Olaparib plus Durvalumab, with or without Bevacizumab, as Treatment in PARP Inhibitor-Naïve Platinum-Sensitive Relapsed Ovarian Cancer: A Phase II Multi-Cohort Study.

PURPOSE: Early results from the phase II MEDIOLA study (NCT02734004) in germline BRCA1- and/or BRCA2-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSROC) showed promising efficacy and safety with olaparib plus durvalumab. We report efficacy and safety of olaparib plus durvalumab in an expansion cohort of women with gBRCAm PSROC (gBRCAm expansion doublet cohort) and two cohorts with non-gBRCAm PSROC, one of which also received bevacizumab (non-gBRCAm doublet and triplet cohorts). PATIENTS AND METHODS: In this open-label, multicenter study, PARP inhibitor-naïve patients received olaparib plus durvalumab treatment until disease progression; the non-gBRCAm triplet cohort also received bevacizumab. Primary endpoints were objective response rate (ORR; gBRCAm expansion doublet cohort), disease control rate (DCR) at 24 weeks (non-gBRCAm cohorts), and safety (all cohorts). RESULTS: The full analysis and safety analysis sets comprised 51, 32, and 31 patients in the gBRCAm expansion doublet, non-gBRCAm doublet, and non-gBRCAm triplet cohorts, respectively. ORR was 92.2% [95% confidence interval (CI), 81.1-97.8] in the gBRCAm expansion doublet cohort (primary endpoint); DCR at 24 weeks was 28.1% (90% CI, 15.5-43.9) in the non-gBRCAm doublet cohort (primary endpoint) and 74.2% (90% CI, 58.2-86.5) in the non-gBRCAm triplet cohort (primary endpoint). Grade ≥ 3 adverse events were reported in 47.1%, 65.6%, and 61.3% of patients in the gBRCAm expansion doublet, non-gBRCAm doublet, and non-gBRCAm triplet cohorts, respectively, most commonly anemia. CONCLUSIONS: Olaparib plus durvalumab continued to show notable clinical activity in women with gBRCAm PSROC. Olaparib plus durvalumab with bevacizumab demonstrated encouraging clinical activity in women with non-gBRCAm PSROC. No new safety signals were identified.

Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer.

BACKGROUND: Poly(adenosine diphosphate-ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with BRCA1 or BRCA2 germline mutation-associated early breast cancer. METHODS: We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease-free survival. RESULTS: A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease-free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P<0.001). The 3-year distant disease-free survival was 87.5% in the olaparib group and 80.4% in the placebo group (difference, 7.1 percentage points; 95% CI, 3.0 to 11.1; hazard ratio for distant disease or death, 0.57; 99.5% CI, 0.39 to 0.83; P<0.001). Olaparib was associated with fewer deaths than placebo (59 and 86, respectively) (hazard ratio, 0.68; 99% CI, 0.44 to 1.05; P = 0.02); however, the between-group difference was not significant at an interim-analysis boundary of a P value of less than 0.01. Safety data were consistent with known side effects of olaparib, with no excess serious adverse events or adverse events of special interest. CONCLUSIONS: Among patients with high-risk, HER2-negative early breast cancer and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was associated with significantly longer survival free of invasive or distant disease than was placebo. Olaparib had limited effects on global patient-reported quality of life. (Funded by the National Cancer Institute and AstraZeneca; OlympiA ClinicalTrials.gov number, NCT02032823.).

Anticancer activity of the type I insulin-like growth factor receptor antagonist, ganitumab, in combination with the death receptor 5 agonist, conatumumab.

Agents targeting the insulin-like growth factor receptor type 1 (IGF1R) have shown antitumor activity. Based on the evidence for interaction between the IGF-1 and TRAIL pathways, we hypothesized that the combination of ganitumab (monoclonal antibody to IGF1R) with the pro-apoptotic death receptor 5 agonist, conatumumab, might increase antitumor response. Ganitumab and conatumumab were tested in combination in a Colo-205 xenograft model. Part 1 of the clinical study was a phase Ib program of three doses of conatumumab (1, 3, 15 mg/kg) in combination with 18 mg/kg ganitumab to determine the maximum tolerated dose (MTD) in patients with advanced solid tumors. Part 2 was conducted in six cohorts with advanced non-small cell lung cancer (squamous or non-squamous histology), colorectal cancer, sarcoma, pancreatic cancer, or ovarian cancer, treated at the recommended doses of the combination. The combination was significantly more active in the Colo-205 xenograft model than either single agent alone (p < 0.0015). In part 1 of the clinical study, no dose-limiting toxicities were observed and the MTD of conatumumab was 15 mg/kg in combination with 18 mg/kg ganitumab. In part 2, 78 patients were treated and there were no objective responses but 28 patients (36 %) had stable disease (median 46 days, range 0-261). The combination was well-tolerated with no new toxicities. In conclusion, the combination of ganitumab and conatumumab was well-tolerated but had no objective responses in the population tested. The successful future application of this combination of antitumor mechanisms may rely on the identification of predictive biomarkers.

Methodological quality of meta-analyses: matched-pairs comparison over time and between industry-sponsored and academic-sponsored reports.

CONTEXT: Meta-analyses are regularly used to inform healthcare decisions. Concerns have been expressed about the quality of meta-analyses and, in particular, about those supported by the pharmaceutical industry. OBJECTIVE: The objective of this study is to compare the quality of pharmaceutical-industry-supported meta-analyses with academic meta-analyses and of meta-analyses published before and after companies started to disclose their data. DATA SOURCES: We identified industry-supported meta-analyses by searching the Scopus bibliographic database, using author affiliations. We matched each industry-supported meta-analysis with an academic meta-analysis using high-level MeSH terms in PubMed. STUDY SELECTION: We included meta-analyses of randomized trials assessing the efficacy or safety of any pharmaceutical intervention in humans, published in 2002-2004 or 2008-2009. Cochrane reviews were excluded. Two individuals independently selected papers, with discrepancies resolved by two further individuals. ASSESSMENT: We developed and piloted a quality-assessment tool, consisting of 43 questions in four domains, with a key summary question covering each domain. Two individuals independently assessed each meta-analysis. RESULTS: We examined 126 meta-analysis publications in 63 matched pairs. The average quality was low, with fewer than 50% adequate in three of the four domains. Industry-supported meta-analyses less often demonstrated adequate methods for locating studies and assessing their quality (odds ratio 0.44, 95% confidence interval 0.21 to 0.92), for analysing the included studies (0.52, 0.25 to 1.06), for undertaking meta-analyses (0.82, 0.40 to 1.68) and in reaching sound conclusions (0.62, 0.30 to 1.28). Quality generally improved over time, particularly for some aspects of industry reports. CONCLUSIONS: Academic meta-analysis papers are generally of higher quality than industry-supported ones. This is largely due to less detailed reporting in industry-supported meta-analyses and a tendency for them to take the included studies at face value, probably arising from the implicit assumption that these studies already have high methodological standards to meet licensing requirements. The improved quality over time does not appear to be due to the use of data disclosed by industry. The main limitations of this study are the small sample of papers and the subjective nature of some of the assessment processes.

A tool to assess the quality of a meta-analysis.

BACKGROUND: Because meta-analyses are increasingly prevalent and cited in the medical literature, it is important that tools are available to assess their methodological quality. When performing an empirical study of the quality of published meta-analyses, we found that existing tools did not place a strong emphasis on statistical and interpretational issues. METHODS: We developed a quality-assessment tool using existing materials and expert judgment as a starting point, followed by multiple iterations of input from our working group, piloting, and discussion. After having used the tool for our empirical study, agreement for four key items in the tool was measured using weighted kappa coefficients. RESULTS: Our tool contained 43 items divided into four key areas (data sources, analysis of individual studies, meta-analysis methods, and interpretation), and each area ended with a summary question. We also produced guidance for completing the tool. Agreement between raters was fair to moderate. CONCLUSIONS: The tool should usefully inform subsequent initiatives to develop quality-assessment tools for meta-analysis. We advocate use of consensus between independent raters when assessing statistical appropriateness and adequacy of interpretation in meta-analyses.

Randomized phase II study of dulanermin in combination with paclitaxel, carboplatin, and bevacizumab in advanced non-small-cell lung cancer.

PURPOSE: To evaluate the efficacy and safety of dulanermin combined with paclitaxel and carboplatin (PC) and bevacizumab (PCB) as first-line treatment for advanced or recurrent non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with squamous NSCLC and/or CNS metastases received PC every 3 weeks alone (arm 1) or with dulanermin 8 mg/kg for 5 days (arm 2). Patients with nonsquamous NSCLC received PCB alone (arm 3) or with dulanermin 8 mg/kg for 5 days (arm 4) or 20 mg/kg for 2 days (arm 5). The primary end point was the objective response rate (ORR). RESULTS: Overall, 213 patients were randomly assigned (arm 1, n = 41; arm 2, n = 39; arm 3, n = 42; arm 4, n = 40; arm 5, n = 41). The ORR in arms 1 to 5 was 39% (95% CI, 24% to 56%), 38% (95% CI, 24% to 54%), 50% (95% CI, 35% to 65%), 40% (95% CI, 25% to 56%), and 40% (95% CI, 25% to 56%), respectively. The odds ratio for ORR was 1.04 (P = 1.000) for arm 1 versus arm 2, 1.53 (P = .391) for arm 3 and versus arm 4, and 1.53 (P = .391) for arm 3 versus arm 5. The most common grade ≥ 3 adverse events were neutropenia, asthenia, anemia, thrombocytopenia, and hemoptysis. Of 161 available serum samples, a trend toward increased caspase-cleaved cytokeratin-18 was observed after dulanermin treatment in cycles 1 and 2. Among 84 patients evaluated for GalNT14 expression, there was a trend toward favorable progression-free survival and overall survival with dulanermin treatment in those with high GalNT14 expression. CONCLUSION: The addition of dulanermin to PC and PCB did not improve outcomes in unselected patients with previously untreated advanced or recurrent NSCLC.

A single dose of pegfilgrastim compared with daily filgrastim for supporting neutrophil recovery in patients treated for low-to-intermediate risk acute myeloid leukemia: results from a randomized, double-blind, phase 2 trial.

BACKGROUND: Patients with acute myeloid leukemia (AML) are often neutropenic as a result of their disease. Furthermore, these patients typically experience profound neutropenia following induction and/or consolidation chemotherapy and this may result in serious, potentially life-threatening, infection. This randomized, double-blind, phase 2 clinical trial compared the efficacy and tolerability of pegfilgrastim with filgrastim for assisting neutrophil recovery following induction and consolidation chemotherapy for de novo AML in patients with low-to-intermediate risk cytogenetics. METHODS: Patients (n = 84) received one or two courses of standard induction chemotherapy (idarubicin + cytarabine), followed by one course of consolidation therapy (high-dose cytarabine) if complete remission was achieved. They were randomized to receive either single-dose pegfilgrastim 6 mg or daily filgrastim 5 mug/kg, beginning 24 hours after induction and consolidation chemotherapy. RESULTS: The median time to recovery from severe neutropenia was 22.0 days for both pegfilgrastim (n = 42) and filgrastim (n = 41) groups during Induction 1 (difference 0.0 days; 95% CI: -1.9 to 1.9). During Consolidation, recovery occurred after a median of 17.0 days for pegfilgrastim versus 16.5 days for filgrastim (difference 0.5 days; 95% CI: -1.1 to 2.1). Therapeutic pegfilgrastim serum concentrations were maintained throughout neutropenia. Pegfilgrastim was well tolerated, with an adverse event profile similar to that of filgrastim. CONCLUSION: These data suggest no clinically meaningful difference between a single dose of pegfilgrastim and multiple daily doses of filgrastim for shortening the duration of severe neutropenia following chemotherapy in de novo AML patients with low-to-intermediate risk cytogenetics. TRIAL REGISTRATION: Clinicaltrials.gov NCT00114764.

A phase 2 pilot study of pegfilgrastim and filgrastim for mobilizing peripheral blood progenitor cells in patients with non-Hodgkin's lymphoma receiving chemotherapy.

BACKGROUND: Growth factors are frequently used to aid peripheral blood progenitor cell mobilization from bone marrow. This phase 2 study examined the efficacy and safety of pegfilgrastim for mobilizing peripheral blood progenitors cells for autologous transplantation. DESIGN AND METHODS: Patients with non-Hodgkin's lymphoma received one cycle of mobilizing chemotherapy (ifosfamide, carboplatin and etoposide, ICE). Twenty-four hours later they were randomized, double-blind, to receive a single dose of pegfilgrastim 6 mg or 12 mg, or filgrastim 5 mug/kg/day (until the end of leukapheresis). Following leukapheresis (collection phase), patients rested or received one or two 'salvage' cycles of ICE. High-dose BEAM chemotherapy was then given before peripheral blood progenitor cell transplantation. The primary end-point was the patients' mean yield of CD34(+) cells/kg during the collection phase. RESULTS: Ninety patients were randomized and received a study drug; 63% completed the collection phase. The patients' mean (95% CI) CD34(+) cell harvest per leukapheresis was 0.8 (0.5-1.4), 0.8 (0.5-1.6) and 1.2 (0.7-2.0)x10(6) cells/kg for the pegfilgrastim 6 mg, pegfilgrastim 12 mg and filgrastim groups, respectively. Twenty (69%), 17 (59%) and 23 (72%) patients in these three groups achieved the targeted minimum harvest (>/=2 x 10(6) cells/kg). The mean total harvests were 1.7, 1.4 and 2.2 x 10(6) cells/kg, respectively. Post-transplantation, the median days to absolute neutrophil count recovery (>/=0.5 x 10(9)/L) were 12, 11, and 11, respectively. Pegfilgrastim and filgrastim were generally well tolerated. CONCLUSIONS: Pegfilgrastim (6 or 12 mg) was effective for mobilizing peripheral blood progenitors cells in patients with non-Hodgkin's lymphoma. These data may aid the design of studies to clarify optimal dosing and leukapheresis with pegfilgrastim.

Randomized, double-blind, placebo-controlled study to evaluate the effect of two dosing regimens of darbepoetin alfa in patients with heart failure and anaemia.

AIMS: Anaemia is common in chronic heart failure (CHF) and associated with worse outcome. This randomized, double-blind, placebo-controlled study evaluated the effect of two darbepoetin alfa dosing regimens on haemoglobin (Hb) rate of rise and clinical effects in patients with CHF and anaemia. METHODS AND RESULTS: Patients with CHF (>or=3 months), left ventricular ejection fraction (LVEF)

Effect of darbepoetin alfa on exercise tolerance in anemic patients with symptomatic chronic heart failure: a randomized, double-blind, placebo-controlled trial.

OBJECTIVES: This study sought to investigate whether darbepoetin alfa, an erythropoiesis-stimulating protein (ESP), improves exercise capacity in patients with symptomatic chronic heart failure (CHF) and anemia. BACKGROUND: Anemia is common in patients with CHF. METHODS: In a multicenter, randomized, double-blind, placebo-controlled study, CHF patients with anemia (hemoglobin > or =9.0 to < or =12.0 g/dl) received subcutaneous placebo (n = 22) or darbepoetin alfa (n = 19) at a starting dose of 0.75 microg/kg every 2 weeks for 26 weeks. The primary end point was change in exercise tolerance from baseline to week 27 as measured by peak oxygen uptake (ml/min/kg body weight). Other end points included changes in absolute peak VO2 (ml/min), exercise duration, and health-related quality of life. RESULTS: Differences (95% confidence interval) in mean changes from baseline to week 27 between treatment groups were 1.5 g/dl (0.5 to 2.4) for hemoglobin concentration (p = 0.005), 0.5 ml/kg/min (-0.7 to 1.7) for peak VO2 (p = 0.40), 45 ml/min (-35 to 127) for absolute peak VO2 (p = 0.27), and 108 s (-11 to 228) for exercise duration (p = 0.075). Patients receiving darbepoetin alfa compared with placebo had an improvement in self-reported Patient's Global Assessment of Change (79% vs. 41%, p = 0.01) but no significant differences in the Kansas City Cardiomyopathy and Minnesota Living with Heart Failure Questionnaire scores. Darbepoetin alfa was well tolerated. CONCLUSIONS: In patients with symptomatic CHF and anemia, darbepoetin alfa increased and maintained hemoglobin concentrations and improved health-related quality of life. A trend toward increased exercise time but not peak VO2 was observed. (Impact of Darbepoetin Alfa on Exercise Tolerance and Left Ventricular Structure in Subjects With Symptomatic Congestive Heart Failure (CHF) and Anemia; http://clinicaltrials.gov/ct/show/NCT00117234?order = 1; NCT00117234).

Treatment of anaemia in dialysis patients with unit dosing of darbepoetin alfa at a reduced dose frequency relative to recombinant human erythropoietin (rHuEpo).

BACKGROUND: Darbepoetin alfa is an erythropoietic agent with a 3-fold longer elimination half-life than recombinant human erythropoietin (rHuEpo), which allows less frequent dosing. This study investigated the safety and efficacy of darbepoetin alfa for treating anaemia in dialysis patients, using a dosing regimen that was independent of the patient's body weight (unit dosing). METHODS: Dialysis patients (n=341) maintained on rHuEpo treatment (alfa or beta) were switched to darbepoetin alfa at a reduced dosing frequency, but by the same route of administration [intravenous (i.v.) or subcutaneous (s.c.)]. Patients receiving rHuEpo two or three times weekly changed to once-weekly darbepoetin alfa, and those receiving rHuEpo once weekly changed to once every other week darbepoetin alfa. The unit doses of darbepoetin alfa (10-150 microg) were titrated to maintain haemoglobin concentrations within -1.0 and +1.5 g/dl of the individual mean baseline haemoglobin and between 10 and 13 g/dl for 24 weeks. RESULTS: Mean change in haemoglobin from baseline to the evaluation period (weeks 21-24) was 0.13 g/dl (95% CI, 0.01, 0.25), which was not clinically relevant. An analysis by route of administration revealed that mean haemoglobin concentrations had increased by 0.58 g/dl (95% CI, 0.33, 0.82) in patients receiving i.v. darbepoetin alfa, and previously treated with i.v. rHuEpo, while remaining unchanged in s.c. patients (0.00 g/dl; 95% CI, -0.13, 0.13) previously treated by s.c. rHuEpo. In addition, there was a statistically significant decrease in mean weekly i.v. darbepoetin alfa dose requirements from 25.2 microg/week at baseline to 21.5 microg/week (P=0.004) during the evaluation period (-17.3%). Subcutaneous weekly dosage requirements increased slightly during the study period (20.8 to 22.7 microg/week; P=0.014). An i.v./s.c. dose ratio of 0.95 (95% CI, 0.78, 1.14) at evaluation confirms previous findings that dose requirements by the i.v. and s.c. routes were not different in patients treated with darbepoetin alfa. Haemoglobin concentrations were also effectively maintained in patients who received darbepoetin alfa once weekly and once every other week. Darbepoetin alfa was well tolerated. CONCLUSIONS: The treatment of renal anaemia in dialysis patients with unit doses of darbepoetin alfa effectively and safely maintains target haemoglobin concentrations with less frequent dosing. Dose requirements for darbepoetin alfa following i.v. and s.c. administration were not different. The results of this study demonstrate that darbepoetin alfa administered i.v. once weekly, or once every other week is an effective treatment regimen for haemodialysis patients with renal anaemia.

Randomized trial of darbepoetin alfa for treatment of renal anemia at a reduced dose frequency compared with rHuEPO in dialysis patients.

BACKGROUND: Darbepoetin alfa is a glycoprotein with a three-fold longer terminal half-life than recombinant human erythropoietin (rHuEPO). We aimed to determine whether darbepoetin alfa is as effective and well tolerated as rHuEPO for treating renal anemia in dialysis patients when administered at a reduced dose frequency. METHODS: A total of 522 European and Australian hemodialysis and peritoneal dialysis patients receiving stable rHuEPO therapy by either the intravenous (IV) or subcutaneous (SC) route were randomized, open-label in a 1:2 ratio to continue rHuEPO or to receive an equivalent dose of darbepoetin alfa at a reduced dose frequency. Patients receiving rHuEPO once weekly changed to once every other week darbepoetin alfa, and those receiving rHuEPO two or three times weekly changed to once-weekly darbepoetin alfa. The doses of rHuEPO and darbepoetin alfa were titrated to maintain hemoglobin close to the patient's baseline level for up to 52 weeks. The primary endpoint was the change in hemoglobin between baseline and the evaluation period at weeks 25 to 32 of treatment. RESULTS: The mean change in hemoglobin from baseline to the evaluation period was similar in the darbepoetin alfa (-0.03 g/dL; SE 0.11) and rHuEPO (-0.06 g/dL; SE 0.13) groups, and the difference between the two treatments was 0.03 g/dL (95% CI -0.16, 0.21). This was not a statistically significant or clinically relevant difference, despite the reduced frequency of darbepoetin alfa administration. At the end of the evaluation period, >/=95% of patients had their hemoglobin successfully maintained on their assigned dose frequency for darbepoetin alfa (once weekly and once every other week) and rHuEPO (once, twice and three times weekly). The safety profiles of darbepoetin alfa and rHuEPO were similar, and no antibodies to either treatment were detected. CONCLUSIONS: Darbepoetin alfa maintains hemoglobin as effectively as rHuEPO, but with a reduced dose frequency.