A double-blind,randomised, placebo-controlled,phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer

BackgroundWe conducted a phase 2b, randomised, double-blind, placebo-controlled screening trial to evaluate the addition of the multikinase inhibitor sorafenib (antiproliferative/antiangiogenic) to first-line paclitaxel for human epidermal growth factor receptor 2 (HER2)-negative locally recurrent/metastatic breast cancer.MethodsPatients were randomised to paclitaxel (90 mg/m², weekly, intravenously, 3 weeks on/1 week off) plus sorafenib (400 mg, orally, twice daily) or placebo. The primary endpoint was progression-free survival (PFS). A sample size of 220 patients was planned with relative risk ?0.82 (1-sided α = 0.14) after 120 events supporting a treatment effect.FindingsPatients were randomised in India (n = 170), the United States (n = 52) and Brazil (n = 15). Median PFS was 6.9 months for sorafenib versus 5.6 months for placebo (hazard ratio (HR) = 0.788; 95% confidence interval (CI), 0.558–1.112; P = 0.1715 [1-sided P = 0.0857]). The addition of sorafenib increased time to progression (median, 8.1 versus 5.6 months; HR = 0.674; 95% CI 0.465–0.975; P = 0.0343) and improved overall response (67% versus 54%; P = 0.0468). Overall survival did not statistically differ (median, 16.8 versus 17.4 months; HR = 1.022; 95% CI 0.715–1.461; P = 0.904). Grade 3/4 toxicities (sorafenib versus placebo) included hand-foot skin reaction (31% versus 3%), neutropenia (13% versus 7%) and anaemia (11% versus 6%). Two treatment-related deaths occurred (malaria and liver dysfunction) in the sorafenib arm.InterpretationThe addition of sorafenib to paclitaxel improved disease control but did not significantly improve PFS to support a phase 3 trial of similar design. Toxicity of the combination was manageable with dose reductions.FundingNorthwestern University, Onyx Pharmaceuticals, Bayer Healthcare Pharmaceuticals.     

Transarterial chemoembolization followed by moderately hypofractionated radiotherapy in hepatocellular carcinoma: Long-term results of RTF3 regimen

PurposeIn early-stage hepatocellular carcinoma (HCC) patients merely fit for surgery, transarterial chemoembolization (TACE) achieve low long-term disease control. We evaluated the efficacy and safety of its combination with moderately hypofractionated radiotherapy (hRT) using RTF3 regimen.Material and methodsBetween 2006 and 2016, 61 consecutive patients treated in our single expert center for a Barcelona Clinic Liver Cancer (BCLC) A HCC by TACE followed by hRT 3 Gy/fraction were retrospectively included.ResultsSixty of the 61 included presented Child-Pugh A cirrhosis (A5, n = 41, 67.2%; A6: n = 19, 31.1%). Fourteen patients (22.9%) were already treated for a HCC, mainly by radiofrequency (n = 12). All patient received a TACE followed by 3 Gy per fraction hRT. Mean radiation dose was 54 Gy (range: 48–60). After a median follow-up of 118 months, median time-to-progression, progression-free survival (PFS) and overall survival (OS) was 21.3, 18.1, and 31.5 months, respectively. In univariate analysis, PFS was related to dose > 54 Gy (HR: 2, P = 0.036), and OS was correlated to Child-Pugh A6 or B7 (HR: 1.93, P = 0.03) and overall hRT time (HR: 1.06, P = 0.015). At progression, orthotopic liver transplantation was performed in 8 patients (13.1%). Severe symptomatic adverse events occurred in 12 patients (19.7%), mainly ascites (n = 7).ConclusionIn BCLC-A Child-Pugh A HCC patients ineligible to surgery or thermoablation, TACE-hRT is a safe and effective treatment. Prospective studies are needed to compare this association with radioembolization, TACE-stereotactic radiotherapy, and systemic treatments combinations.     

Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma

BackgroundIn Japan and South Korea, transarterial chemoembolisation (TACE) is an important locoregional treatment for patients with unresectable hepatocellular carcinoma (HCC). Sorafenib, a multikinase inhibitor, has been shown effective and safe in patients with advanced HCC. This phase III trial assessed the efficacy and safety of sorafenib in Japanese and Korean patients with unresectable HCC who responded to TACE.MethodsPatients (n = 458) with unresectable HCC, Child-Pugh class A cirrhosis and ?25% tumour necrosis/shrinkage 1–3 months after 1 or 2 TACE sessions were randomised 1:1 to sorafenib 400 mg bid or placebo and treated until progression/recurrence or unacceptable toxicity. Primary end-point was time to progression/recurrence (TTP). Secondary end-point was overall survival (OS).FindingsBaseline characteristics in the two groups were similar; >50% of patients started sorafenib >9 weeks after TACE. Median TTP in the sorafenib and placebo groups was 5.4 and 3.7 months, respectively (hazard ratio (HR), 0.87; 95% confidence interval (CI), 0.70–1.09; P = 0.252). HR (sorafenib/placebo) for OS was 1.06 (95% CI, 0.69–1.64; P = 0.790). Median daily dose of sorafenib was 386 mg, with 73% of patients having dose reductions and 91% having dose interruptions. Median administration of sorafenib and placebo was 17.1 and 20.1 weeks, respectively. No unexpected adverse events were observed.InterpretationThis trial, conducted prior to the reporting of registrational phase III trials, found that sorafenib did not significantly prolong TTP in patients who responded to TACE. This may have been due to delays in starting sorafenib after TACE and/or low daily sorafenib doses.     

Gemcitabine plus sorafenib versus gemcitabine alone in advanced biliary tract cancer: A double-blind placebo-controlled multicentre phase II AIO study with biomarker and serum programme

BackgroundSince sorafenib has shown activity in different tumour types and gemcitabine regimens improved the outcome for biliary tract cancer (BTC) patients, we evaluated first-line gemcitabine plus sorafenib in a double-blind phase II study.Patients and methods102 unresectable or metastatic BTC patients with histologically proven adenocarcinoma of gallbladder or intrahepatic bile ducts, Eastern Cooperative Oncology Group (ECOG) 0–2 were randomised to gemcitabine (1000 mg/m² once weekly, first 7-weeks + 1-week rest followed by once 3-weeks + 1-week rest) plus sorafenib (400 mg twice daily) or placebo. Treatment continued until progression or unacceptable toxicity. Tumour samples were prospectively stained for sorafenib targets and potential biomarkers. Serum samples (first two cycles) were measured for vascular endothelial growth factors (VEGFs), vascular endothelial growth factor receptor 2 (VEGFR-2) and stromal cell-derived factor 1 (SDF1)α by enzyme-linked immunosorbent assay (ELISA).ResultsGemcitabine plus sorafenib was generally well tolerated. Four and three patients achieved partial responses in the sorafenib and placebo groups, respectively. There was no difference in the primary end-point, median progression-free survival (PFS) for gemcitabine plus sorafenib versus gemcitabine plus placebo (3.0 versus 4.9 months, P = 0.859), and no difference for median overall survival (OS) (8.4 versus 11.2 months, P = 0.775). Patients with liver metastasis after resection of primary BTC survived longer with sorafenib (P = 0.019) compared to placebo. Patients who developed hand-foot syndrome (HFS) showed longer PFS and OS than patients without HFS. Two sorafenib targets, VEGFR-2 and c-kit, were not expressed in BTC samples. VEGFR-3 and Hif1α were associated with lymph node metastases and T stage. Absence of PDGFRβ expression correlated with longer PFS.ConclusionThe addition of sorafenib to gemcitabine did not demonstrate improved efficacy in advanced BTC patients. Biomarker subgroup analysis suggested that some patients might benefit from combined treatment.     

Hepatic resection for hepatocellular carcinoma exceeding Milan criteria

BackgroundMany hepatocellular carcinomas (HCCs) are discovered at an advanced stage. The efficacy of transplantation for such tumors is doubtable. The aim of this retrospective study was to determine liver resection efficacy in patients with large HCC regarding long term and disease- free survival.MethodsBetween 2002 and 2008, sixty six patients with large HCC (>5 cm) underwent hepatectomy. Fifty nine patients had background cirrhosis due to hepatitis B, C or other reason and preserved liver function (Child A). Liver function was assessed by both Child's–Pugh grading and MELD score. Conventional approach of liver resection was performed in most cases.ResultsThe 5-year overall survival was 32% with a median follow up of 33 months. The three year disease-free survival was 33% in our cohort. On multivariate analysis, only tumor size and grade remained independent predictors of adverse long term outcome. Multivariate analysis identified size of the primary tumour and degree of differentiation as risk factors for recurrence. Median blood loss was 540 ml and median transfusion requirements were two units of pack red blood cells. Morbidity included pleural effusion (n = 18), biliary fistula (n = 4), peri-hepatic abscess (n = 4), hyperbilirubinemia (n = 3), pneumonia (n = 5) and wound infection (n = 6). No peri-operative mortality was reported in our study.ConclusionPartial hepatectomy is safe in selective patients with large HCC. Surgical resection if feasible is suggested in patients with large HCC because it prolongs both overall and disease-free survival with low morbidity.     

Regorafenib plus modified FOLFOX6 as first-line treatment of metastatic colorectal cancer: A phase II trial

BackgroundThe oral multikinase inhibitor regorafenib improves overall survival (OS) in patients with metastatic colorectal cancer (CRC) for which all standard treatments have failed. This study investigated regorafenib plus modified FOLFOX (mFOLFOX6) as first-line treatment of metastatic CRC.MethodsIn this single-arm, open-label, multicentre, phase II study, patients received mFOLFOX6 on days 1 and 15, and regorafenib 160 mg orally once daily on days 4–10 and 18–24 of each 28-day cycle. The primary end-point was centrally assessed objective response rate (ORR). Secondary end-points included disease control rate (DCR), OS, progression-free survival (PFS) and safety.ResultsMedian overall treatment duration with any study drug was 9.9 months (range 0.6–19.6); median treatment duration with regorafenib was 7.7 months (range 0.1–19.5); six patients remained on regorafenib for more than 1 year. Fifty-three patients received at least one dose of regorafenib. ORR was 43.9% (all partial responses); DCR was 85.4%; median OS was not reached; median PFS was 8.5 months. Treatment-emergent adverse events were experienced by all patients but were manageable with dose modifications.ConclusionRegorafenib + mFOLFOX6 as first-line treatment in patients with metastatic CRC did not improve ORR over historical controls. Regorafenib plus mFOLFOX6 did not appear to be associated with a markedly worse tolerability profile versus mFOLFOX6 alone.ClinicalTrials.gov identifier: NCT01289821.     

Nintedanib for the treatment of patients with refractory metastatic colorectal cancer (LUME-Colon 1): a phase III,international, randomized,placebo-controlled study

BackgroundAngiogenesis is critical to colorectal cancer (CRC) growth and metastasis. Phase I/II studies have demonstrated the efficacy of nintedanib, a triple angiokinase inhibitor, in patients with metastatic CRC. This global, randomized, phase III study investigated the efficacy and safety of nintedanib in patients with refractory CRC after failure of standard therapies.Patients and methodsEligible patients (Eastern Cooperative Oncology Group performance status 0–1, with histologically/cytologically confirmed metastatic/locally advanced CRC adenocarcinoma unamenable to surgery and/or radiotherapy) were randomized 1 : 1 to receive nintedanib (200 mg twice daily) or placebo (twice daily), until disease progression or undue toxicity. Patients were stratified by previous regorafenib, time from onset of metastatic disease to randomization, and region. Co-primary end points were overall survival (OS) and progression-free survival (PFS) by central review. Secondary end points included objective tumor response and disease control by central review.ResultsFrom October 2014 to January 2016, 768 patients were randomized; 765 were treated (nintedanib n = 384; placebo n = 381). Median follow-up was 13.4 months (interquartile range 11.1–15.7). OS was not improved [median OS 6.4 months with nintedanib versus 6.0 months with placebo; hazard ratio (HR), 1.01; 95% confidence interval (CI), 0.86–1.19; P = 0.8659]. There was a significant but modest increase in PFS with nintedanib versus placebo (median PFS 1.5 versus 1.4 months, respectively; HR 0.58; 95% CI 0.49–0.69; P < 0.0001). There were no complete or partial responses. Adverse events (AEs) occurred in 97% of 384 nintedanib-treated patients and 93% of 381 placebo-treated patients. The most frequent grade ≥3 AEs were liver-related AEs (nintedanib 16%; placebo 8%) and fatigue (nintedanib 9%; placebo 6%).ConclusionsThe study failed to meet both co-primary end points. Nintedanib did not improve OS and was associated with a significant but modest increase in PFS versus placebo. Nintedanib was well tolerated.ClinicalTrials.gov numberNCT02149108 (LUME-Colon 1).     

An open-label,phase 2 study evaluating the efficacy and safety of the anti-IGF-1R antibody cixutumumab in patients with previously treated advanced or metastatic soft-tissue sarcoma or Ewing family of tumours

BackgroundCixutumumab (IMC-A12), a fully human immunoglobulin G1 (IgG1) monoclonal antibody, exerts preclinical activity in several sarcoma models and may be effective for the treatment of these tumours.MethodsIn this open-label, multicentre, phase 2 study, patients with previously treated advanced or metastatic rhabdomyosarcoma, leiomyosarcoma, adipocytic sarcoma, synovial sarcoma or Ewing family of tumours received intravenous cixutumumab (10 mg/kg) for 1 h every other week until disease progression or discontinuation. The primary end-point was the progression-free survival rate (PFR), defined as stable disease or better at 12 weeks. In each tier of disease histology, Simon’s optimum 2-stage design was applied (PFR at 12 weeks P0 = 20%, P1 = 40%, α = 0.10, β = 0.10). Stage 1 enrolled 17 patients in each disease group/tier, with at least four patients with stable disease or better required at 12 weeks to proceed to stage 2.ResultsA total of 113 patients were enrolled; all tiers except adipocytic sarcoma were closed after stage 1 due to futility. The 12-week PFR was 12% for rhabdomyosarcoma (n = 17), 14% for leiomyosarcoma (n = 22), 32% for adipocytic sarcoma (n = 37), 18% for synovial sarcoma (n = 17) and 11% for Ewing family of tumours (n = 18). Median progression-free survival (weeks) was 6.1 for rhabdomyosarcoma, 6.0 for leiomyosarcoma, 12.1 for adipocytic sarcoma, 6.4 for synovial sarcoma and 6.4 for Ewing family of tumours. Among all patients, the most frequent treatment-emergent adverse events (AEs) were nausea (26%), fatigue (23%), diarrhoea (23%) and hyperglycaemia (20%).ConclusionsPatients with adipocytic sarcoma may benefit from treatment with cixutumumab. Cixutumumab treatment was well tolerated, with limited gastrointestinal AEs, fatigue and hyperglycaemia.     

Sorafenib plus hepatic arterial infusion chemotherapy with cisplatin versus sorafenib for advanced hepatocellular carcinoma: randomized phase II trial

BackgroundSorafenib (Sor) is acknowledged as a standard therapy for advanced hepatocellular carcinoma (HCC). This trial was conducted to evaluate the effect of addition of hepatic arterial infusion chemotherapy with cisplatin (SorCDDP) to Sor for the treatment of advanced HCC.Patients and methodsWe conducted a multicenter open-labeled randomized phase II trial in chemo-naïve patients with advanced HCC with Child-Pugh scores of 5–7. Eligible patients were randomly assigned 2:1 to receive SorCDDP (sorafenib: 400 mg bid; cisplatin: 65 mg/m², day 1, every 4–6 weeks) or Sor (400 mg bid). The primary end point was overall survival.ResultsA total of 108 patients were randomized (Sor, n = 42; SorCDDP, n = 66). The median survival in the Sor and SorCDDP arms were 8.7 and 10.6 months, respectively [stratified hazard ratio (95% confidence interval), 0.60 (0.38–0.96), P = 0.031]. The median time to progression and the response rate were, respectively, 2.8 months and 7.3% in the Sor arm and 3.1 months and 21.7% in the SorCDDP arm. The adverse events were more frequent in the SorCDDP arm than in the Sor arm, but well-tolerated.ConclusionSorCDDP yielded favorable overall survival when compared with Sor in patients with advanced HCC.Clinical Trial registrationUMIN-CTR (http://www.umin.ac.jp/ctr/index-j.htm), identification number: UMIN000005703.     

A randomised,open-label phase II trial of afatinib versus cetuximab in patients with metastatic colorectal cancer

PurposeThis randomised phase II trial aimed to compare efficacy of the irreversible ErbB family blocker, afatinib, with cetuximab in patients with KRAS wild-type metastatic colorectal adenocarcinoma (mCRC) with progression following oxaliplatin- and irinotecan-based regimens. Efficacy in patients with KRAS mutations was also evaluated.Patients and methodsPatients with KRAS wild-type tumours were randomised 2:1 to afatinib (40 mg/day, increasing to 50 mg/day if minimal toxicity) or cetuximab weekly (400 mg/m² loading dose, then 250 mg/m²/week) according to number of previous chemotherapy lines. All patients with KRAS-mutated tumours received afatinib. Primary end-points were objective response (OR) for the wild-type group and disease control for the KRAS-mutated group. Secondary end-points were progression-free survival (PFS) and overall survival (OS).ResultsPatients with KRAS wild-type tumours (n = 50) received afatinib (n = 36) or cetuximab (n = 14). Unconfirmed and confirmed ORs were 3% and 0% for afatinib versus 20% and 13% for cetuximab (odds ratio: 0.122 [P = 0.0735] and <0.001, respectively). Median PFS was 46.0 and 144.5 days for afatinib and cetuximab, respectively. Median OS was 355 days with afatinib but not reached for cetuximab. In the KRAS-mutated group (n = 41), five (12%) patients achieved confirmed disease control (stable disease; P = 0.6394 [comparison versus 10%]); no ORs were reported. Median PFS and OS were 41.0 and 173 days, respectively. Most frequent treatment-related adverse events were diarrhoea and rash across groups.ConclusionsThe efficacy of afatinib was inferior to cetuximab in patients with KRAS wild-type mCRC. In patients with KRAS-mutated tumours, disease control was modest with afatinib. Afatinib had a manageable safety profile.     

A phase 1b,open-label study of trebananib in combination with paclitaxel and carboplatin in patients with ovarian cancer receiving interval or primary debulking surgery

AimTo evaluate the tolerability, pharmacokinetics and tumour response of first-line trebananib plus paclitaxel and carboplatin followed by trebananib maintenance in high-risk or advanced ovarian cancer.MethodsIn this open-label phase 1b study, patients received intravenous (IV) trebananib 15 mg/kg administered weekly (QW) plus paclitaxel 175 mg/m² once every 3 weeks (Q3W) and carboplatin 6 mg/mL·min Q3W followed by trebananib 15 mg/kg QW monotherapy for 18 months. End-points were dose-limiting toxicities (DLTs; primary); treatment-emergent adverse events (AEs), anti-trebananib antibodies, pharmacokinetics and tumour response (secondary).ResultsTwenty seven patients (interval debulking surgery [IDS], n = 13) were enrolled. No DLTs occurred. During the combination therapy phase, AEs (>50%) in patients with IDS were nausea, diarrhoea, fatigue, decreased appetite and thrombocytopenia. In patients with primary debulking surgery (PDS), they were nausea, diarrhoea, fatigue and localised oedema. Grade 4 AEs were neutropenia (IDS, PDS; all n = 3) and thrombocytopenia (IDS, PDS; all n = 1). No deaths occurred. Toxicity results pertaining to trebananib maintenance were immature. The treatment combination did not markedly affect the pharmacokinetics across agents. In patients with IDS (n = 14 after one patient was reassigned from PDS to IDS), 12 patients had a partial response (PR), two patients had stable disease. In patients with PDS (n = 4), three patients had a complete response, one patient had a PR.ConclusionsIn women with ovarian cancer receiving IDS or PDS, IV trebananib 15 mg/kg QW plus paclitaxel and carboplatin appears tolerable. Results suggest that the treatment combination followed by trebananib 15 mg/kg monotherapy is associated with antitumour activity.     

Maintenance pazopanib versus placebo in Non-Small Cell Lung Cancer patients non-progressive after first line chemotherapy: A double blind randomised phase III study of the lung cancer group,EORTC 08092 (EudraCT: 2010-018566-23, NCT01208064)

BackgroundSwitch maintenance is an effective strategy in the treatment of advanced Non-Small Cell Lung Cancer (NSCLC). Pazopanib is an oral, multi-targeted tyrosine kinase inhibitor (TKI). EORTC 08092 evaluated pazopanib given as maintenance treatment following standard first line platinum-based chemotherapy in patients with advanced NSCLC.MethodsPatients with non-progressive disease after 4–6 cycles of chemotherapy were randomised to receive either pazopanib 800 mg/day or matched placebo until progression or unacceptable toxicity. The primary end-point was overall survival and secondary end-points were progression-free survival (PFS) and safety.ResultsA total of 600 patients were planned to be randomised. The trial was prematurely stopped following an early interim analysis, after 102 patients were randomised to pazopanib (n = 50) or placebo (n = 52). Median age was 64 years in both arms. Median overall survival was 17.4 months for pazopanib and 12.3 months for placebo (adjusted hazard ratio (HR) 0.72 [95% confidence interval (CI) 0.40–1.28]; p = 0.257). Median PFS was 4.3 months versus 3.2 months (HR 0.67, [95% CI 0.43–1.03], p = 0.068). PFS rates at 4 months were 56% and 45% respectively. The majority of treatment-related adverse events (AEs) were grade 1–2. Grade 3–4 AEs (pazopanib versus placebo) were hypertension (38% versus 8%), neutropenia (8% versus 0%), and elevated SGPT (6% versus 0%). Of the patients randomised to pazopanib, 22% withdrew due to a treatment-related AE.ConclusionsSwitch maintenance with pazopanib following platinum-based chemotherapy in advanced NSCLC patients had limited side-effects. This study was stopped due to lack of efficacy by stringent criteria for PFS at a futility interim analysis.     

Phase IIa study of the CD19 antibody MOR208 in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma

BackgroundThis two-stage, phase IIa study investigated the antitumor activity and safety of MOR208, an Fc-engineered, humanized, CD19 antibody, in patients with relapsed or refractory (R-R) B-cell non-Hodgkin’s lymphoma (NHL). CD19 is broadly expressed across the B-lymphocyte lineage, including in B-cell malignancies, but not by hematological stem cells.Patients and methodsPatients aged ≥18 years, with R-R NHL progressing after ≥1 prior rituximab-containing regimen were enrolled into subtype-specific cohorts: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), other indolent (i)NHL and mantle cell lymphoma (MCL). Treatment was MOR208, 12 mg/kg intravenously, weekly, for 8 weeks. Patients with at least stable disease could continue treatment for an additional 4 weeks. Those with a partial or complete response after 12 weeks could receive extended MOR208 treatment (12 mg/kg, either monthly or every second week) until progression. The primary end point was overall response rate.ResultsNinety-two patients were enrolled: DLBCL (n = 35), FL (n = 34), other iNHL (n = 11) and MCL (n = 12). Responses were observed in DLBCL, FL and other iNHL cohorts (26%, 29% and 27%, respectively). They lasted ≥12 months in 5/9 responding patients with DLBCL, 4/9 with FL and 2/3 with other iNHL. Responses in nine patients are ongoing (>26 months in five instances). Patients with rituximab refractory disease showed a similar response rate and progression-free survival time to patients with non-refractory disease. The most common adverse events (any grade) were infusion-related reactions (12%) and neutropenia (12%). One patient experienced a grade 4 infusion-related reaction and eight patients (9%) experienced grade 3/4 neutropenia. No treatment-related deaths were reported.ConclusionsMOR208 monotherapy demonstrated promising clinical activity in patients with R-R DLBCL and R-R FL, including in patients with rituximab refractory tumors. These efficacy data and the favorable safety profile support further investigation of MOR208 in phase II/III combination therapy trials in R-R DLBCL.ClinicalTrials.gov numberNCT01685008.     

Systematic review and meta-analysis of randomised,phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer

BackgroundPrevious studies have demonstrated the efficacy and safety of bevacizumab in the treatment of non-small-cell lung cancer (NSCLC).MethodsSummary data from randomised trials comparing first-line bevacizumab plus platinum-based chemotherapy with chemotherapy alone for inoperable locally advanced, recurrent or metastatic NSCLC were meta-analysed. Pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and pooled odds ratio (OR) for adverse events were calculated. The chi-squared tests evaluated interactions between treatment effects, and prognostic factors and patient characteristics.ResultsData of 2194 patients (1313 bevacizumab; 881 controls) from four phase II and III trials: AVF-0757g, JO19907, ECOG 4599 and AVAiL, were analysed. Compared with chemotherapy alone, bevacizumab significantly prolonged OS (HR 0.90; 95% confidence interval [CI] 0.81, 0.99; P = 0.03), and PFS (0.72; 95% CI 0.66, 0.79; P < 0.001). Bevacizumab showed a significantly greater effect on OS in patients with adenocarcinoma versus other histologies (P = 0.02), and patients with body weight loss ≤5% versus >5% (P = 0.03). Bevacizumab significantly increased the risk of grade ≥3 proteinuria, hypertension, haemorrhagic events, neutropenia, and febrile neutropenia.ConclusionsBevacizumab significantly prolonged OS and PFS when added to first-line platinum-based chemotherapy in patients with advanced NSCLC; no unexpected toxicity was evident.     

Sorafenib for Egyptian patients with advanced hepatocellular carcinoma; single center experience

BackgroundAccording to the results of a number of phase 3 randomized studies, sorafenib is the only approved systemic therapy for advanced HCC; however the issue of high economic cost remains challenging; thus we have conducted this retrospective analysis of our HCC patients treated with sorafenib.MethodsHCC patients treated at Ain Shams University Hospitals, in the period between 2010 and 2012 were reviewed. Eligible patients were those who had received sorafenib for advanced HCC not eligible for or progressed after surgery or locoregional therapy. We investigated the impact of baseline clinicopathological factors (age, gender, child status, performance score, BCLC tumor stage, cause of chronic liver disease, median baseline alpha fetoprotein level and previous treatment received for HCC) on overall survival (OS) in an adjusted Cox regression model.Results41 patients were included in the analysis fulfilling the inclusion criteria. At a median follow up period of 13 months, the median PFS for the whole group was 4 months; the median OS for the whole group is 6.25 months. Multivariate analysis identified three baseline characteristics that were prognostic indicators for overall survival: ECOG performance status (median OS for ECOG 1 = 7.01 months and for ECOG 2 = 3.03 months), Child–Pugh status (median OS for child A = 12.04 months and for child B = 5.23 months), and median baseline levels of alpha-fetoprotein.ConclusionsIn limited resource countries like Egypt, we suggest that the use of sorafenib for the treatment of advanced HCC cases should be restricted to a highly selected subgroup of patients with good performance and child A.     

Statins and survival outcomes in patients with metastatic renal cell carcinoma

BackgroundA growing body of evidence has demonstrated the anti-neoplastic activity of statins. The objective of this study was to investigate the effect of statin use on survival in patients with metastatic renal cell carcinoma (mRCC) treated in the modern therapy era.Patients and methodsWe conducted a pooled analysis of mRCC patients treated on phase II and III clinical trials. Statistical analyses were performed using Cox regression and the Kaplan–Meier method.ResultsWe identified 4736 patients treated with sunitinib (n = 1059), sorafenib (n = 772), axitinib (n = 896), temsirolimus (n = 457), temsirolimus + interferon (IFN)-α (n = 208), bevacizumab + temsirolimus (n = 393), bevacizumab + IFN-α (n = 391) or IFN-α (n = 560), of whom 511 were statin users. Overall, statin users demonstrated an improved overall survival (OS) compared to non-users (25.6 versus 18.9 months, adjusted hazard ratio [aHR] 0.801, 95% confidence interval [CI] 0.659–0.972, p = 0.025). When stratified by therapy type, a benefit in OS was demonstrated in statin users compared to non-users in individuals receiving therapy targeting vascular endothelial growth factor (28.4 versus 22.2 months, aHR 0.749, 95% CI 0.584–0.961, p = 0.023) or mammalian target of rapamycin (18.6 versus 14.0 months, aHR 0.657, 95% CI 0.445–0.972, p = 0.035) but not in those receiving IFN-α (15.6 versus 14.8 months, aHR 1.292, 95% CI 0.703–2.275, p = 0.410). Adverse events were similar between users and non-users.ConclusionsWe demonstrate that statin use may be associated with improved survival in patients with mRCC treated in the targeted therapy era. Statins could represent an adjunct therapy for patients with mRCC; however, this is hypothesis generating and requires prospective evaluation.     

Phase I study of the HER3-targeted antibody patritumab (U3-1287) combined with erlotinib in Japanese patients with non-small cell lung cancer

ObjectivesHuman epidermal growth factor receptor 3 (HER3) is a key dimerization partner for HER family members and is associated with resistance to other HER family receptor-targeted therapeutics. This study evaluated the safety, tolerability, pharmacokinetics and efficacy of patritumab (U3-1287), a fully human anti-HER3 monoclonal antibody, in combination with erlotinib, an epidermal growth factor receptor-tyrosine kinase inhibitor in patients with previously treated advanced non-small cell lung cancer (NSCLC).Patients and methodsThis study enrolled patients with stage IIIB/IV NSCLC with Eastern Cooperative Oncology Group performance status 0–1, life expectancy >3 months and who had progressed after at least one prior course of chemotherapy (excluding erlotinib). This open-label study included two parts: dose escalation (Part 1) and dose expansion (Part 2). In Part 1, patients received intravenous patritumab 9 or 18 mg/kg every 3 weeks in addition to per-oral erlotinib 150 mg/day daily. In Part 2, patients received the recommended dose of patritumab as determined in Part 1. Adverse event rates, pharmacokinetics and tumor responses were determined.ResultsTwenty-four Japanese patients received patritumab at 9 mg/kg (n = 3) or 18 mg/kg (n = 21), and erlotinib. No dose-limiting toxicities were reported, indicating the maximum-tolerated dose was not reached. The most frequent adverse events were gastrointestinal or skin toxicities, which were generally mild and manageable. Patritumab pharmacokinetics were similar to those reported in previous studies. The median progression-free survival (95% confidence interval) was 44.0 (22.0–133.0) days for the EGFR wild-type group (n = 9) and 107.0 (74.0–224.0) days for the EGFR-activating mutation group (n = 13). Evaluation of biomarkers by immunohistochemical analysis did not indicate a relationship between efficacy and HER3 expression in tumor tissues.ConclusionPatritumab in combination with erlotinib was well tolerated and the efficacy of the combination was encouraging, especially in patients where prior gefitinib treatment failed.     

Comparison of RECIST and Choi criteria for computed tomographic response evaluation in patients with advanced gastrointestinal stromal tumor treated with sunitinib

BackgroundControversies exist about computed tomography (CT) response evaluation criteria for patients with gastrointestinal stromal tumor (GIST).Patients and methodsFifty-one patients with advanced GIST treated second line with sunitinib were evaluated with contrast-enhanced CT every 3 months. Response was rated according to RECIST and Choi criteria. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan–Meier analysis.ResultsAccording to RECIST, patients were categorized as complete response (CR; n = 0; 0%), partial remission (PR; n = 1; 2.0%), stable disease (SD; n = 37; 72.5%), and progressive disease (PD; n = 13; 25.5%) at 3 months. When Choi criteria were applied responses were CR (n = 0; 0%), PR (n = 16; 31.4%), SD (n = 21; 41.1%), and PD (n = 14; 27.5%). Despite these discrepancies, patients rated as SD with RECIST and PR as well as SD according to Choi criteria displayed similar PFS (41.3, 40.7, and 41.3 weeks, respectively) and OS (100.4, 91.6, and 108.0 weeks, respectively). Patients with PD had significantly shorter PFS (10.1 weeks for both criteria) and OS (29.1 weeks for RECIST; 28.9 weeks for Choi) regardless of the response classification applied.ConclusionIn contrast to absence of progression, discrimination of PR from SD with Choi criteria was of no predictive value.     

Bortezomib in combination with CHOP as first-line treatment for patients with stage III/IV peripheral T-cell lymphomas: A multicentre,single-arm,phase 2 trial

BackgroundWe performed a phase II study to evaluate the efficacy of bortezomib in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) as first-line treatment for patients with stage III/IV peripheral T-cell lymphomas (PTCLs) based on our phase I study results.MethodsPatients received bortezomib on days 1 and 8 at a dose of 1.6 mg/m² in addition to CHOP every 3 weeks for a total of six cycles.ResultsForty-six patients were enrolled: PTCL, not otherwise specified (PTCL-NOS, n = 16), extranodal NK/T-cell lymphoma, nasal type (ENKTL, n = 10), angioimmunoblastic T-cell lymphoma (AITL, n = 8), ALK-negative anaplastic large-cell lymphoma (ALCL, n = 6), cutaneous T-cell lymphoma (CTCL, n = 5) and hepatosplenic T-cell lymphoma (n = 1). Thirty patients achieved complete response (CR, 65%) and the overall response rate was 76% (35/46). Although the CR rate of ENKTL was only 30% (3/10), three subtypes of PTCLs (PTCL-NOS, AITL and ALCL) showed 87% of overall response rate (ORR) (26/30) and 73% of CR rate (22/30). However, the 3-year overall survival and progression-free survival were 47% and 35%, respectively due to frequent relapse after remission. Grade 3/4 leucopenia was the most frequent toxicity whereas neurotoxicity was tolerable: grade 1 or 2 of peripheral neuropathy.ConclusionsThe combined treatment of bortezomib and CHOP is an effective and feasible regimen for advanced-stage PTCLs other than ENKTL, with acceptable toxicity. However, future studies exploring new drug combinations are warranted to overcome relapse after remission.     

A randomised,double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: Final overall survival results and safety update

BackgroundIn this randomised phase III study (VEG105192; NCT00334282), pazopanib previously demonstrated statistically and clinically meaningful improvement of progression-free survival versus placebo in patients with advanced/metastatic renal cell carcinoma (mRCC). Final overall survival (OS) and updated safety results are now reported.MethodsTreatment-naive or cytokine-pretreated mRCC patients (n = 435) stratified and randomised (2:1) to pazopanib 800 mg daily or placebo, were treated until disease progression, death or unacceptable toxicity. Upon progression, placebo patients could receive pazopanib through an open-label study. Final OS in the intent-to-treat population was analysed using a stratified log-rank test. Rank-preserving structural failure time (RPSFT) and inverse probability of censoring weighted (IPCW) analyses were performed post-hoc to adjust for crossover.FindingsThe difference in final OS between pazopanib- and placebo-treated patients was not statistically significant (22.9 versus 20.5 months, respectively; hazard ratio [HR] = 0.91; 95% confidence interval [CI], 0.71–1.16; one-sided P = .224). Early and frequent crossover from placebo to pazopanib and prolonged duration of crossover treatment confounded the OS analysis. In IPCW analyses, pazopanib decreased mortality (HR = 0.504; 95% CI, 0.315–0.762; two-sided P = .002). Similar, albeit non-significant, results were obtained in RPSFT analyses (HR = 0.43; 95% CI, 0.215–1.388; two-sided P = .172). Since the last cutoff, cumulative exposure to pazopanib increased by 30%. The pazopanib safety profile showed no new safety signals or changes in the type, frequency and severity of adverse events.InterpretationAlthough no significant difference in OS was observed in this study, extensive crossover from placebo to pazopanib confounded final OS analysis. Post-hoc analyses adjusting for crossover suggest OS benefit with pazopanib treatment for mRCC patients.