Explore the vast range of titles available.

Despite recent advances in the treatment of advanced non-small-cell lung cancer, there remains a need for effective treatments for progressive disease. We assessed the efficacy of pembrolizumab for patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. We did this randomised, open-label, phase 2/3 study at 202 academic medical centres in 24 countries. Patients with previously treated non-small-cell lung cancer with PD-L1 expression on at least 1% of tumour cells were randomly assigned (1:1:1) in blocks of six per stratum with an interactive voice-response system to receive pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m2 every 3 weeks. The primary endpoints were overall survival and progression-free survival both in the total population and in patients with PD-L1 expression on at least 50% of tumour cells. We used a threshold for significance of p<0·00825 (one-sided) for the analysis of overall survival and a threshold of p<0·001 for progression-free survival. This trial is registered at ClinicalTrials.gov, number NCT01905657. Between Aug 28, 2013, and Feb 27, 2015, we enrolled 1034 patients: 345 allocated to pembrolizumab 2 mg/kg, 346 allocated to pembrolizumab 10 mg/kg, and 343 allocated to docetaxel. By Sept 30, 2015, 521 patients had died. In the total population, median overall survival was 10·4 months with pembrolizumab 2 mg/kg, 12·7 months with pembrolizumab 10 mg/kg, and 8·5 months with docetaxel. Overall survival was significantly longer for pembrolizumab 2 mg/kg versus docetaxel (hazard ratio [HR] 0·71, 95% CI 0·58–0·88; p=0·0008) and for pembrolizumab 10 mg/kg versus docetaxel (0·61, 0·49–0·75; p<0·0001). Median progression-free survival was 3·9 months with pembrolizumab 2 mg/kg, 4·0 months with pembrolizumab 10 mg/kg, and 4·0 months with docetaxel, with no significant difference for pembrolizumab 2 mg/kg versus docetaxel (0·88, 0·74–1·05; p=0·07) or for pembrolizumab 10 mg/kg versus docetaxel (HR 0·79, 95% CI 0·66–0·94; p=0·004). Among patients with at least 50% of tumour cells expressing PD-L1, overall survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 14·9 months vs 8·2 months; HR 0·54, 95% CI 0·38–0·77; p=0·0002) and with pembrolizumab 10 mg/kg than with docetaxel (17·3 months vs 8·2 months; 0·50, 0·36–0·70; p<0·0001). Likewise, for this patient population, progression-free survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 5·0 months vs 4·1 months; HR 0·59, 95% CI 0·44–0·78; p=0·0001) and with pembrolizumab 10 mg/kg than with docetaxel (5·2 months vs 4·1 months; 0·59, 0·45–0·78; p<0·0001). Grade 3–5 treatment-related adverse events were less common with pembrolizumab than with docetaxel (43 [13%] of 339 patients given 2 mg/kg, 55 [16%] of 343 given 10 mg/kg, and 109 [35%] of 309 given docetaxel). Pembrolizumab prolongs overall survival and has a favourable benefit-to-risk profile in patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. These data establish pembrolizumab as a new treatment option for this population and validate the use of PD-L1 selection. Merck & Co.

Docetaxel (Taxotere®) has been one of the most important chemotherapeutic drugs for cancer treatment since 1996. Although a large number of clinical studies have been conducted in various cancer fields, there is a discrepancy in the standard dose between Japan and Western countries. This article reviews the pharmacokinetic, pharmacodynamic and toxicological profiles of docetaxel, and explains why there exists an ethnic difference in dose, and further discusses which direction we should go forward to solve this problem. The original recommended dose was 100 mg/m2 every 3 weeks in US and European populations, while a Japanese phase I study suggested the recommended dose as 60 mg/m2 every 3 weeks. A prospective population pharmacokinetic analysis of docetaxel conducted in both the USA/Europe and Japan, indicated an absence of ethnic difference in the pharmacokinetics. Both analyses demonstrated that docetaxel clearance is related to α1‐acid glycoprotein level, hepatic function, age and body surface area. The relationship was observed between increasing docetaxel dose and increased tumor response rates across the dose range of 60 to 100 mg/m2. The area under the serum concentration time curve (AUC) of docetaxel at the first cycle was significantly related to time to progression. Hematological toxicities were well correlated with the AUC of docetaxel, and severe hematological toxicities were more frequently observed in Japanese patients treated with 60 mg/m2, compared to the US/European patients treated with 75–100 mg/m2 dose. The Japanese population seems more susceptible to the toxicity of docetaxel. A docetaxel dose of 75 mg/m2 is now standard not only in global trials but also in recent Japanese trials. Although the optimal dose of docetaxel is still unclear, we need to continue to seek the appropriate dose of docetaxel depending on patient status and the goals of chemotherapy. Docetaxel has been one of the most important chemotherapeutic drugs for cancer treatment, but a practical problem is discrepancy in standard dose between Japan and Western countries. This article reviews extensively the pharmacokinetic, pharmacodynamic and toxicological profiles of docetaxel, and explains why there exists an ethnic difference in dose, and further discusses which direction we should go forward to solve this problem.

Paclitaxel (Taxol) is a taxane and a chemotherapeutic drug that stabilizes microtubules. While the interaction of paclitaxel with microtubules is well described, the lack of high-resolution structural information on a tubulin-taxane complex precludes a comprehensive description of the binding determinants that affect its mechanism of action. Here, we solved the crystal structure of baccatin III the core moiety of paclitaxel-tubulin complex at 1.9 Å resolution. Based on this information, we engineered taxanes with modified C13 side chains, solved their crystal structures in complex with tubulin, and analyzed their effects on microtubules (X-ray fiber diffraction), along with those of paclitaxel, docetaxel, and baccatin III. Further comparison of high-resolution structures and microtubules’ diffractions with the apo forms and molecular dynamics approaches allowed us to understand the consequences of taxane binding to tubulin in solution and under assembled conditions. The results sheds light on three main mechanistic questions: (1) taxanes bind better to microtubules than to tubulin because tubulin assembly is linked to a βM-loopconformational reorganization (otherwise occludes the access to the taxane site) and, bulky C13 side chains preferentially recognize the assembled conformational state; (2) the occupancy of the taxane site has no influence on the straightness of tubulin protofilaments and; (3) longitudinal expansion of the microtubule lattices arises from the accommodation of the taxane core within the site, a process that is no related to the microtubule stabilization (baccatin III is biochemically inactive). In conclusion, our combined experimental and computational approach allowed us to describe the tubulin-taxane interaction in atomic detail and assess the structural determinants for binding.

The curative effects of nanoparticle albumin-bound (nab)-paclitaxel in the first-line treatment of metastatic breast cancer (MBC) are still controversial, with even more after the removal of marketing approval of indication of bevacizumab. Five electronic databases and the related resources were searched for eligible randomized clinical trials (RCTs) without year and language restrictions to perform a meta-analysis. The studies were comparing the efficacy and safety between nab-paclitaxel chemotherapy versus solvent-based (sb)-taxanes chemotherapy such as sb-paclitaxel and docetaxel. The primary end points were overall response rate (ORR) and disease control rate (DCR). Secondary end points were progression-free survival (PFS), overall survival (OS), adverse events (AEs), and dose discontinuation rate (DDR). Five RCTs (1,554 patients) were finally identified from 1,902 studies. When compared to sb-paclitaxel, nab-paclitaxel showed significant beneficial effects in terms of ORR (OR 2.39, 95% CI 1.69–3.37, p < 0.001), DCR (OR 1.89, 95% CI 1.07–3.35, p = 0.03), and PFS (HR 0.75, 95% CI 0.62–0.90, p = 0.002). Nab-paclitaxel also showed significantly longer OS (HR 0.73, 95% CI 0.54–0.99, p = 0.04) than docetaxel. AEs and DDR were comparable between the two arms. Using nab-paclitaxel could significantly improve efficacy with comparable toxicities in the treatment of MBC.

Microtubule-stabilizing agents (MSAs) are efficacious chemotherapeutic drugs widely used for the treatment of cancer. Despite the importance of MSAs for medical applications and basic research, their molecular mechanisms of action on tubulin and microtubules remain elusive. We determined high-resolution crystal structures of αβ-tubulin in complex with two unrelated MSAs, zampanolide and epothilone A. Both compounds were bound to the taxane pocket of β-tubulin and used their respective side chains to induce structuring of the M-loop into a short helix. Because the M-loop establishes lateral tubulin contacts in microtubules, these findings explain how taxane-site MSAs promote microtubule assembly and stability. Further, our results offer fundamental structural insights into the control mechanisms of microtubule dynamics.

Until recently, patients with castration-resistant prostate cancer (CRPC) had limited therapeutic options once they became refractory to docetaxel chemotherapy, and no treatments improved survival. This changed in June 2010 when the Food and Drug Administration (FDA) approved cabazitaxel as a new option for patients with CRPC whose disease progresses during or after docetaxel treatment. For most of these patients, cabazitaxel will now replace mitoxantrone (a drug that was FDA-approved because of its palliative effects) as the treatment of choice for docetaxel-refractory disease. The approval of cabazitaxel was based primarily on the TROPIC trial, a large (n = 755) randomized Phase III study showing an overall median survival benefit of 2.4 months for men with docetaxel-pretreated metastatic CRPC receiving cabazitaxel (with prednisone) compared to mitoxantrone (with prednisone). Cabazitaxel is a novel tubulin-binding taxane that differs from docetaxel because of its poor affinity for P-glycoprotein (P-gp), an ATP-dependent drug efflux pump. Cancer cells that express P-gp become resistant to taxanes, and the effectiveness of docetaxel can be limited by its high substrate affinity for P-gp. Preclinical and early clinical studies show that cabazitaxel retains activity in docetaxel-resistant tumors, and this was confirmed by the TROPIC study. Common adverse events with cabazitaxel include neutropenia (including febrile neutropenia) and diarrhea, while neuropathy was rarely observed. Thus, the combination of cabazitaxel and prednisone is an important new treatment option for men with docetaxel-refractory metastatic CRPC, but this agent should be administered cautiously and with appropriate monitoring (especially in men at high risk of neutropenic complications).

Docetaxel is a highly potent anticancer agent being used in a wide spectrum of cancer types. There are important matters of concern regarding the drug's pharmacokinetics related to the conventional formulation. Poly(lactide- -glycolide) (PLGA) is a biocompatible/biodegradable polymer with variable physicochemical characteristics, and its application in human has been approved by the United States Food and Drug Administration. PLGA gives polymeric nanoparticles with unique drug delivery characteristics. The application of PLGA nanoparticles (NPs) as intravenous (IV) sustained-release delivery vehicles for docetaxel can favorably modify pharmacokinetics, biofate, and pharmacotherapy of the drug in cancer patients. Surface modification of PLGA NPs with poly(ethylene glycol) (PEG) can further enhance NPs' long-circulating properties. Herein, an optimized fabrication approach has been used for the preparation of PLGA and PLGA-PEG NPs loaded with docetaxel for IV application. Both types of NP formulations demonstrated in vitro characteristics that were considered suitable for IV administration (with long-circulating sustained-release purposes). NP formulations were IV administered to an animal model, and docetaxel's pharmacokinetic and biodistribution profiles were determined and compared between study groups. PLGA and PEGylated PLGA NPs were able to modify the pharmacokinetics and biodistribution of docetaxel. Accordingly, the mode of changes made to pharmacokinetics and biodistribution of docetaxel is attributed to the size and surface properties of NPs. NPs contributed to increased blood residence time of docetaxel fulfilling their role as long-circulating sustained-release drug delivery systems. Surface modification of NPs contributed to more pronounced docetaxel blood concentration, which confirms the role of PEG in conferring long-circulation properties to NPs.

In a randomized study involving 582 patients with advanced nonsquamous lung cancer that had progressed after primary treatment, nivolumab produced a higher response rate and longer overall survival than standard docetaxel. Effective options are limited for patients with nonsquamous non–small-cell lung cancer (NSCLC) whose disease progresses after first-line chemotherapy. Docetaxel was approved as a second-line treatment for advanced NSCLC on the basis of longer survival than that with best supportive care. 1 – 3 Newer agents, such as pemetrexed and erlotinib, which have a better side-effect profile than docetaxel, have either been shown to be noninferior to docetaxel or have failed to show superiority to docetaxel with respect to overall survival when they are used as second-line therapy. 4 , 5 The programmed death 1 (PD-1) receptor expressed on activated T cells is engaged by . . .

Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m2) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60–71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23–184). Median follow-up was 43 months (IQR 30–60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79–1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66–0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69–0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3–5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

Background Cabazitaxel is a novel taxane that might be active in breast cancer resistant to first-generation taxanes. Methods The purpose of the current multicentre phase II trial was to evaluate the activity and safety of cabazitaxel, as second-line treatment, in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) previously treated with taxanes. The primary endpoint was objective response rate (ORR). Results Eighty-four patients were enrolled between October 2012 and November 2016. Taxane resistance to previous treatment was detected in 43 cases. The ORR was 22.6% in the intent-to-treat population, 23.3% in taxane-resistant and 20.5% in taxane-non-resistant cases. At a median follow-up of 39.6 months, the median progression-free survival and overall survival were 3.7 months (95% CI 2.2–4.4) and 15.2 months (95% CI 11.3–19.4), respectively. Regarding toxicity, grade 3–4 neutropenia was reported in 22.6% and febrile neutropenia in 6% of the patients, respectively. Two fatal events (one febrile neutropenia and one sepsis) were reported as being related to study treatment. Conclusions This phase II trial suggests that cabazitaxel is active as second-line treatment in taxane-pretreated patients with HER2-negative MBC, with manageable toxicity.