patients were enrolled. The clinical depth of the lesions was diagnosed as T1 in 19 patients and T2 in 7 patients by endosonography. PDT using talaporfin sodium was performed in all patients without any serious adverse events. The patients are currently followed up to assess primary and secondary endpoints. Conclusions: The efficacy and safety of second-generation PDT using talaporfin sodium for local failure of EC after CRT will be reported. Disclosure: All authors have declared no conflicts of interest.