Improved overall survival after implementation of targeted therapy for patients with metastatic renal cell carcinoma: Results from the Danish Renal Cancer Group (DARENCA) study-2

AimTo evaluate the implementation of targeted therapy on overall survival (OS) in a complete national cohort of patients with metastatic renal cell carcinoma (mRCC).MethodsAll Danish patients with mRCC referred for first line treatment with immunotherapy, TKIs or mTOR-inhibitors between 2006 and 2010 were included. Baseline and outcome data were collected retrospectively. Prognostics factors were identified using log-rank tests and Cox proportional hazard model. Differences in distributions were tested with the Chi-square test.Results1049 patients were referred; 744 patients received first line treatment. From 2006 to 2010 we observed a significant increase in the number of referred patients; a significant increase in treated patients (64% versus 75%, P = 0.0188); a significant increase in first line targeted therapy (22% versus 75%, P < 0.0001); a significant increase in second line treatment (20% versus 40%, P = 0.0104), a significant increased median OS (11.5 versus 17.2 months, P = 0.0435) whereas survival for untreated patients remained unchanged. Multivariate analysis validated known prognostic factors. Moreover, treatment start years 2008 (HR 0.74, 95% CI, 0.55–0.99; P = 0.0415), 2009 (HR 0.72, 95% CI, 0.54–0.96; P = 0.0277) and 2010 (HR 0.63, 95% CI, 0.47–0.86; P = 0.0035) compared to 2006, and more than two treatment lines received for patients with performance status 0–1 (HR 0.76, 95% CI, 0.58–0.99; P = 0.0397) and performance status 2–3 (HR 0.19, 95% CI, 0.06–0.60; P = 0.0051) were significantly associated with longer OS.ConclusionThis retrospective study documents that the implementation of targeted therapy has resulted in significantly improved treatment rates and overall survival in a complete national cohort of treated mRCC patients.     

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.     

An indirect comparison of the toxicity of sunitinib and pazopanib in metastatic clear cell renal cancer

BackgroundBoth sunitinib and pazopanib are widely used as first line therapy in metastatic renal cancer (mRCC). The efficacy of these agents appears similar but they may have distinct toxicity profiles. In this study we compare the severity of symptomatic and asymptomatic toxicity associated with sunitinib and pazopanib.MethodsTwo sequential prospective single arm phase II studies investigated either 12 weeks of sunitinib (n = 43) or pazopanib (n = 34) prior to nephrectomy in untreated mRCC. Toxicity was defined as either symptomatic (hand and foot syndrome, mucositis, nausea, fatigue, diarrhoea, oedema, headache, pain, anorexia and change in taste) or asymptomatic (liver toxicity or haematological toxicity). Pazopanib (800 mg once daily (OD)) and sunitinib (50 mg 4/2) were given. Regular Common Toxicity Criteria (CTC) toxicity assessment was performed during the first 12 weeks of therapy.ResultsThere was no significant difference in the overall number of toxic events (grade 1–4) for sunitinib and pazopanib (mean number of toxic events/patients: 1.97 versus 1.96: p > 0.05). Increased grade 2–4 symptomatic toxicity events occurred with sunitinib (hazard ratio (HR) 1.67 [95% confidence interval (CI): 1.11–2.56] p < 0.03). Sunitinib was associated with an increased grade 2–4 mucositis (16% versus 0% p = 0.02) and fatigue (42% versus 15% p = 0.01). Pazopanib was associated with more frequent grade 1 diarrhoea (39% versus 12%: p = 0.03). Dose reductions for symptomatic toxicity occurred more frequently with sunitinib (26% versus 6% p < 0.05). There was no difference in the occurrence of asymptomatic toxicity.ConclusionThis indirect analysis suggests sunitinib and pazopanib have distinct toxicity profiles which may help guide patient’s choice. Further comparative data from randomised trials are awaited.     

Sequential therapy for the locally advanced larynx and hypopharynx cancer subgroup in TAX 324: survival,surgery, and organ preservation

BackgroundLocally advanced laryngeal and hypopharyngeal cancers (LHC) represent a group of cancers for which surgery, laryngectomy-free survival (LFS), overall survival (OS), and progression-free survival (PFS) are clinically meaningful end points.Patients and methodsThese outcomes were analyzed in the subgroup of assessable LHC patients enrolled in TAX 324, a phase III trial of sequential therapy comparing docetaxel plus cisplatin and fluorouracil (TPF) against cisplatin and fluorouracil (PF), followed by chemoradiotherapy.ResultsAmong 501 patients enrolled in TAX 324, 166 had LHC (TPF, n = 90; PF, n = 76). Patient characteristics were similar between subgroups. Median OS for TPF was 59 months [95% confidence interval (CI): 31–not reached] versus 24 months (95% CI: 13–42) for PF [hazard ratio (HR) for death: 0.62; 95% CI: 0.41–0.94; P = 0.024]. Median PFS for TPF was 21 months (95% CI: 12–59) versus 11 months (95% CI: 8–14) for PF (HR: 0.66; 95% CI: 0.45–0.97; P = 0.032). Among operable patients (TPF, n = 67; PF, n = 56), LFS was significantly greater with TPF (HR: 0.59; 95% CI: 0.37–0.95; P = 0.030). Three-year LFS with TPF was 52% versus 32% for PF. Fewer TPF patients had surgery (22% versus 42%; P = 0.030).ConclusionsIn locally advanced LHC, sequential therapy with induction TPF significantly improved survival and PFS versus PF. Among operable patients, TPF also significantly improved LFS and PFS. These results support the use of sequential TPF followed by carboplatin chemoradiotherapy as a treatment option for organ preservation or to improve survival in locally advanced LHC.     

A randomized phase II trial of CRLX101 in combination with bevacizumab versus standard of care in patients with advanced renal cell carcinoma

BackgroundNanoparticle-drug conjugates enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel nanoparticle–drug conjugate containing camptothecin, a potent inhibitor of topoisomerase I and the hypoxia-inducible factors 1α and 2α. In a phase Ib/2 trial, CRLX101 + bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase II trial comparing CRLX101 + bevacizumab versus standard of care (SOC) in refractory mRCC.Patients and methodsPatients with mRCC and 2–3 prior lines of therapy were randomized 1:1 to CRLX101 + bevacizumab versus SOC, defined as investigator’s choice of any approved regimen not previously received. The primary end point was progression-free survival (PFS) by blinded independent radiological review in patients with clear cell mRCC. Secondary end points included overall survival, objective response rate and safety.ResultsIn total, 111 patients were randomized and received ≥1 dose of drug (CRLX101 + bevacizumab, 55; SOC, 56). Within the SOC arm, patients received single-agent bevacizumab (19), axitinib (18), everolimus (7), pazopanib (4), sorafenib (4), sunitinib (2), or temsirolimus (2). In the clear cell population, the median PFS on the CRLX101 + bevacizumab and SOC arms was 3.7 months (95% confidence interval, 2.0–4.3) and 3.9 months (95% confidence interval 2.2–5.4), respectively (stratified log-rank P = 0.831). The objective response rate by IRR was 5% with CRLX101 + bevacizumab versus 14% with SOC (Mantel–Haenszel test, P = 0.836). Consistent with previous studies, the CRLX101 + bevacizumab combination was generally well tolerated, and no new safety signal was identified.ConclusionsDespite promising efficacy data on the earlier phase Ib/2 trial of mRCC, this randomized trial did not demonstrate improvement in PFS for the CRLX101 + bevacizumab combination when compared with approved agents in patients with heavily pretreated clear cell mRCC. Further development in this disease is not planned.Clinical trial identificationNCT02187302 (NIH).     

A randomised,open label phase III trial with nimotuzumab,an anti-epidermal growth factor receptor monoclonal antibody in the treatment of newly diagnosed adult glioblastoma

PurposeA randomised, open label phase III trial was conducted to evaluate efficacy of nimotuzumab, a monoclonal antibody against epidermal growth factor receptor (EGF-R) added to standard therapy for newly diagnosed glioblastoma.Patients and methods149 glioblastoma patients stratified as with or without residual tumour were randomly assigned to receive either intravenous nimotuzumab 400 mg weekly added to standard radiochemotherapy followed by 400 mg biweekly after twelve weeks or standard radiochemotherapy. Progression status after 52 weeks (12moPFS) and progression-free survival (PFS) based on Macdonald criteria were co-primary and overall survival (OS), toxicity and quality of life secondary end-points.Results142 patients were evaluated for efficacy (per protocol cohort). 12moPFS was 25.6% in the experimental arm and 20.3% in the control group. In residual tumour patients (n = 81) median PFS was 5.6 versus 4.0 months, (hazard ratio (HR), 0.87; 95% confidence interval (CI), 0.55–1.37), for patients without residual tumour (n = 61) it was 10.6 versus 9.9 months, (HR, 1.01; 95% CI, 0.57–1.77). Median OS in patients with residual tumour was 19.5 versus 16.7 months, (HR, 0.90; 95% CI, 0.52–1.57; P = 0.7061), for patients without 23.3 versus 21.0 months (HR, 0.77; 95% CI, 0.41–1.44; P = 0.4068). A small cohort of MGMT non-methylated patients with residual tumour showed PFS of 6.2 versus 4.0 months (HR, 0.77; 95% CI, 0.35–1.67; P = 0.4997) and OS of 19.0 versus 13.8 months (HR, 0.66; 95% CI, 0.27–1.64; P = 0.3648). EGF-R amplification did not correlate with clinical efficacy of nimotuzumab. Nimotuzumab was well tolerated.ConclusionThis study, albeit negative, contains hypothesis generating signals supporting evaluation of correlative, efficacy-predicting tumour parameters for nimotuzumab in the treatment of glioblastoma.     

Second line treatment of metastatic renal cell carcinoma: The Institut Gustave Roussy experience with targeted therapies in 251 consecutive patients

BackgroundSequential treatment is currently the standard of care in metastatic renal cell carcinoma (mRCC). However, very little is known on how many patients (pts) can receive second line or further, and on how to predict those pts. The goal of this study was to evaluate these questions in a large series of pts treated in our institution.Patients and MethodsData from all mRCC patients treated at the IGR from 2005 to 2009 with first line targeted therapy (sunitinib (SU), sorafenib (SO), bevacizumab (B), temsirolimus or everolimus (pooled together as mammalian target of rapamycin – mTOR)) were analysed. Only patients with subsequent follow-up have been included in this analysis. Patients were defined as ‘non-eligible’ for second treatment if: they were (i) still on first line treatment, (ii) not showing progressive (durable stable disease or partial response or complete response) or (iii) if they refused a second line treatment.Results251 patients, median age 60 years, median follow-up 20.2 months were treated with targeted therapy with a median overall survival (OS) of 25.8 months. Median OS with SU (127), SO (60) or B (61) were 26.3, 16.4 and 32.5 months respectively. Only three patients received an mTOR inhibitor as first line. According to the eligibility criteria, the percentage of patients who received a second line was 59% (n = 61/103), 52% (n = 30/58) and 79% (n = 38/48) for Su, So and B, respectively. Memorial Sloan-Kettering Cancer Centre (MSKCC) classification (P = 0.02) and first line agent (P = 0.001) were significant predictive factor for receiving a second line of treatment. Overall, patients receiving B were in better general condition, with 77% of performance status score (PS) = 0 compared to SO (53%) and SU (48%) (P = 0.005). Among the 131 patients who received a second line, the median OS from the start of second line treatment was 20.8 months for a tyrosine kinase inhibitor (TKI) (n = 98; 75%) and 16.6 months for an mTOR (n = 32; 42%) (P = 0.12). Furthermore, the percentage of patients who received a third line was 56% (27/48), 28% (7/25) and 65% (13/20) for SU, SO and B, respectively.ConclusionThe median OS in patients treated with targeted therapies for mRCC in The Institut Gustave Roussy exceeds 2 years. The use of second line varies from 52% to 79%. Further studies are needed to validate the MSKCC groups and first line therapy as predictive factor for second line treatment.     

Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer

BackgroundWe analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC).Patients and methodsALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders.ResultsAmong 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9 months (95% CI: 2.4–5.6) versus 10.3 months (95% CI: 8.6–12.0), P < 0.001; OS 15.0 months (95% CI: 5.0–24.9) versus 50.0 months (95% CI: 22.9–77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6 months (95% CI: 1.3–4.1) versus 6.2 months (95% CI: 1.8–10.5), P = 0.021; OS 2.0 months (95% CI: 0.0–4.6) versus 9.0 months (95% CI: 6.1–11.9), P = 0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0 months (95% CI: 2.9–7.2) versus 14.0 months (95% CI: 8.0–20.1), P < 0.001; OS 17.0 months (95% CI: 6.7–27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4 months (95% CI: 0.1–10.7) versus 9.9 months (95% CI: 6.4–13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001).ConclusionsIn ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.     

nab-Paclitaxel plus carboplatin or gemcitabine versus gemcitabine plus carboplatin as first-line treatment of patients with triple-negative metastatic breast cancer: results from the tnAcity trial

BackgroundMetastatic triple-negative breast cancer (mTNBC) has a poor prognosis and aggressive clinical course. tnAcity evaluated the efficacy and safety of first-line nab-paclitaxel plus carboplatin (nab-P/C), nab-paclitaxel plus gemcitabine (nab-P/G), and gemcitabine plus carboplatin (G/C) in patients with mTNBC.Patients and methodsPatients with pathologically confirmed mTNBC and no prior chemotherapy for metastatic BC received (1 : 1 : 1) nab-P 125 mg/m² plus C AUC 2, nab-P 125 mg/m² plus G 1000 mg/m², or G 1000 mg/m² plus C AUC 2, all on days 1, 8 q3w. Phase II primary end point: investigator-assessed progression-free survival (PFS); secondary end points included overall response rate (ORR), overall survival (OS), percentage of patients initiating cycle 6 with doublet therapy, and safety.ResultsIn total, 191 patients were enrolled (nab-P/C, n = 64; nab-P/G, n = 61; G/C, n = 66). PFS was significantly longer with nab-P/C versus nab-P/G [median, 8.3 versus 5.5 months; hazard ratio (HR), 0.59 [95% CI, 0.38–0.92]; P = 0.02] or G/C (median, 8.3 versus 6.0 months; HR, 0.58 [95% CI, 0.37–0.90]; P = 0.02). OS was numerically longer with nab-P/C versus nab-P/G (median, 16.8 versus 12.1 months; HR, 0.73 [95% CI, 0.47–1.13]; P = 0.16) or G/C (median, 16.8 versus 12.6 months; HR, 0.80 [95% CI, 0.52–1.22]; P = 0.29). ORR was 73%, 39%, and 44%, respectively. In the nab-P/C, nab-P/G, and G/C groups, 64%, 56%, and 50% of patients initiated cycle 6 with a doublet. Grade ≥3 adverse events were mainly hematologic.ConclusionsFirst-line nab-P/C was active in mTNBC and resulted in a significantly longer PFS and improved risk/benefit profile versus nab-P/G or G/C.     

Glycemic index,glycemic load and cancer risk

BackgroundDietary glycemic index (GI) and glycemic load (GL) have been related to the risk of selected cancers, but the issue remains open.Patients and methodsMailed questionnaires were completed between 1994 and 1997 in eight Canadian provinces for incident, histologically confirmed cases of the stomach (n = 1182), colon (n = 1727), rectum (n = 1447), liver (n = 309), pancreas (n = 628), lung (n = 3341), breast (n = 2362), ovary (n = 442), prostate (n = 1799), testis (n = 686), kidney (n = 1345), bladder (n = 1029), brain (n = 1009), non-Hodgkin's lymphomas (NHL, n = 1666), leukemias (n = 1069), multiple myelomas (n = 343), and 5039 population controls. Dietary information on eating habits 2 years before participants' enrollment in the study was obtained using a validated food frequency questionnaire (FFQ). Odds ratios (ORs) and 95% confidence intervals (CI) were derived by unconditional logistic regression including recognized confounding factors.ResultsDietary GI was positively associated with the risk of prostate cancer (OR, 1.26 for the highest versus the lowest quartile). A higher dietary GL significantly increased the risk of colorectal (OR, 1.28), rectal (OR, 1.44) and pancreatic (OR, 1.41) cancers. No other significant associations were found.ConclusionsOur findings suggest that a diet high in GI and GL is associated with increased risk of selected cancers.     

Efficacy of sunitinib in patients with metastatic or unresectable renal cell carcinoma and renal insufficiency

AimThe aim of this retrospective, registry-based study was to analyse treatment outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib and renal insufficiency (RI).MethodsThe cohort included 790 patients treated with sunitinib between 2006 and 2013. At the start of sunitinib therapy 22, 234, and 534 patients had severe (glomerular filtration rate [GFR] <30 ml/min/1.73 m²), moderate (GFR 30–60 ml/min/1.73 m²) or mild RI/normal renal function (GFR >60 ml/min/1.73 m²), respectively.ResultsFor the three groups defined above, median progression-free survival (PFS) (95% confidence interval [CI]) was 5.3 months (0.1–18.5), 8.1 months (6.2–9.9) and 11.3 months (9.4–13.2) (p = 0.244), and median overall survival (OS) was 26.3 months (1.2–51.4), 21.2 months (13.2–29.1) and 26.3 months (22.6–29.9) (p = 0.443), respectively. The disease control rates were 45.5%, 56.4% and 59.2%, respectively (p = 0.374). No unexpected toxicity was reported in the patients with RI, but the treatment was more frequently discontinued because of adverse events and the duration of therapy was significantly shorter in these patients (p = 0.007).ConclusionsDuration of first-line targeted treatment for mRCC was significantly shorter for patients with RI, and may have translated into a trend to shorter PFS. These results highlight the need for optimal management of side-effects in patients with mRCC and RI.     

Effects of erlotinib first-line maintenance therapy versus placebo on the health-related quality of life of patients with metastatic non-small-cell lung cancer

IntroductionMaintenance therapy can delay progression and prolong survival in metastatic non-small-cell lung cancer (mNSCLC). As treatment for mNSCLC is non-curative, its impact on patient health-related quality of life (HRQoL) is an important consideration. SATURN (Sequential Tarceva in Unresectable NSCLC) was a randomised, double-blind, placebo-controlled, multicentre study investigating the impact of erlotinib maintenance therapy on HRQoL in patients with locally advanced or recurrent NSCLC.Patients and MethodsEligible patients who had previously completed four cycles of platinum-based chemotherapy were randomised 1:1 to receive erlotinib 150 mg/day or placebo until disease progression, unacceptable toxicity or death. Patient HRQoL was assessed using the Functional Assessment of Cancer Therapy-Lung questionnaire, in terms of time to symptom progression (TSP), time to deterioration (TTD) in Trial Outcome Index (TOI) and TTD. Exploratory analysis was based on time to analgesia and appearance of key symptoms (pain, cough and dyspnoea).ResultsCompared with placebo, erlotinib maintenance therapy prolonged progression-free and overall survival by 41% and 23%, respectively. At baseline, HRQoL measures were comparable between the two treatment groups. Maintenance therapy with erlotinib did not impact on deterioration in HRQoL: TSP (hazard ratio [HR] = 0.91 [95% confidence interval (CI) 0.74–1.12]; n = 785), TTD in TOI (HR = 1.06 [95% CI 0.87–1.31]; n = 781) and TTD in HRQoL (HR = 0.96 [95% CI 0.79–1.16]; n = 776). Time to pain and time to analgesic use were significantly delayed in patients receiving erlotinib compared with placebo (HR = 0.61 [95% CI 0.42–0.88]; p = 0.0080 and HR = 0.66 [95% CI 0.46–0.94]; p = 0.0199, respectively). A non-significant trend towards delayed time to cough and time to dyspnoea (HR = 0.77 [95% CI 0.49–1.21] and HR = 0.75 [95% CI 0.48–1.17], respectively) was also observed.ConclusionsErlotinib maintenance therapy significantly extends progression-free survival without compromising patient HRQoL in comparison with placebo, with some improvement in symptoms.     

Bisphosphonates combined with sunitinib may improve the response rate, progression free survival and overall survival of patients with bone metastases from renal cell carcinoma

BackgroundBisphosphonates are used to prevent skeletal events of bone metastases, and may exhibit antitumour effects. We aimed to evaluate whether bisphosphonates can bring a response rate (RR), progression free survival (PFS) and overall survival (OS) benefit to patients with bone metastasis from renal cell carcinoma (RCC) that is treated with sunitinib.MethodsWe performed a multicentre retrospective study of patients with bone metastases from RCC that was treated with sunitinib. The effect of bisphosphonates on RR, PFS and OS was tested with adjustment for known prognostic factors using a chi-square test from contingency table and partial likelihood test from Cox regression model.ResultsBetween 2004 and 2011, 209 patients with metastatic RCC were treated with sunitinib, 76 had bone metastases, 35 bisphosphonates users and 41 non-users. The groups of bisphosphonates users and non-users were balanced regarding known prognostic factors. Objective response was partial response/stable disease 86% (n = 30) versus 71% (n = 29), and progressive disease 14% (n = 5) versus 29% (n = 12) (p = 0.125, OR 2.48) in users versus non-users, respectively. Median PFS was 15 versus 5 months (HR = 0.55, p < 0.0001), and median OS was not reached (with a median follow-up time of 45 months) versus 14 months (HR = 0.4, p = 0.029), in favour of users. In multivariate analysis of the entire patient cohort (n = 76), factors associated with PFS were bisphosphonates use (HR = 0.58, p = 0.035), and pre-treatment neutrophil to lymphocyte ratio >3 (HR = 3.5, p = 0.009). Factors associated with OS were bisphosphonates use (HR = 0.5, p = 0.008), elevated pre-treatment alkaline phosphatase (HR = 2.9, p = 0.003) and sunitinib induced HTN (HR = 0.63, p < 0.0001).ConclusionsBisphosphonates may improve the RR, PFS and OS of sunitinib treatment in RCC with bone metastases.     

Sunitinib objective response in metastatic renal cell carcinoma: Analysis of 1059 patients treated on clinical trials

BackgroundRetrospective analyses were performed in patients with metastatic renal cell carcinoma (mRCC) to characterise the objective response (OR) rate to sunitinib and differentiate pretreatment features and outcomes of patients with early (response by ⩽12 weeks) versus late response, and responders versus non-responders.MethodsData were pooled from 1059 patients in six trials. Median progression-free survival (PFS) and overall survival (OS) were estimated by Brookmeyer and Crowley method and compared between groups by log-rank test. Baseline characteristics were compared by Fisher-exact, t-, or Wilcoxon rank-sum tests. Associations between characteristics and survival were investigated by Cox proportional regression analysis.Results398 patients (38%) had confirmed OR (12 complete responses); 26%, 61%, 79% and 86% responded by 6, 12, 18 and 24 weeks, respectively. Median (range) time to tumour response (TTR) was 10.6 (2.7–94.4) weeks and was similar in treatment-naïve and cytokine-refractory patients. Median response duration in early and late responders was 52.0 and 55.0 weeks, respectively. Median PFS in early versus late responders was 13.8 versus 20.2 months (P = 0.001); however, median OS did not significantly differ (37.8 versus 40.8 months; P = 0.144). Early responders had more lung metastases (P < 0.01), but baseline characteristics were otherwise mostly similar. Median PFS (16.3 versus 5.3 months) and OS (40.1 versus 14.5 months) were longer in responders versus non-responders (both P < 0.001); responders had more favourable prognostic factors.ConclusionsOR occurred in 38% of sunitinib-treated mRCC patients. Sixty-one percent of responses occurred by 12 weeks of therapy, and responders had favourable pretreatment features and significantly longer survival.     

Everolimus for patients with metastatic renal cell carcinoma refractory to anti-VEGF therapy: Results of a pooled analysis of non-interventional studies

AimTo assess the efficacy and safety of everolimus in patients with metastatic renal cell carcinoma (mRCC) who failed one or two anti-VEGF therapies.Patients and methodsData from four prospective, non-interventional studies conducted in Germany, France, Greece and Austria were pooled for this analysis. Patients with mRCC of any histology (clear cell or non-clear cell) were included. VEGF-refractory patients received everolimus 10 mg/day until disease progression or unacceptable toxicity. The primary objective was to determine everolimus efficacy as measured by time to progression (TTP; from baseline to progression).ResultsThe overall population comprised 632 patients; 493 patients received everolimus in the second-line setting. Most patients were of favourable/intermediate MSKCC risk (91%), had clear cell mRCC (89%), and had undergone nephrectomy (89%). Median TTP was 6.3 months (95% confidence interval [CI], 5.9–6.8) for the overall population and 6.4 months (95% CI, 5.8–6.9) for the second-line everolimus population. Similarly, median progression-free survival was 5.5 months (95% CI, 5.0–6.1) for the overall population and 5.8 months (95% CI, 5.0–6.4) for second-line everolimus population. Best tumour response (n = 349) was complete or partial remission in 12% of patients and stable disease in 59% of patients. Overall population median overall survival (OS) was 11.2 months (95% CI, 9.0–not reached). Commonly reported adverse events (AEs) (any grade) were stomatitis (25%), anaemia (15%) and asthenia (11%).ConclusionsResults of this pooled analysis provide evidence of safety and effectiveness of second-line everolimus in routine clinical use and support everolimus as a standard of care for VEGF-refractory patients with mRCC.     

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.     

Role of cardioprotective therapy for prevention of cardiotoxicity with chemotherapy: A systematic review and meta-analysis

BackgroundCardiotoxicity is a well-recognised complication of chemotherapy with anthracycline and/or trastuzumab, and its prevention remains an important challenge in cancer survivorship. Several successful preventative strategies have been identified in animal trials. We sought to assemble the clinical evidence that prophylactic pharmacological interventions could prevent left ventricular (LV) dysfunction and heart failure in patients undergoing chemotherapy.MethodsWe undertook a systemic review of the evidence from randomised trials and observational studies where a prophylactic intervention was compared with a control arm in patients with a normal ejection fraction and no past history of heart failure. The primary outcome was development of heart failure (HF), a drop in ejection fraction (EF) or both. A random-effects model was used to combine relative risks (RR) and 95% confidence intervals (CIs), and a meta-regression was undertaken to assess the impact of potential covariates.FindingsData were collated from 14 published articles (n = 2015 paediatric and adult patients) comprising 12 randomised controlled trials and two observational studies. The most studied chemotherapeutic agents were anthracyclines, and prophylactic agents included dexrazoxane, statins, beta-blocker and angiotensin antagonists. There were 304 cardiac events in the control arm compared to 83 in the prophylaxis arm (RR = 0.31 [95% CI: 0.25–0.39], p < 0.00001). Cardiac events were reduced with dexrazoxane (RR = 0.35 [95% CI 0.27–0.45], p < 0.00001), beta-blockade (RR = 0.31 [95% CI 0.16–0.63], p = 0.001), statin (RR = 0.31 [95% CI 0.13–0.77], p = 0.01) and angiotensin antagonists (RR = 0.11 [95% CI 0.04–0.29], p < 0.0001).InterpretationProphylactic treatment with dexrazoxane, beta-blocker, statin or angiotensin antagonists appear to have similar efficacy for reducing cardiotoxicity.     

A phase III,randomized, open-label study of ASP8273 versus erlotinib or gefitinib in patients with advanced stage IIIB/IV non-small-cell lung cancer

BackgroundASP8273, a novel, small molecule, irreversible tyrosine kinase inhibitor (TKI) specifically inhibits the epidermal growth factor receptor (EGFR) in patients with activating mutations or EGFR T790M resistance mutations. The current study examines the efficacy, safety, and tolerability of ASP8273 versus erlotinib or gefitinib in patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations not previously treated with an EGFR inhibitor.Patients and methodsThis global, phase III, open-label, randomized study evaluated ASP8273 versus erlotinib/gefitinib in patients with locally advanced, metastatic, or unresectable stage IIIB/IV NSCLC with activating EGFR mutations. They were ineligible if they received prior chemotherapy for metastatic disease. The primary end point was progression-free survival (PFS), and secondary end points included overall survival, investigator-assessed PFS, best overall response rate (ORR), disease control rate, duration of response (DoR), and the safety/tolerability profile.ResultsPatients (n = 530) were randomized 1 : 1 to receive ASP8273 (n = 267) or erlotinib/gefitinib (n = 263). Patient demographics between both treatment groups were generally balanced. Median PFS was 9.3 months (95% CI 5.6–11.1 months) for patients receiving ASP8273 and 9.6 months (95% CI 8.8–NE) for the erlotinib/gefitinib group, with a hazard ratio of 1.611 (P = 0.992). The ORR in the ASP8273 group was 33% (95% CI 27.4–39.0) versus 47.9% (95% CI 41.7–54.1) in the erlotinib/gefitinib group. Median DoR was similar for both groups (9.2 months for ASP8273 versus 9.0 months for erlotinib/gefitinib). More grade ≥3 treatment-emergent adverse events (TEAEs) occurred in patients receiving ASP8273 than in those receiving erlotinib/gefitinib (54.7% versus 43.5%). An independent data monitoring committee carried out an interim safety analysis and recommended discontinuing the study due to toxicity and limited predicted efficacy of ASP8273 relative to erlotinib/gefitinib.ConclusionsFirst-line ASP8273 did not show improved PFS or equivalent toxicities versus erlotinib/gefitinib.ClinicalTrial.gov numberNCT02588261.     

Carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in very platinum-sensitive ovarian cancer patients: Results from a subset analysis of the CALYPSO phase III trial

AimTo perform a subset analysis of patients with very platinum-sensitive recurrent ovarian cancer (ROC) enrolled in the phase III CALYPSO trial.Patients and methodsThe international non-inferiority trial enrolled women with ROC that relapsed >6 months following first- or second-line platinum- and paclitaxel-based therapies. Patients were randomised to CD [carboplatin–pegylated liposomal doxorubicin (PLD)] or CP (carboplatin–paclitaxel) and stratified by treatment-free interval (TFI). In this analysis, patients with a TFI > 24 months were analysed separately for progression free survival (PFS), the primary endpoint of CALYPSO, overall survival (OS) and safety.ResultsA total of 259 very platinum-sensitive patients were included (n = 131, CD; n = 128, CP). Median PFS was 12.0 months for the CD arm and 12.3 months for CP [HR = 1.05 (95% CI, 0.79–1.40); P = 0.73 for superiority] and median OS was 40.2 months for CD and 43.9 for CP [HR = 1.18 (95% CI 0.85–1.63); P = 0.33 for superiority]. Overall response rates were 42% and 38%, respectively (P = 0.46). Toxicities were more common with CP versus CD, including grade 3/4 neutropenia (40.8% versus 27.5%; P = 0.025), nausea (4.8% versus 3.1%; P = 0.47), allergic reaction (8% versus 3.1%; P = 0.082) sensory neuropathy (4.8% versus 2.3%; P = 0.27) and grade 2 alopecia (88% versus 9.2%; P < 0.001). Grade 3/4 thrombocytopenia (12.2% versus 3.2%; P = 0.007) and mucositis (2.3% versus 0%; P = 0.089) were more common with CD. Grade 3/4 hand-foot syndrome occurred rarely with CD (3 patients versus 0 in CP arm; P = 0.089).ConclusionCP and CD were equally effective treatment regimens for patients with very platinum-sensitive ROC. The favourable risk–benefit profile suggests carboplatin–PLD as treatment of choice for these patients.     

Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study

BackgroundTo demonstrate the noninferiority of capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid and oxaliplatin (FOLFOX-4) as second-line therapy in patients with metastatic colorectal cancer after prior irinotecan-based chemotherapy.Patients and methodsA total of 627 patients were randomly assigned to receive XELOX (n = 313) or FOLFOX-4 (n = 314) following disease progression/recurrence or intolerance to irinotecan-based chemotherapy. The primary end point was progression-free survival (PFS).ResultsPFS for XELOX was noninferior to FOLFOX-4 [hazard ratio (HR) = 0.97; 95% confidence interval (CI) 0.83–1.14] in the intention-to-treat (ITT) population. Median PFS was 4.7 months with XELOX versus 4.8 months with FOLFOX-4. The robustness of the primary analysis was supported by multivariate and subgroup analyses. Median overall survival in the ITT population was 11.9 months with XELOX versus 12.5 months with FOLFOX-4 (HR = 1.02; 95% CI 0.86–1.21). Treatment-related grade 3/4 adverse events occurred in 50% of XELOX- and 65% of FOLFOX-4-treated patients. Whereas grade 3/4 neutropenia (35% versus 5% with XELOX) and febrile neutropenia (4% versus < 1%) were more common with FOLFOX-4, grade 3/4 diarrhea (19% versus 5% with FOLFOX-4) and grade 3 hand–foot syndrome (4% versus < 1%) were more common with XELOX.ConclusionXELOX is noninferior to FOLFOX-4 when administered as second-line treatment in patients with metastatic colorectal cancer.