Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial

BackgroundTo compare capecitabine/cisplatin with 5-fluorouracil/cisplatin as first-line treatment for advanced gastric cancer (AGC).Patients and methodsIn this randomised, open-label, phase III study, patients received cisplatin (80 mg/m² i.v. day 1) plus oral capecitabine (1000 mg/m² b.i.d., days 1–14) (XP) or 5-FU (800 mg/m²/day by continuous infusion, days 1–5) (FP) every 3 weeks. The primary end point was to confirm noninferiority of XP versus FP for progression-free survival (PFS).ResultsA total of 316 patients were randomised to XP (n = 160) or FP (n = 156). In the per-protocol population, median PFS for XP (n = 139) versus FP (n = 137) was 5.6 versus 5.0 months. The primary end point was met with an unadjusted hazard ratio (HR) of 0.81 [95% confidence interval (CI) 0.63–1.04, P < 0.001 versus noninferiority margin of 1.25]. Median overall survival was 10.5 versus 9.3 months for XP versus FP (unadjusted HR = 0.85, 95% CI 0.64–1.13, P = 0.008 versus noninferiority margin of 1.25). The most common treatment-related grade 3/4 adverse events in XP versus FP patients were as follows: neutropenia (16% versus 19%), vomiting (7% versus 8%), and stomatitis (2% versus 6%).ConclusionsXP showed significant noninferiority for PFS versus FP in the first-line treatment of AGC. XP can be considered an effective alternative to FP.     

Capecitabine/irinotecan or capecitabine/oxaliplatin in combination with bevacizumab is effective and safe as first-line therapy for metastatic colorectal cancer: a randomized phase II study of the AIO colorectal study group

BackgroundThis randomized phase II trial investigated the efficacy and safety of capecitabine/oxaliplatin (CapOx) plus bevacizumab and dose-modified capecitabine/irinotecan (mCapIri) plus bevacizumab as first-line therapy in patients with metastatic colorectal cancer (mCRC).Patients and methodsPatients received bevacizumab 7.5 mg/kg with oxaliplatin 130 mg/m²/day 1 plus capecitabine 1000 mg/m² bid/days 1–14 or with irinotecan 200 mg/m²/day 1 plus capecitabine 800 mg/m² bid/days 1–14 both every 21 days. The primary end point was 6 months progression-free survival (PFS).ResultsA total of 255 patients were enrolled. The intent-to-treat population comprised 247 patients (CapOx–bevacizumab: n = 127; mCapIri–bevacizumab: n = 120). The six-month PFS rates were 76% (95% CI, 69%–84%) and 84% (95% CI, 77%–90%). Median PFS and OS were 10.4 months (95% CI, 9.0–12.0) and 24.4 months (95% CI, 19.3–30.7) with CapOx–bevacizumab, and 12.1 months (95% CI, 10.8–13.2) and 25.5 months (95% CI, 21.0–31.0) with mCapIri–bevacizumab. Grade 3/4 diarrhea as predominant toxic effect occurred in 22% of patients with CapOx–bevacizumab and in 16% with mCapIri–bevacizumab.ConclusionsBoth, CapOx–bevacizumab and mCapIri–bevacizumab, show promising activity and an excellent toxic effect profile. Efficacy is in the range of other bevacizumab-containing combination regimen although lower doses of irinotecan and capecitabine were selected for mCapIri.     

Paclitaxel and bevacizumab with or without capecitabine as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: A multicentre,open-label,randomised phase 2 trial

BackgroundThe addition of bevacizumab to paclitaxel or capecitabine has demonstrated improved progression-free survival (PFS) and objective response rate (ORR) as compared with chemotherapy alone in patients with HER2-negative locally recurrent or metastatic breast cancer (LR/MBC). We evaluated the efficacy and safety of first-line therapy of paclitaxel and bevacizumab with or without capecitabine in patients with HER2-negative LR/MBC.MethodsIn this multicentre, open-label, randomised phase II trial, women with HER2-negative LR/MBC were randomly assigned in a 1:1 ratio to paclitaxel (90 mg/m² intravenously [IV] on days 1, 8, and 15) and bevacizumab (10 mg/kg IV on days 1 and 15) every 4 weeks for six cycles, followed by bevacizumab (15 mg/kg IV on day 1) every 3 weeks (AT) or to paclitaxel (90 mg/m² IV on days 1 and 8), bevacizumab (15 mg/kg IV on day 1) and capecitabine (825 mg/m² orally twice daily on days 1–14) every 3 weeks for eight cycles, followed by bevacizumab and capecitabine at the same doses every 3 weeks (ATX). The primary end-point was investigator-assessed PFS. Secondary end-points included ORR, duration of response, overall survival (OS) and safety. Exploratory analyses were conducted to evaluate the impact of capecitabine on OS and to validate a novel prognostic model. This trial is registered with EudraCT, number 2006-006058-83.FindingsMedian PFS was significantly longer in ATX as compared with AT (11.2 months versus 8.4 months; stratified hazard ratio (HR), 0.52; 95% confidence interval (CI), 0.41–0.67; p < 0.0001). The ORR in ATX patients with measurable disease (n = 268) was higher than that in AT (69% versus 51%; p = 0.01). The median duration of response was 6.8 versus 5.4 months for, respectively, ATX and AT (p < 0.0001). Median OS was 24.2 months for ATX and 23.1 months for AT (p = 0.53). The increased rate of grade 3–4 adverse events related to the addition of capecitabine, being hand-foot syndrome (34% versus 0% for AT) and neutropenia (20% versus 12% for AT), generally did not preclude continuation of treatment. Exploratory analyses indicated that 1) patients receiving capecitabine at some line for treatment have significantly improved OS and 2) a prognostic model can classify patients into three risk groups associated with OS.InterpretationIn patients with HER2-negative LR/MBC, addition of capecitabine to paclitaxel and bevacizumab significantly improved PFS, ORR and response duration. This combination was reasonably well tolerated and may be considered of use as first-line treatment in rapidly progressive disease.FundingF. Hoffmann-La Roche Ltd, the Netherlands.     

Low dose capecitabine plus weekly paclitaxel in patients with metastatic breast cancer: a multicenter phase II study KBCSG-0609

Purpose

The combination of capecitabine and paclitaxel (XP) has demonstrated synergistic antitumor activity in preclinical models. The purpose of this phase II study was to evaluate the efficacy and safety of a monthly XP regimen in patients with metastatic breast cancer (MBC).

Methods

Eligible patients had received one or fewer prior chemotherapy regimens for MBC. Patients received oral capecitabine of low dose (828 mg/m² twice daily, days 1–21) plus paclitaxel (80 mg/m², i.v., over 60 min, days 1, 8 and 15) every 28 days until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Progression-free survival (PFS), overall survival (OS) and safety were secondary endpoints. An exploratory analysis of efficacy according to hormone receptor (HR) status was performed.

Results

Forty-four patients were enrolled, and 43 patients were evaluable. ORR was 46.5 %. PFS and OS were 8.3 and 22.9 months, respectively. ORR was 45.5 % in patients with HR-positive tumors and 50 % in HR-negative cases. The most frequently observed grade 3/4 adverse events were neutropenia (27.9 %), leukopenia (11.6 %), hand-foot syndrome (HFS, 9.3 %) and fatigue (7.0 %). There were no discontinuations due to HFS.

Conclusions

Monthly XP was an effective and well-tolerated regimen for the first- or second-line treatment for MBC.     

Pooled analysis of individual patient data from capecitabine monotherapy clinical trials in locally advanced or metastatic breast cancer

We assessed the efficacy and safety of capecitabine across treatment lines, and the impact of patient and disease characteristics on outcomes using data from phase II/III trials. Individual patient data were pooled from seven Roche/Genentech-led trials conducted from 1996 to 2008 where single-agent capecitabine was the test or control regimen for metastatic breast cancer (MBC). Data were analyzed from 805 patients: 268 in the first-line metastatic setting and 537 in the second-line or later setting. Baseline characteristics were balanced across treatment lines. Patients receiving second-line or later versus first-line capecitabine had lower objective response rates (ORR: 19.0 vs. 25.0?%, respectively, odds ratio 0.70; 95?% CI: 0.5?C1.0) and significantly shorter progression-free survival (PFS: median 112.0?days [3.7?months] vs. 150.0?days [4.9?months]; p?<?0.0001) and overall survival (OS: median 396.0?days [13.0?months] vs. 666.0?days [21.9?months]; p?<?0.0001). In multivariate analysis by backward elimination, significantly improved ORR (p?=?0.0036), PFS (p?<?0.0001) and OS (p?<?0.0001) with capecitabine were demonstrated in patients with estrogen receptor (ER) and/or progesterone receptor (PgR)-positive versus both ER and PgR-negative tumors. Hand-foot syndrome (HFS) was the most common adverse event (AE) in 63?% of patients. Overall, 7?% of patients discontinued and two patients (<1?%) died from treatment-related AEs. Significantly improved survival was observed in patients developing capecitabine-related HFS (p?<?0.0001 PFS/OS) or diarrhea (p?=?0.004 OS; p?=?0.0045 PFS) versus patients without these events. In this pooled analysis of individual patient data, first-line capecitabine was associated with improved ORR, PFS, and OS versus second or later lines. Multivariate analyses identified greater ORR, PFS, and OS with capecitabine in patients with ER and/or PgR-positive versus ER/PgR-negative tumors. Safety was in-line with previous phase III trials in MBC.     

A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma

BackgroundPEP02 is a novel highly stable liposomal nanocarrier formulation of irinotecan. This randomized phase II study evaluated the efficacy and safety of single agent PEP02 compared with irinotecan or docetaxel in the second-line treatment of advanced oesophago-gastric (OG) cancer.Patients and methodsPatients with locally advanced/metastatic disease who had failed one prior chemotherapy regimen were randomly assigned to PEP02 120 mg/m², irinotecan 300 mg/m² or docetaxel (Taxotere) 75 mg/m² every 3 weeks. The primary end point was objective response rate (ORR). Simon's two-stage design was used and the ORR of interest was 20% (α = 0.05, type II error β = 0.10, null hypothesis of ORR was 5%).ResultsForty-four patients per arm received treatment, and 124 were assessable for response. The ORR statistical threshold for the first stage was reached in all arms. In the intent-to-treat (ITT) population, ORRs were 13.6% (6/44), 6.8% (3/44) and 15.9% (7/44) in the PEP02, irinotecan and docetaxel arms, respectively. The median progression-free survival (PFS) and overall survival were similar between the trial arms. Commonest grade 3–4 adverse event reported was diarrhoea in the PEP02 and irinotecan groups (27.3% versus 18.2%).ConclusionThe ORR associated with PEP02 was comparable with docetaxel and numerically greater than that of irinotecan. PEP02 warrants further evaluation in the advanced gastric cancer setting.     

Docetaxel–cisplatin might be superior to docetaxel–capecitabine in the first-line treatment of metastatic triple-negative breast cancer

BackgroundTriple-negative breast cancer (TNBC) may be more sensitive to platinum. This study was to compare platinum-based regimen with nonplatinum regimen in the first-line treatment of advanced TNBC.Patients and methodsEligible metastatic TNBC (mTNBC) women without prior treatment for advanced disease were randomized (1 : 1) to receive either docetaxel–cisplatin (TP) or docetaxel –capecitabine (TX) q3w for up to 6 cycles, until disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR) and the secondary end points included progression-free survival (PFS) and overall survival (OS). In total 53 patients were enrolled.ResultsThe median follow-up was 24 months. ORR was higher in the TP group than in the TX group (63.0% versus 15.4%, P = 0.001). PFS was more than doubled (10.9 months versus 4.8 months, P < 0.001) and median OS was also greatly improved (32.8 months versus 21.5 months, P = 0.027). Toxic effects were not different except G3/4 vomiting and G2/3 hand-foot syndrome.ConclusionsThis study suggested that cisplatin-based chemotherapy was superior to capecitabine-based regimen in the first-line treatment of mTNBC, as measured by ORR, PFS and OS. Further large-scale study should be warranted. These results are not sufficient to change clinical practice.     

Combination chemotherapy with capecitabine and cisplatin for patients with metastatic hepatocellular carcinoma

BackgroundWe evaluated the efficacy and toxicity of combination chemotherapy with capecitabine and cisplatin (XP) in patients with metastatic hepatocellular carcinoma (HCC).Patients and methodsFrom September 2003 to July 2007, we enrolled patients with HCC who had more than one measurable extrahepatic metastatic lesion. Patients received oral capecitabine (2000 mg/m²/day) with a schedule of 2 weeks on and 1 week off and cisplatin (60 mg/m²) on the first day of the 3-week cycle.ResultsThe study cohort consisted of 32 patients with a median age of 53 years. Overall response rate was 6.3% and disease control rate was 34.4%. The median time to progression (TTP) was 2.0 months [95% confidence interval (CI) 1.5–2.4] and the median overall survival (OS) time was 12.2 months (95% CI 6.5–17.8). The grade 3/4 hematologic toxic effects included thrombocytopenia (7.6%), neutropenia (4.3%) and anemia (2.1%). The grade 3/4 non-hematologic toxic effects included elevated hepatic aminotransferase (12.9%), jaundice (3.2%), mucositis (3.2%) and nausea (3.2%). There was no treatment-related mortality.ConclusionsBased on the observed response rate and TTP, XP combination chemotherapy showed modest antitumor efficacy in patients with metastatic HCC as systemic first-line treatment. However, XP combination chemotherapy showed tolerable toxicity and demonstrated favorable OS time.     

Safety,efficacy and tumor mutational burden as a biomarker of overall survival benefit in chemo-refractory gastric cancer treated with toripalimab,a PD-1 antibody in phase Ib/II clinical trial NCT02915432

BackgroundHigh tumor mutational burden (TMB-H) is correlated with enhanced objective response rate (ORR) and progression-free survival (PFS) for certain cancers receiving immunotherapy. This study aimed to investigate the safety and efficacy of toripalimab, a humanized programmed death-1 (PD-1) antibody, in advanced gastric cancer (AGC), and the predictive survival benefit of TMB and PD-L1.Patients and methodsWe reported on the AGC cohort of phase Ib/II trial evaluating the safety and activity of toripalimab in patients with AGC, oesophageal squamous cell carcinoma, nasopharyngeal carcinoma and head and neck squamous cell carcinoma. In cohort 1, 58 chemo-refractory AGC patients received toripalimab (3 mg/kg d1, Q2W) as a monotherapy. In cohort 2, 18 chemotherapy-naive AGC patients received toripalimab (360 mg d1, Q3W) with oxaliplatin 130 mg/m² qd, d1, capecitabine 1000 mg/m² b.i.d., d1–d14, Q3W as first-line treatment. Primary end point was ORR. Biomarkers such as PD-L1 and TMB were evaluated for correlation with clinical efficacy.ResultsIn cohort 1, the ORR was 12.1% and the disease control rate (DCR) was 39.7%. Median PFS was 1.9 months and median OS was 4.8 months. The TMB-H group showed significant superior OS than the TMB-L group [14.6 versus 4.0 months, HR = 0.48 (96% CI 0.24–0.96), P = 0.038], while PD-L1 overexpression did not correlate with significant survival benefit. A 77.6% of patients experienced at least one treatment-related adverse event (TRAE), and 22.4% of patients experienced a grade 3 or higher TRAE. In cohort 2, the ORR was 66.7% and the DCR was 88.9%. A 94.4% of patients experienced at least one TRAE and 38.9% of patients experienced grade 3 or higher TRAEs.ConclusionsToripalimab has demonstrated a manageable safety profile and promising antitumor activity in AGC patients, especially in combination with XELOX. High TMB may be a predictive marker for OS of AGC patients receiving toripalimab as a single agent.Trial registrationClinicalTrials.gov NCT02915432.     

Epirubicin and cyclophosphamide versus epirubicin and docetaxel as first-line therapy for women with metastatic breast cancer: final results of a randomised phase III trial

BackgroundThis randomised phase III trial was carried out to compare the efficacy and safety of epirubicin and cyclophosphamide (EC) with epirubicin and docetaxel (Taxotere) (ED) as first-line chemotherapy for metastatic breast cancer.Patients and methodsPatients (n = 240) were randomly assigned to receive either ED (epirubicin 75 mg/m² and docetaxel 75 mg/m²) or EC (epirubicin 90 mg/m² and cyclophosphamide 600 mg/m²). The primary end point was objective response rate (ORR). Secondary end points were progression-free survival (PFS), overall survival (OS), and safety.ResultsORR for patients randomly assigned to receive EC and ED were 42% and 47%, respectively (P = 0.63). Median PFS [10.1 versus 10.3 months; hazard ratio (HR) 0.98; log-rank P = 0.38] and OS (19.9 versus 30.0 months; HR 0.663; log-rank P = 0.21) were comparable in both arms. Although grade 3/4 leucopenia occurred more frequently with ED (81% versus 73%; P = 0.01), there were no significant differences in the incidence of febrile neutropenia and grade 3/4 infections. Grade 3/4 non-haematologic toxicity was infrequent in both arms. Congestive heart failure was observed in one patient in each arm.ConclusionIn this randomised trial, no differences in the efficacy study end points were observed between the two treatment arms.     

First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III,randomized, open-label,ENSURE study

BackgroundThe phase III, randomized, open-label ENSURE study (NCT01342965) evaluated first-line erlotinib versus gemcitabine/cisplatin (GP) in patients from China, Malaysia and the Philippines with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC).Patients and methodsPatients ≥18 years old with histologically/cytologically confirmed stage IIIB/IV EGFR mutation-positive NSCLC and Eastern Cooperative Oncology Group performance status 0–2 were randomized 1:1 to receive erlotinib (oral; 150 mg once daily until progression/unacceptable toxicity) or GP [G 1250 mg/m² i.v. days 1 and 8 (3-weekly cycle); P 75 mg/m² i.v. day 1, (3-weekly cycle) for up to four cycles]. Primary end point: investigator-assessed progression-free survival (PFS). Other end points include objective response rate (ORR), overall survival (OS), and safety.ResultsA total of 217 patients were randomized: 110 to erlotinib and 107 to GP. Investigator-assessed median PFS was 11.0 months versus 5.5 months, erlotinib versus GP, respectively [hazard ratio (HR), 0.34, 95% confidence interval (CI) 0.22–0.51; log-rank P < 0.0001]. Independent Review Committee-assessed median PFS was consistent (HR, 0.42). Median OS was 26.3 versus 25.5 months, erlotinib versus GP, respectively (HR, 0.91, 95% CI 0.63–1.31; log-rank P =.607). ORR was 62.7% for erlotinib and 33.6% for GP. Treatment-related serious adverse events (AEs) occurred in 2.7% versus 10.6% of erlotinib and GP patients, respectively. The most common grade ≥3 AEs were rash (6.4%) with erlotinib, and neutropenia (25.0%), leukopenia (14.4%), and anemia (12.5%) with GP.ConclusionThese analyses demonstrate that first-line erlotinib provides a statistically significant improvement in PFS versus GP in Asian patients with EGFR mutation-positive NSCLC (NCT01342965).     

North Central Cancer Treatment Group (NCCTG) N0432: phase II trial of docetaxel with capecitabine and bevacizumab as first-line chemotherapy for patients with metastatic breast cancer

BackgroundDocetaxel (T; Taxotere) with capecitabine (X) is active against metastatic breast cancer (MBC); bevacizumab (BV) has demonstrated efficacy with taxanes in the first-line setting. This study was conducted to assess the safety and efficacy of TX-BV in patients with MBC.Patients and methodsIn this single-arm, multicenter phase II study, patients received first-line bevacizumab 15 mg/kg and docetaxel 75 mg/m² on day 1 and capecitabine 825 mg/m² twice per day on days 1–14 every 21 days. Primary and secondary end points were tumor response rate (RR), overall survival (OS), progression-free survival (PFS), and toxicity.ResultsA total of 45 assessable patients received TX-BV for a median of seven cycles. Two complete and 20 partial responses were observed (overall RR 49%); nine patients had stable disease >6 months, for a clinical benefit rate of 69%. Median response duration was 11.8 months. Median OS and PFS were 28.4 and 11.1 months, respectively. Grade 3/4 adverse events included hand–foot syndrome (29%), fatigue (20%), febrile neutropenia (18%), and diarrhea (18%). In cycles 3–10, median dose levels of docetaxel and capecitabine were 60 mg/m² and 660 mg/m², respectively.ConclusionTX-BV demonstrated significant activity; dose modifications were required to manage drug-related toxic effects.     

Bevacizumab combined with chemotherapy in the second-line treatment of metastatic colorectal cancer: results from the phase II BEVACOLOR study

BackgroundThis prospective phase II study assessed the efficacy and safety of bevacizumab plus chemotherapy regimens commonly used in the second-line treatment of metastatic colorectal cancer (mCRC).MethodsPatients with mCRC who progressed or relapsed after first-line oxaliplatin-based or irinotecan-based treatment received bevacizumab 2.5 mg/kg/week plus chemotherapy until disease progression. The primary endpoint was disease-control rate (DCR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety.ResultsFifty-three patients (66% men; median age, 62 years old) received second-line bevacizumab plus folinic acid, fluorouracil, and irinotecan (FOLFIRI; 57%), folinic acid, fluorouracil, oxaliplatin (FOLFOX; 26%), irinotecan (15%), or capecitabine plus irinotecan (XELIRI; 2%). The DCR was 87% (95% CI, 77%-97%); ORR was 32% (95% CI, 19%-46%). Median PFS was 6.5 months (95% CI, 5.8-7.8 months) and median OS 19.3 months, (95% CI, 14.2-25.1 months).The most frequent grade 3/4 adverse events included neutropenia (21%), diarrhea (15%), asthenia, and vomiting (9% each). Five patients (9%) had grade 3/4 targeted toxicities: grade 3 hypertension (n = 2), grade 3 venous thromboembolism (n = 2), and grade 4 arterial thromboembolism (n = 1). None of these events led to death during the study.ConclusionBevacizumab plus standard second-line chemotherapy is highly active in patients with mCRC and has an acceptable safety profile.     

FOLFOX4 plus cetuximab administered weekly or every second week in the first-line treatment of patients with KRAS wild-type metastatic colorectal cancer: a randomized phase II CECOG study

BackgroundThis randomized phase II study investigated first-line chemotherapy plus cetuximab administered every second week in KRAS wild-type metastatic colorectal cancer.Patients and methodsPatients received FOLFOX4 plus either standard weekly cetuximab (arm 1) or cetuximab (500 mg/m²) every second week (arm 2), until disease progression or unacceptable toxicity. Primary end point was the objective response rate (ORR). Progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety were also investigated. The study was not powered to establish non-inferiority, but aimed at the estimation of treatment differences.ResultsOf 152 randomized eligible patients, 75 were treated in arm 1 and 77 in arm 2; ORRs [53% versus 62%, odds ratio 1.40, 95% confidence interval (CI) 0.74–2.66], PFS [median 9.5 versus 9.2 months, hazard ratio (HR) 0.92, 95% CI 0.63–1.34], OS (median 25.8 versus 23.0 months, HR 0.86, 95% CI 0.56–1.30) and DCR (87%) were comparable. HRs adjusted for baseline factors were 1.01 and 0.99 for PFS and OS, respectively. Frequencies of grade 3/4 adverse events in arms 1 versus 2 were similar: most common were neutropenia (28% versus 34%) and rash (15% versus 17%).ConclusionsActivity and safety of FOLFOX4 plus either cetuximab administered weekly or every second week were similar.     

Capecitabine in combination with oxaliplatin or irinotecan in elderly patients with advanced colorectal cancer: results of a randomized phase II study

BackgroundTo determine the efficacy and tolerability of capecitabine combined with oxaliplatin (CAPOX) or irinotecan (CAPIRI) as first-line treatment in patients with advanced/metastatic colorectal cancer aged ≥70 years.Patients and methodsPatients aged ≥70 years were randomly assigned to receive CAPOX [oxaliplatin 65 mg/m² intravenously (i.v.) days 1 and 8 and capecitabine 1000 mg/m² orally b.i.d. days 1–14; q21d] or CAPIRI (irinotecan 80 mg/m² i.v. days 1 and 8 and capecitabine 1000 mg/m² orally b.i.d. days 1–14; q21d). The primary study end point was overall response rate (ORR).ResultsNinety-four patients were enrolled. In an intent-to-treat analysis, 2 complete responses (CRs) and 16 partial responses (PRs) were reported with CAPOX (ORR 38%), and 2 CRs and 15 PRs with CAPIRI (ORR 36%; P = 0.831). Median time to progression was 8 months for CAPOX and 7 months for CAPIRI (P = 0.195), with median survival times of 19.3 months and 14.0 months (P = 0.165), respectively. Global health status was improved in 45% and in 21% of patients in the CAPOX and CAPIRI arms, respectively. The most common treatment-related grade 3–4 adverse events in CAPIRI versus CAPOX patients were diarrhea (32% versus 15%; P = 0.052) and neutropenia (23% versus 6%; P = 0.021).ConclusionCAPOX and CAPIRI had similar efficacy in elderly patients, although CAPOX seemed to be better tolerated.     

Comparison of two different S-1 plus cisplatin dosing schedules as first-line chemotherapy for metastatic and/or recurrent gastric cancer: a multicenter,randomized phase III trial (SOS)

BackgroundFive-weekly S-1 plus cisplatin (SP5) is one of the standard first-line regimens for advanced gastric cancer (GC), proven in a Japanese phase III study. To enhance the dose intensity of cisplatin, 3-weekly S-1 plus cisplatin (SP3) was developed.Patients and methodsThis multicenter, randomized, open-label, phase III study evaluated whether SP3 (S-1 80 mg/m²/day on days 1–14 and cisplatin 60 mg/m² on day 1) was noninferior/superior to SP5 (S-1 80–120 mg/day on days 1–21 and cisplatin 60 mg/m² on day 1 or 8) in terms of progression-free survival (PFS). Chemotherapy-naive patients with metastatic, recurrent gastric or gastroesophageal junction adenocarcinoma were randomized 1 : 1 to receive either SP3 or SP5. The trial is registered at ClinicalTrials.gov (NCT00915382).ResultsBetween February 2009 and January 2012, 625 patients were randomized at 42 sites in Korea and Japan. With a median follow-up duration of 32.4 months (range, 13.3–48.6 months) in surviving patients, SP3 was not only noninferior but also superior to SP5 in terms of PFS [median 5.5 versus 4.9 months; hazard ratio (HR) = 0.82; 95% confidence interval (CI) 0.68–0.99; P = 0.0418 for superiority). There was no difference in overall survival (OS) between the groups (median 14.1 versus 13.9 months; HR = 0.99; 95% CI 0.81–1.21; P = 0.9068). In patients with measurable disease, the response rates were 60% in the SP3 arm and 50% in the SP5 arm (P = 0.065). Both regimens were generally well tolerated, but grade 3 or higher anemia (19% versus 9%) and neutropenia (39% versus 9%) were more frequent in SP3.ConclusionsSP3 is superior to SP5 in terms of PFS. However, since the improvement in PFS was only slight and there was no difference in OS, both SP3 and SP5 can be recommended as first-line treatments for patients with advanced GC.     

Matuzumab plus epirubicin,cisplatin and capecitabine (ECX) compared with epirubicin,cisplatin and capecitabine alone as first-line treatment in patients with advanced oesophago-gastric cancer: a randomised,multicentre open-label phase II study

BackgroundClinical data showed promising antitumour activity with feasible tolerability for matuzumab plus epirubicin, cisplatin and capecitabine (ECX) chemotherapy in untreated advanced oesophago-gastric (OG) cancer. The aim was to evaluate the efficacy of matuzumab plus ECX versus ECX alone.Patients and methodsIn this multicentre, randomised open-label phase II study, 72 patients with metastatic OG cancer were randomly assigned to either 800 mg matuzumab weekly plus epirubicin 50 mg/m², cisplatin 60 mg/m² on day 1 and capecitabine 1250 mg/m² daily in a 21-day cycle (ECX) or the same ECX regimen alone. The primary end point was objective response. Secondary end points included progression-free survival (PFS), overall survival (OS), quality of life, safety and tolerability.ResultsFollowing random assignment, 35 patients (median age 59 years) received ECX/matuzumab and 36 patients (median age 64 years) ECX. The addition of matuzumab to ECX did not improve objective response: 31% for ECX/matuzumab [95% confidence interval (CI) 17–49] compared with 58% for the ECX arm (95% CI 41–74) P = 0.994 (one sided). There was no significant difference in median PFS: 4.8 months (95% CI 2.9–8.1) for ECX/matuzumab versus 7.1 months (95% CI 4.4–8.5) for ECX, or in median OS: 9.4 months (95% CI 7.5–16.2), compared with 12.2 months (95% CI 9.8–13.8 months). Grade 3/4 treatment-related toxicity was observed in 27 and 25 patients in the ECX/matuzumab and ECX groups, respectively.ConclusionMatuzumab 800 mg weekly combined with ECX chemotherapy does not increase response or survival for patients with advanced OG cancer. Therefore, ECX/matuzumab should not be examined further in phase III trials.     

A randomized phase II study of irinotecan plus cisplatin versus irinotecan plus capecitabine with or without isosorbide-5-mononitrate in advanced non-small-cell lung cancer

BackgroundWe investigated the efficacy of irinotecan/cisplatin (IP) versus irinotecan/capecitabine (IX) with or without isosorbide-5-mononitrate (ISMN) in chemo-naïve advanced non-small-cell lung cancer.Patients and methodsInitially, 74 patients were randomly assigned to either IP or IX. Given the potential benefits of ISMN on chemotherapy, the protocol was amended during the study. Subsequently, 72 patients were randomly assigned to either IP + ISMN or IX + ISMN. Patients were treated with predefined second-line therapies (docetaxel/capecitabine for IP or IP + ISMN, docetaxel/cisplatin for IX or IX + ISMN) when disease progressed.ResultsA total of 146 received treatment. Response rate (RR), median progression-free survival (PFS) and overall survival (OS) were 49%, 5.5 months, 14.5 months in IP; 33%, 3.3 months, 13.0 months in IP + ISMN; 30%, 4.3 months, 16.1 months in IX; and 25%, 3.4 months, 13.6 months in IX + ISMN, respectively. While IP arm showed a trend toward higher RR and longer PFS than IX arm, IX arm showed a trend toward longer OS than IP arm. No significant differences were observed between IP + ISMN and IX + ISMN.ConclusionIP showed better RR and PFS but no OS benefit when compared with IX. The addition of ISMN to IP or IX chemotherapy did not seem to improve the treatment outcome.     

Phase II randomized,double-blind,placebo-controlled study of AMG 386 (trebananib) in combination with cisplatin and capecitabine in patients with metastatic gastro-oesophageal cancer

BackgroundWe evaluated AMG 386, an investigational peptibody that neutralizes the interaction between angiopoietins-1 and -2 and the Tie2 receptor, combined with cisplatin/capecitabine (CX) as first-line treatment for metastatic gastro-oesophageal cancer.Patients and MethodsPatients with metastatic gastric, gastro-oesophageal junction, or distal oesophageal adenocarcinoma were randomized 1:1:1 to CX (cisplatin 80 mg/m² IV Q3W; capecitabine 1000 mg/m² P.O. BID for 14 days Q3W) plus intravenous AMG 386 10 mg/kg QW (Arm A) or 3 mg/kg QW (Arm B), or placebo QW (Arm C). The primary end point was estimated progression-free survival (PFS).ResultsA total of 171 patients were enrolled. Median estimated PFS in Arms A, B, and C was 4.2, 4.9, and 5.2 months, respectively (hazard ratio for Arms A+B combined versus Arm C, 0.98; 95% CI 0.67–1.43; P = 0.92). Objective response rates were 27% (Arm A), 43% (Arm B), and 35% (Arm C). Incidence of grade ≥3 adverse events was 80% in Arm A, 84% in Arm B, and 75% in Arm C. There was no evidence of pharmacokinetic interactions.ConclusionsIn this study, PFS and ORR were estimated to be similar with AMG 386 plus CX and placebo plus CX treatment. Compared with placebo, toxicity of AMG 386 plus CX was greater but manageable.Previous presentationThe results of this study have not been previously published or submitted for publication elsewhere. The results were presented in part at the Gastrointestinal Cancers Symposium, San Francisco, CA, January 20–22, 2011.Clinical trial registrationClinicalTrials.gov registration number: NCT00583674     

Efficacy and safety of bevacizumab-based combination regimens in patients with previously untreated metastatic colorectal cancer: Final results from a randomised phase ii study of bevacizumab plus 5-fluorouracil,leucovorin plus irinotecan versus bevacizumab plus capecitabine plus irinotecan (FNCLCC ACCORD 13/0503 study)

BackgroundThe combination of bevacizumab and bolus 5-fluorouracil, leucovorin and irinotecan is highly effective in patients with metastatic colorectal cancer (mCRC). This randomised, multicenter, non-comparative phase II trial assessed the efficacy and safety of bevacizumab plus oral capecitabine plus irinotecan (XELIRI) or infusional 5-fluorouracil, leucovorin plus irinotecan (FOLFIRI) as first-line therapy for patients with mCRC.Patients and MethodsPatients received bevacizumab 7.5 mg/kg on day 1 plus XELIRI (irinotecan 200 mg/m² on day 1 and oral capecitabine 1000 mg/m² bid on days 1–14) every 3 weeks or bevacizumab 5 mg/kg on day 1 plus FOLFIRI (5-fluorouracil 400 mg/m² on day 1 plus 2400 mg/m² as a 46-h infusion, leucovorin 400 mg/m² on day 1, and irinotecan 180 mg/m² on day 1) every 2 weeks. Patients aged ?65 years received a lower dose of capecitabine (800 mg/m² twice daily). The primary endpoint was 6-month progression-free survival (PFS) rate.ResultsA total of 145 patients were enrolled (bevacizumab–XELIRI, n = 72; bevacizumab–FOLFIRI, n = 73). The 6-month PFS rate was 82% (95% confidence intervals (CI) 71–90%) in the bevacizumab–XELIRI arm and 85% (95% CI 75–92%) in the bevacizumab–FOLFIRI arm. In both the bevacizumab–XELIRI and bevacizumab–FOLFIRI arms, median PFS and overall survival (OS) were 9 and 23 months, respectively. The most frequent toxicities were grade 3/4 neutropenia (bevacizumab–XELIRI 18%; bevacizumab–FOLFIRI 26%) and grade 3 diarrhoea (12% and 5%, respectively).ConclusionsThis randomised non-comparative study demonstrates that bevacizumab–XELIRI and bevacizumab–FOLFIRI are effective regimens for the first-line treatment of patients with mCRC with manageable toxicity profiles.