Optimisation of the tumour response threshold in patients treated with everolimus for metastatic renal cell carcinoma: analysis of response and progression-free survival in the RECORD-1 study

Background and objectivesObjective response as determined by Response Evaluation Criteria in Solid Tumors (RECIST) is low among patients with metastatic renal cell carcinoma (mRCC) treated with targeted agents, despite significantly improved progression-free survival (PFS). A modified response threshold may be more clinically meaningful than RECIST for identifying patients who may derive a PFS benefit from targeted therapy.Patients and methodsWe performed a retrospective analysis of data from the phase III RECORD-1 trial of everolimus versus placebo in patients with mRCC who had failed sunitinib or sorafenib (ClinicalTrials.gov identifier: NCT00410124). A series of tumour response thresholds, defined by the best change in the sum of the longest tumour diameters (ΔSLD) of target lesions, was evaluated to distinguish ‘responders’ from ‘non-responders’ with respect to significant improvement in PFS.ResultsThe optimal threshold for determining a response to everolimus was −5% ΔSLD. At this threshold, median PFS was 8.4 months in responders and 5.0 months in non-responders (hazard ratio [HR] 2.4, 95% confidence interval [CI] 1.6–3.7).ConclusionIn patients who have failed vascular endothelial growth factor receptor–tyrosine kinase inhibitor (VEGFr-TKI) therapy, everolimus affords superior PFS to placebo, regardless of change in tumour burden. However, a ⩾5% reduction in SLD is a better predictor of PFS benefit than the classical ⩾30% reduction used with RECIST.     

To predict progression-free survival and overall survival in metastatic renal cancer treated with sorafenib: pilot study using dynamic contrast-enhanced Doppler ultrasound

IntroductionThe objective of this study was to evaluate dynamic contrast-enhanced Doppler ultrasound (DCE-US) with perfusion software (Vascular Recognition Imaging) and contrast agent injection as a predictor of tumour response, progression-free survival (PFS) and overall survival (OS).Patients and methodsThirty patients with a metastatic renal cell carcinoma (RCC) already enrolled in a double-blind randomised study were evaluated. Examinations were performed at baseline, and after 3 and 6 weeks on sorafenib or a placebo in patients with tumour targets that were accessible to DCE-US.ResultsA total of 85 examinations were performed, 30 at baseline, 28 at 3 weeks and 27 at 6 weeks. The combination of a decrease in contrast uptake exceeding 10% and stability or a decrease in tumour volume allowed us to discriminate seven good responders and 20 poor responders at 3 weeks. There was a statistically significant difference in PFS (p = 10⁻⁴) and OS (p = 10⁻⁴) between good and poor responders.ConclusionDCE-US is a new noninvasive imaging technique which might be an effective tool for evaluating antiangiogenic drugs in renal cancer.     

Cediranib monotherapy in patients with advanced renal cell carcinoma: results of a randomised phase II study

BackgroundCediranib is a highly potent vascular endothelial growth factor (VEGF) signalling inhibitor with activity against VEGF receptors 1, 2 and 3. This Phase II, randomised, double-blind, parallel-group study compared the efficacy of cediranib with placebo in patients with metastatic or recurrent clear cell renal cell carcinoma who had not previously received a VEGF signalling inhibitor.MethodsPatients were randomised (3:1) to cediranib 45 mg/day or placebo. The primary objective was comparison of change from baseline in tumour size after 12 weeks of therapy. Secondary objectives included response rate and duration, progression-free survival (PFS) and safety and tolerability. Patients in the placebo group could cross over to open-label cediranib at 12 weeks or earlier if their disease had progressed. This study has been completed and is registered with ClinicalTrials.gov, number NCT00423332.FindingsPatients (n = 71) were randomised to receive cediranib (n = 53) or placebo (n = 18). The primary study outcome revealed that, after 12 weeks of therapy, there was a significant difference in mean percentage change from baseline in tumour size between the cediranib (–20%) and placebo (+20%) arms (p < 0.0001). Eighteen patients (34%) on cediranib achieved a partial response and 25 (47%) experienced stable disease. Cediranib treatment prolonged PFS significantly compared with placebo (hazard ratio (HR) = 0.45, 90% confidence interval: 0.26–0.76, p = 0.017; median PFS 12.1 versus 2.8 months). The most common adverse events in patients receiving cediranib were diarrhoea (74%), hypertension (64%), fatigue (58%) and dysphonia (58%).InterpretationCediranib monotherapy demonstrated significant evidence of antitumour activity in patients with advanced renal cell carcinoma. The adverse event profile was consistent with previous studies of cediranib 45 mg.     

Prostate-specific antigen flare induced by cabazitaxel-based chemotherapy in patients with metastatic castration-resistant prostate cancer

BackgroundA prostate-specific antigen (PSA) flare occurs in about 15% of metastatic castration-resistant prostate cancer (mCRPC) patients receiving docetaxel. This flare has no standard definition. Its impact on treatment efficacy is unclear. We sought to evaluate the incidence and characteristics of PSA flare on cabazitaxel, and its impact on survival.MethodsMulticentre retrospective review of consecutive patients treated with cabazitaxel second-line chemotherapy for mCRPC. Collection of baseline characteristics, disease history and PSA levels before and during cabazitaxel therapy. Overall survival (OS) and radiological/clinical progression-free survival (PFS) for patient groups corresponding to different definitions of PSA flare estimated by the Kaplan–Meier method and compared using the log-rank test.ResultsOverall, 125 patients were included. Median PFS and OS were 6.5 and 13.3 months, respectively. Depending upon the definition used, flare incidence ranged from 8.3% to 30.6%. The flare lasted <2.6 months. A PSA flare followed by a ⩾50% decrease was associated with a median PFS and OS of 11.2 and 25.2 months, respectively. Median PFS and OS for a ⩾30% rather than ⩾50% decrease were 10.4 and 16.5 months. These outcomes were not significantly different from those in patients with immediate PSA decreases of ⩾50% or ⩾30% from baseline, but were significantly better than in patients experiencing no PSA decrease (p = 0.006 and 0.015, respectively, for OS).ConclusionThe PSA response to cabazitaxel, with or without initial flare, was associated with a strong survival benefit. The taxane-induced flare during the first 12 weeks of therapy can be ignored when evaluating PSA response.     

A phase II trial of second-line pemetrexed in adults with advanced/metastatic osteosarcoma

BackgroundOsteosarcoma is the most common primary malignant tumour in young adults. An effective treatment strategy for relapsed patients is still not defined. Pemetrexed is a multitargeted antifolate with a mode of action similar to, and a range of action broader than that of methotrexate. The primary objective of this phase II study was to determine tumour response rate in patients with high-grade, advanced/metastatic osteosarcoma. Secondary end-points included progression-free survival (PFS), overall survival (OS) and safety.MethodsPemetrexed 500 mg/m² was administered on day 1 of 21-day cycles with folic acid and vitamin B₁₂ supplementation. At least 5 tumour responses in a targeted population of 32 were required to consider further investigation.ResultsThirty-two patients (median age, 43.3 years; range, 18.6–76.0) with 1 prior chemotherapy regimen for high-grade advanced/metastatic osteosarcoma were enrolled. Thirty (93.8%) patients had an ECOG performance status ⩽1 and 29 (90.6%) had metastases in the lung. One patient had partial response (3.1%) and 5 (15.6%) had stable disease. Median PFS and OS were 1.4 months (95% CI: 1.4–1.7) and 5.5 months (95% CI: 2.3–10.5), respectively. The most common drug-related grade 3/4 toxicities were leukopaenia, asthaenia and elevated alanine aminotransferase in 3 (9.4%) patients each. One patient died due to multi-organ failure considered possibly related to the study drug.ConclusionsPemetrexed 500 mg/m² administered on day 1 of 21-day cycles as second-line treatment to patients with advanced/metastatic high-grade osteosarcoma was generally well tolerated but did not meet minimal response expectations for further investigation in this patient population.     

Everolimus in metastatic renal cell carcinoma: Subgroup analysis of patients with 1 or 2 previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies enrolled in the phase III RECORD-1 study

IntroductionIn the phase III RECORD-1 trial (ClinicalTrials.gov: NCT00410124), patients with metastatic renal cell carcinoma (mRCC) who progressed on previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy were randomised 2:1 to everolimus 10 mg once daily (n = 277) or placebo (n = 139). Median progression-free survival (PFS) was 4.9 months with everolimus and 1.9 months with placebo (hazard ratio [HR], 0.33; P < .001). This preplanned, prospective sub-analysis evaluated PFS benefit of everolimus versus placebo in patients who had previously received 1 or 2 VEGFr-TKIs.Patients and methodsMedian PFS was estimated using the Kaplan–Meier method, and Cox proportional hazards model was used to analyse differences in PFS.ResultsAll patients (100%) received ⩾1 previous VEGFr-TKI; 26% of patients received 2 previous VEGFr-TKIs. Among patients who received 1 previous VEGFr-TKI, median PFS was 5.4 months with everolimus and 1.9 months with placebo (HR, 0.32; 95% confidence interval [CI], 0.24–0.43; P < .001). Among patients who received 2 previous VEGFr-TKIs, median PFS was 4.0 months with everolimus and 1.8 months with placebo (HR, 0.32; 95% CI, 0.19–0.54; P < .001). The everolimus safety profile was similar for both groups.ConclusionsEverolimus was associated with prolonged PFS relative to placebo in patients who received 1 or 2 previous VEGFr-TKIs. Patients who received only 1 previous VEGFr-TKI had apparently longer PFS with everolimus in reference to those who received 2 previous VEGFr-TKIs. These results support the use of everolimus as the standard of care in patients who fail initial VEGFr-TKI therapy.     

Health-related quality of life in patients with advanced renal cell carcinoma receiving pazopanib or placebo in a randomised phase III trial

BackgroundIn a double-blind, randomised phase III trial of advanced renal cell carcinoma patients, pazopanib 800 mg QD (n = 290) versus placebo (n = 145) significantly prolonged progression-free survival (hazard ratio (HR) = 0.46, 95% confidence interval [CI] 0.34–0.62, p-value < 0.0001), without important differences in health-related quality of life (HRQoL). This post-hoc analysis evaluated time to HRQoL deterioration and whether tumour response/stabilisation was associated with HRQoL improvement.MethodsHRQoL was assessed using EORTC QLQ-C30 and EQ-5D. Effect of pazopanib on time to ⩾20% decline from baseline in summary scores was estimated for all patients and by prior treatment. Analyses were conducted for different HRQoL deterioration thresholds. HRQoL changes were stratified by benefit and compared: complete response (CR) or partial response (PR) versus progressive disease (PD); CR/PR versus stable disease (SD), and SD versus PD.ResultsThere was a trend for pazopanib patients to be less likely than placebo patients to experience ⩾20% HRQoL deterioration in EORTC-QLQ-C-30 global health status/QOL scale (HR = 0.77; 95% CI 0.57–1.03, not significant). Results by prior treatment and different HRQoL deterioration thresholds were similar. Patients with CR/PR and SD experienced significantly less HRQoL deterioration than those with PD (p < 0.001, p = 0.0024, respectively); mean differences between patients with CR/PR and PD exceeded the pre-determined minimally important difference (MID). Differences between patients with SD and PD did not exceed pre-determined MID. Results were generally consistent across treatment and EQ-5D summary scores.ConclusionResults support the favourable benefit-risk profile of pazopanib and suggest patients experiencing tumour response/stabilisation also may have better HRQoL compared to those without this response.     

Phase II study of NGR-hTNF,a selective vascular targeting agent,in patients with metastatic colorectal cancer after failure of standard therapy

BackgroundNGR-hTNF consists of human tumour necrosis factor (hTNF) fused with the tumour-homing peptide Asp-Gly-Arg (NGR), which is able to selectively bind an aminopeptidase N overexpressed on tumour blood vessels. Preclinical antitumour activity was observed even at low doses. We evaluated the activity and safety of low-dose NGR-hTNF in colorectal cancer (CRC) patients failing standard therapies.Patients and methodsThirty-three patients with progressive disease at study entry received NGR-hTNF 0.8 μg/m² given intravenously every 3 weeks. The median number of prior treatment regimens was three (range, 2–5). One-quarter of patients had previously received four or more regimens and two-thirds targeted agents. Progression-free survival (PFS) was the primary study objective.ResultsNGR-hTNF was well tolerated. No treatment-related grade 3 to 4 toxicities were detected, most common grade 1 to 2 adverse events being short-lived, infusion-time related chills (50.0%). One partial response and 12 stable diseases were observed, yielding a disease control rate of 39.4% (95% CI, 22.9–57.8%). Median PFS and overall survival were 2.5 months (95% CI, 2.1–2.8) and 13.1 months (95% CI, 8.9–17.3), respectively; whereas in patients who achieved disease control the median PFS and overall survival were 3.8 and 15.4 months, respectively. In an additional cohort of 13 patients treated at same dose with a weekly schedule, there was no increased toxicity and 2 patients experienced PFS longer than 10 months.ConclusionBased on tolerability and preliminary evidence of disease control in heavily pretreated CRC patients, NGR-hTNF deserves further evaluation in combination with standard chemotherapy.     

Gastrointestinal perforation associated with bevacizumab use in metastatic colorectal cancer: results from a large treatment observational cohort study

BackgroundBevacizumab prolongs overall and progression-free survival when added to fluorouracil-based chemotherapy in patients with metastatic colorectal cancer in randomised controlled trials (RCTs). However, gastrointestinal perforation (GIP) occurs in 1–2% of treated patients. We sought to describe the incidence, temporal pattern, outcomes and potential risk factors for GIP in a large, community-based observational cohort study of patients treated with bevacizumab.Patients and methodsBaseline patient and tumour characteristics, including potential GIP risk factors, were collected at study entry. Treatment, targeted adverse events, progression events and survival data were recorded every 3 months. Detailed clinical information was collected for all patients experiencing a GIP event. Effects of baseline risk factors on GIP risk were investigated using Cox proportional hazards regression.ResultsOf 1953 evaluable patients followed for a median of 20.1 months, 37 (1.9%) experienced GIP. Most GIP events were surgically managed with successful outcomes; four events were fatal. The majority of GIP events (26/37) occurred ⩽6 months after starting bevacizumab (median, 3.35 months). Univariate and multivariate analyses showed that age ⩾65 years was significantly associated with lower GIP risk. In multivariate analyses, intact primary tumour and prior adjuvant radiotherapy were significantly associated with increased risk of GIP within 6 months after starting bevacizumab. A regression analysis that assessed the risk of GIP over time showed no cumulative risk associated with bevacizumab exposure.ConclusionThe observed rate of GIP in this large, community-based experience was consistent with rates reported in RCTs. Most events were successfully managed with surgical intervention.     

Impact of age on choice of chemotherapy and outcome in advanced colorectal cancer

BackgroundAge is a major risk factor for development of sporadic colorectal cancer but elderly patients are underrepresented in clinical trials and are potentially offered chemotherapy less often.MethodsData were obtained from South Australian Clinical Registry for advanced colorectal cancer between 1st February 2006 and 9th September 2010. Patients who received chemotherapy were analysed to assess the impact of single versus combination chemotherapy and to assess the outcome in two age cohorts, age <70 years and ⩾70 years.ResultsOut of a total of 1745 patients in the database during this time period, 951 (54.5%) received systemic chemotherapy. 286 (30%) received first line therapy (median age 74 years) with single agent fluoropyrimidine and 643 patients (68%) received first line combination chemotherapy (median age 64 years). The median overall survival of patients receiving first line combination chemotherapy was 23.9 months compared to 17.2 months for those who received single agent fluoropyrimidine (p < 0.001). Combination chemotherapy was given to 81% of patients aged <70 years compared to 53% of those ⩾70 years. There was no significant difference in median overall survival of patients receiving chemotherapy by age cohort, 21.3 months for age <70 years and 21.1 months for age ⩾70 years (p = 0.4).ConclusionTreatment outcomes are comparable in both the elderly and younger patients. Patients who received initial combination chemotherapy were younger and had a longer median overall survival. In our study, age appeared to influence the treatment choices but not necessarily outcome.     

Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials

BackgroundThe CRYSTAL and OPUS randomised clinical trials demonstrated that adding cetuximab to first-line chemotherapy in patients with KRAS wild-type metastatic colorectal cancer (mCRC) significantly improved treatment outcome compared with chemotherapy alone. The objective of this pooled analysis was to further investigate these findings in patients with KRAS wild-type tumours using extended survival data and following an enhancement in the ascertainment rate of KRAS and BRAF tumour mutation status from these studies.MethodsPooled individual patient data from each study were analysed for overall survival (OS), progression-free survival (PFS) and best overall response rate (ORR) in patients evaluable for KRAS and BRAF mutation status. Treatment arms were compared according to mutation status using log–rank and Cochran–Mantel–Haenszel tests.ResultsIn 845 patients with KRAS wild-type tumours adding cetuximab to chemotherapy led to a significant improvement in OS (hazard ratio [HR] 0.81; p = 0.0062), PFS (HR 0.66; p < 0.001) and ORR (odds ratio 2.16; p < 0.0001). BRAF mutations were detected in 70/800 evaluable tumours. No significant differences were found in outcome between the treatment groups in these patients. Prognosis was worse in each treatment arm for patients with BRAF tumour mutations compared with those with BRAF wild-type tumours.ConclusionAnalysis of pooled data from the CRYSTAL and OPUS studies confirms the consistency of the benefit obtained across all efficacy end-points from adding cetuximab to first-line chemotherapy in patients with KRAS wild-type mCRC. BRAF mutation does not appear to be a predictive biomarker in this setting, but is a marker of poor prognosis.     

Comorbidity, age and overall survival in patients with advanced pancreatic cancer - results from NCIC CTG PA.3: a phase III trial of gemcitabine plus erlotinib or placebo

BackgroundThe effect of comorbidity, age and performance status (PS) on treatment of advanced pancreatic cancer is poorly understood. We examined these factors as predictors of outcome in advanced pancreatic cancer patients treated with gemcitabine +/– erlotinib.Patients and methodsComorbidity was evaluated by two physicians using the Charlson Comorbidity Index (CCI) and correlated with clinical outcome data from the NCIC Clinical Trials Group (NCIC CTG) PA.3 clinical trial.ResultsFive hundred and sixty-nine patients were included; 47% were aged ⩾65 years old, 36% had comorbidity (CCI > 0). In multivariate analysis, neither age (p = 0.22) nor comorbidity (p = 0.21) was associated with overall survival. The baseline presence of better PS and lower pain intensity scores was associated with better overall survival (p < 0.0001 and p = 0.01, respectively). An improvement in survival with the addition of erlotinib therapy was seen in patients age <65 (adjusted hazard ratio (HR) 0.73, p = 0.01) or in the presence of comorbidity (adjusted HR 0.72, p = 0.03). However, neither age nor CCI score was predictive of erlotinib benefit after test for interaction. Patients treated with gemcitabine plus erlotinib who were ⩾65 years of age or those with comorbidity had a higher rate of infections ⩾grade 3.ConclusionLow baseline pain intensity and better PS were associated with improved overall survival, while age and comorbidity were not independent prognostic factors for patients treated with gemcitabine-based therapy.     

Trabectedin in patients with advanced soft tissue sarcoma: A retrospective national analysis of the French Sarcoma Group

AimThe French Sarcoma Group performed this retrospective analysis of the ‘RetrospectYon’ database with data of patients with recurrent advanced soft tissue sarcoma (STS) treated with trabectedin 1.5 mg/m² as a 24-h infusion every three weeks.MethodsPatients who achieved non-progressive disease after six initial cycles could receive long-term trabectedin treatment until disease progression.ResultsOverall, 885 patients from 25 French centres were included. Patients received a median of four trabectedin cycles (range: 1–28). The objective response rate was 17% (six complete/127 partial responses) and 50% (n = 403) of patients had stable disease for a disease control rate of 67%. After a median follow-up of 22.0 months, median progression-free survival (PFS) and overall survival (OS) were 4.4 and 12.2 months, respectively. After six cycles, 227/304 patients with non-progressive disease received trabectedin until disease progression and obtained a significantly superior median PFS (11.7 versus 7.6 months, P < 0.003) and OS (24.9 versus 16.9 months, P < 0.001) compared with those who stopped trabectedin treatment. Deaths and unscheduled hospitalisation attributed to drug-related events occurred in 0.5% and 9.4% of patients, respectively.ConclusionThe results of this real-life study demonstrate that treatment with trabectedin of patients with STS yielded comparable or improved efficacy outcomes versus those observed in clinical trials. A long-term treatment with trabectedin given until disease progression is associated with significantly improved PFS and OS.     

A randomized phase II study evaluating the combination of carboplatin-based chemotherapy with pertuzumab versus carboplatin-based therapy alone in patients with relapsed,platinum-sensitive ovarian cancer

BackgroundPertuzumab, a humanized monoclonal antibody targeting human epidermal growth factor receptor (HER)-mediated signalling, has shown activity in ovarian cancer in preclinical models and in the clinic. This randomized phase II study evaluated efficacy and safety of pertuzumab in combination with carboplatin-based chemotherapy in patients with platinum-sensitive, recurrent advanced ovarian cancer.Patients and methodsPatients were randomized to receive six cycles of chemotherapy (carboplatin and either paclitaxel (Taxol) or gemcitabine) with or without pertuzumab. The primary end point was progression-free survival (PFS) as determined by Response Evaluation Criteria in Solid Tumors and/or by CA 125 measurements. Secondary end points evaluated the response rate, safety profile, duration of response, time to progression and overall survival for both treatment arms.ResultsA total of 149 patients received either chemotherapy with pertuzumab (arm A, n = 74) or chemotherapy alone (arm B, n = 75). There was no significant difference either in median PFS or in the secondary end points between the two arms. No differences were seen in an exploratory biomarker analysis of HER3 mRNA expression between the two arms. Pertuzumab was well tolerated, with no increase in cardiac adverse events compared with chemotherapy alone.ConclusionsThe addition of pertuzumab to carboplatin-based chemotherapy did not substantially prolong PFS in unselected patients with platinum-sensitive ovarian cancer.     

Capecitabine and streptozocin ± cisplatin in advanced gastroenteropancreatic neuroendocrine tumours

BackgroundCytotoxic chemotherapy is widely used for advanced, unresectable pancreatic and other gastrointestinal foregut neuroendocrine tumours (NETs) and the most commonly used regimen combines 5-fluorouracil with streptozocin. The NET01 trial was designed to investigate whether capecitabine combined with streptozocin was an acceptable regimen with or without adding cisplatin.MethodsPatients with advanced, unresectable NETs of pancreatic, gastrointestinal foregut or unknown primary site were randomised to receive three-weekly capecitabine (Cap) 625 mg/m² twice daily orally, streptozocin (Strep) 1.0 g/m² intravenously on day 1, with or without cisplatin (Cis) 70 mg/m² intravenously on day 1. The primary outcome measure was objective response. Secondary outcome measures included progression-free and overall survival, quality of life, toxicity and biochemical response.Results86 (44 CapStrep, 42 CapStrepCis) patients were randomised. Best objective response rate was 12% (95% confidence interval (CI) = 2–22%) with CapStrep and 16% (95% CI = 4–27.4%) with CapStrepCis. Disease-control rate was 80% with CapStrep and 74% with CapStrepCis. The estimated median progression-free and overall survival were 10.2 and 26.7 months for CapStrep and 9.7 and 27.5 months for CapStrepCis. 44% of CapStrep and 68% of CapStrepCis patients experienced grade ⩾3 adverse events.InterpretationThe efficacies of the novel CapStrep ± Cis regimens were very similar. CapStrep was better tolerated than CapStrepCis.The trial was registered as EudraCT: 2004-005202-71 and ISRCTN: 35124268.     

Sorafenib as third- or fourth-line treatment of advanced gastrointestinal stromal tumour and pretreatment including both imatinib and sunitinib,and nilotinib: A retrospective analysis

BackgroundTyrosine kinase inhibitors (TKI) improve the outcome of patients with advanced gastrointestinal stromal tumour (GIST), but treatment failure is frequent, and prognosis then bleak. Smaller trials in this setting suggested activity for sorafenib, a multikinase inhibitor of receptor tyrosine kinases and RAF serine/threonine kinases.Patients and methodsWe retrospectively evaluated the efficacy of sorafenib, starting dose 400 mg twice daily, in a large community-based cohort of 124 patients treated in 12 European and one United States (U.S.) cancer centre. All but one patient had a WHO performance score 0–2. All had failed both imatinib and sunitinib, 68 patients nilotinib and 26 had failed investigational therapy, too.ResultsTwelve (10%) patients responded to sorafenib and 70 (57%) patients achieved disease stabilisation. Sorafenib was moderately tolerated, and toxicity reported in 56% of the patients. Rash, hand-foot-syndrome and diarrhea occurred frequently. Sorafenib dosage was reduced in a third of patients, but this did not have an impact on progression-free survival (PFS) (p = 0.15). Median PFS was 6.4 months (95% confidence interval [CI], 4.6–8.0 months) and median overall survival (OS) 13.5 months (95% CI, 10.0–21.0 months). Patients with a good performance status and those who responded to sorafenib had a significant better PFS.ConclusionWe conclude that sorafenib is active in GIST resistant to imatinib, sunitinib and nilotinib. These results warrant further investigation of sorafenib or similar molecules in GIST.     

Radioembolisation for liver metastases: Results from a prospective 151 patient multi-institutional phase II study

PurposeTo investigate the safety, response rate, progression-free and overall survival of patients with liver metastases treated with ⁹⁰Y (glass) radioembolisation in a prospective, multicenter phase II study.Methods151 patients with liver metastases (colorectal n = 61, neuroendocrine n = 43 and other tumour types n = 47) refractory to standard of care therapies were enrolled in this prospective, multicenter, phase II study under an investigational device exemption. Clinical/laboratory/imaging follow-up were obtained at 30 days followed by 3-month intervals for 1 year and every 6 months thereafter. The primary end-point was progression-free survival (PFS); secondary end-points included safety, hepatic progression-free survival (HPFS), response rate and overall survival.ResultsMedian age was 66 (range 25–88). Grade 3/4 adverse events included pain (12.8%), elevated alkaline phospatase (8.1%), hyperbilirubinemia (5.3%), lymphopaenia (4.1%), ascites (3.4%) and vomiting (3.4%). Treatment parameters including dose delivery were reproducible among centers. Disease control rates were 59%, 93% and 63% for colorectal, neuroendocrine and other primaries, respectively. Median PFS was 2.9 and 2.8 months for colorectal and other primaries, respectively. PFS was not achieved in the neuroendocrine group. Median survival from ⁹⁰Y treatment was 8.8 months for colorectal and 10.4 months for other primaries. Median survival for neuroendocrine patients has not been reached.ConclusionPatients with liver metastases can be safely treated with ⁹⁰Y microspheres. This study is the first to demonstrate technical and dose reproducibility of ⁹⁰Y glass microspheres between centers in a prospective setting. Based on these promising data, three international, multicenter, randomised phase III studies in colorectal and hepatocellular carcinoma have been initiated.     

Phase II trial of the histone deacetylase inhibitor belinostat in women with platinum resistant epithelial ovarian cancer and micropapillary (LMP) ovarian tumours

AimMicropapillary/borderline (LMP) ovarian tumours are rarely included in clinical trials and are intrinsically resistant to radiation and chemotherapy. Platinum resistant epithelial ovarian cancer (EOC) has a poor prognosis. The histone deacetylase inhibitor belinostat demonstrated antitumour activity in pre-clinical ovarian cancer models.MethodsA phase II study was performed to evaluate the activity of belinostat in two patient populations: women with metastatic or recurrent platinum resistant (progression within 6 months) EOC and LMP ovarian tumours, both groups had received no more than 3 prior lines of chemotherapy. Belinostat 1000 mg/m²/d was administered iv days 1–5 of a 21 d cycle. Peripheral blood mononuclear cells (PBMCs) and tumour biopsies, where possible, for correlative studies were obtained prior to and following treatment.ResultsEighteen patients with EOC and 14 patients with LMP tumours were enrolled on study. Belinostat was well tolerated with no grade four toxicity (179 cycles). Grade 3 toxicity consisted of thrombosis (3 patients), hypersensitivity (1) and elevated ALP (1). One patient with LMP tumour had a partial response (unconfirmed) and 10 had stable disease (SD), 3 were non-evaluable. Median progression-free survival (PFS) was 13.4 months (95% confidence interval (CI), 5.6 – not reached). Best response in patients with EOC was SD (nine patients) and median PFS was 2.3 months (95% CI, 1.2–5.7 months). An accumulation of acetylated histones H3 and H4 was noted in PBMCs and in tumour tissue.ConclusionsBelinostat is well tolerated in both patient groups and shows some activity in patients with micropapillary (LMP) disease.     

A randomized phase III adjuvant study in high-risk cervical cancer: simultaneous radiochemotherapy with cisplatin (S-RC) versus systemic paclitaxel and carboplatin followed by percutaneous radiation (PC-R): a NOGGO-AGO Intergroup Study

BackgroundSimultaneous adjuvant platinum-based radiochemotherapy in high-risk cervical cancer (CC) is an established treatment strategy. Sequential paclitaxel (Taxol) and platinum followed by radiotherapy may offer further advantages regarding toxicity.Patients and methodsAn open-labeled randomized phase III trial was conducted to compare paclitaxel (175 mg/m²) plus carboplatin (AUC5) followed by radiation (50.4 Gy) (experimental arm-A) versus simultaneous radiochemotherapy with cisplatin (40 mg/m²/week) (arm-B) in patients with stage IB–IIB CC after surgery. Primary objective was progression-free survival (PFS).ResultsOverall, 271 patients were randomized and 263 were eligible for evaluation; 132 in arm-A and 131 in arm-B appropriately balanced. The estimated 2-year PFS was 81.8% [95% confidence interval (CI) 74.4–89.1] in arm-B versus 87.2% (95% CI 81.2–93.3) in arm-A (P = 0.235) and the corresponding 5-year survival rates were 85.8% in arm-A and 78.9% in arm-B (P = 0.25). Hematological grade 3/4 toxicity was higher in arm-B. Alopecia (87.9% versus 4.1%; P < 0.001) and neurotoxicity (65.9% versus 15.6%; P < 0.001) were significantly higher in arm-A. Early treatment termination was significantly more frequent in arm-B than in arm-A (32.1% versus 12.9%; P = 0.001).ConclusionsSequential chemotherapy and radiation in high-risk CC could not show any significant survival benefit; however, a different toxicity profile appeared. This sequential regime may constitute an alternative option when contraindications for immediate postoperative radiation are present.     

A randomised,double-blind,placebo-controlled trial of trametinib,an oral MEK inhibitor,in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas

BackgroundTrametinib, an oral mitogen/extracellular signal-related kinase (MEK)1/2 inhibitor, holds promise for malignancies with rat sarcoma (RAS) mutations, like pancreas cancer. This phase II study was designed to determine overall survival (OS) in patients with pancreas cancer treated with trametinib and gemcitabine. Secondary end-points included progression-free survival (PFS), overall response rate (ORR) and duration of response (DOR); safety end-points were also assessed.MethodsAdults with untreated metastatic adenocarcinoma of the pancreas were randomised (1:1) to receive intravenous gemcitabine 1000 mg/m² (weekly × 7 for 8 weeks, then days 1, 8 and 15 of 28-day cycles) plus trametinib or placebo 2 mg daily. RAS mutations were determined in circulating free DNA (cfDNA) and archival tumour tissue. OS was evaluated in kirsten rat sarcoma viral oncogene homolog (KRAS) mutant and wild-type subgroups.ResultsBaseline characteristics for 160 patients were similar in both treatment arms. There was no significant difference in OS (hazard ratio (HR) 0.98; 95% confidence interval (CI), 0.67–1.44; P = .453); median OS was 8.4 months with gemcitabine plus trametinib and 6.7 months with gemcitabine plus placebo. Median PFS (16 versus 15 weeks), ORR (22% versus 18%) and median DOR (23.9 versus 16.1 weeks) were also similar for trametinib and placebo arms, respectively. KRAS mutation-positive patients (n = 103) showed no difference in OS between arms. Thrombocytopenia, diarrhoea, rash and stomatitis were more frequent with trametinib, as was grade 3 anaemia.ConclusionsThe addition of trametinib to gemcitabine did not improve OS, PFS, ORR or DOR in patients with previously untreated metastatic pancreas cancer. Outcomes were independent of KRAS mutations determined by cfDNA.