Showing papers by "Jonathan A. Ledermann published in 2020"
St Bartholomew's Hospital1, University College London2, Université Paris-Saclay3, University of Melbourne4, Peter MacCallum Cancer Centre5, Institute of Cancer Research6, University of Glasgow7, Glasgow Royal Infirmary8, Netherlands Cancer Institute9, University of Cambridge10, University of Lyon11, Memorial Sloan Kettering Cancer Center12, University of Washington13, Wellcome Trust Sanger Institute14
TL;DR: Current available HRD tests are useful for predicting likely magnitude of benefit from PARPis but better biomarkers are urgently needed to better identify current homologous recombination proficiency status and stratify HGSC management.
194 citations
University College London1, University of Sydney2, Harvard University3, Princess Margaret Cancer Centre4, Sheba Medical Center5, Pomeranian Medical University6, University of New South Wales7, Hannover Medical School8, Netherlands Cancer Institute9, Yonsei University10, University of São Paulo11, Katholieke Universiteit Leuven12, AstraZeneca13, Paris Descartes University14
TL;DR: maintenance therapy with the PARP inhibitor olaparib in pts with platinum-sensitive relapsed ovarian cancer (PSROC) and a BRCA mutation ...
Abstract: 6002Background: SOLO2 (ENGOT ov-21; NCT01874353) showed that maintenance therapy with the PARP inhibitor olaparib in pts with platinum-sensitive relapsed ovarian cancer (PSROC) and a BRCA mutation ...
87 citations
University College London1, Princess Margaret Cancer Centre2, Agostino Gemelli University Polyclinic3, Memorial Sloan Kettering Cancer Center4, European Institute of Oncology5, Ottawa Hospital Research Institute6, University of Manchester7, Institut Gustave Roussy8, Auckland City Hospital9, Royal Brisbane and Women's Hospital10, University of Queensland11, Ohio State University12, Johns Hopkins University School of Medicine13, The Royal Marsden NHS Foundation Trust14, University of Washington15, University of Texas MD Anderson Cancer Center16
TL;DR: Prespecified, investigator-assessed, exploratory post-progression endpoints and updated safety data are reported on rucaparib maintenance treatment in patients with platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma and patients with BRCA mutations.
Abstract: Background In ARIEL3, rucaparib maintenance treatment significantly improved progression-free survival versus placebo. Here, we report prespecified, investigator-assessed, exploratory post-progression endpoints and updated safety data. Methods In this ongoing (enrolment complete) randomised, placebo-controlled, phase 3 trial, patients aged 18 years or older who had platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least two previous platinum-based chemotherapy regimens and responded to their last platinum-based regimen were randomly assigned (2:1) to oral rucaparib (600 mg twice daily) or placebo in 28-day cycles using a computer-generated sequence (block size of six with stratification based on homologous recombination repair gene mutation status, progression-free interval following penultimate platinum-based regimen, and best response to most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary endpoint of investigator-assessed progression-free survival has been previously reported. Prespecified, exploratory outcomes of chemotherapy-free interval (CFI), time to start of first subsequent therapy (TFST), time to disease progression on subsequent therapy or death (PFS2), and time to start of second subsequent therapy (TSST) and updated safety were analysed (visit cutoff Dec 31, 2017). Efficacy analyses were done in all patients randomised to three nested cohorts: patients with BRCA mutations, patients with homologous recombination deficiencies, and the intention-to-treat population. Safety analyses included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT01968213. Findings Between April 7, 2014, and July 19, 2016, 564 patients were enrolled and randomly assigned to rucaparib (n=375) or placebo (n=189). Median follow-up was 28·1 months (IQR 22·0-33·6). In the intention-to-treat population, median CFI was 14·3 months (95% CI 13·0-17·4) in the rucaparib group versus 8·8 months (8·0-10·3) in the placebo group (hazard ratio [HR] 0·43 [95% CI 0·35-0·53]; p Interpretation In these exploratory analyses over a median follow-up of more than 2 years, rucaparib maintenance treatment led to a clinically meaningful delay in starting subsequent therapy and provided lasting clinical benefits versus placebo in all three analysis cohorts. Updated safety data were consistent with previous reports. Funding Clovis Oncology.
62 citations
University College London1, University of Milan2, University of Toronto3, Saitama Medical University4, University of Alabama at Birmingham5, University of California, Irvine6, I.M. Sechenov First Moscow State Medical University7, Catholic University of the Sacred Heart8, University Health System9, Pfizer10
37 citations
Copenhagen University Hospital1, Northside Hospital2, Oslo University Hospital3, Ludwig Maximilian University of Munich4, Université de Sherbrooke5, University College London6, Cedars-Sinai Medical Center7, Odense University Hospital8, McGill University9, Hospital Clínico San Carlos10, Katholieke Universiteit Leuven11, Wolfson Medical Center12, GlaxoSmithKline13, Harvard University14
TL;DR: These data demonstrate the importance of appropriate dose reduction according to toxicity criteria and support the safe long-term use of niraparib for maintenance treatment in patients with recurrent ovarian cancer.
24 citations
University of Oxford1, University College London2, University Hospital Coventry3, Imperial College London4, Seoul National University Hospital5, St James's University Hospital6, Clatterbridge Cancer Centre NHS Foundation Trust7, Newcastle University8, Northwood University9, University College Hospital10, University of Manchester11
TL;DR: The findings do not support routine use of weekly paclitaxel- regimens in the management of newly diagnosed ovarian cancer and no evidence of a difference in global quality of life between treatment groups at 9 months is found.
Abstract: Summary Background The ICON8 study reported no significant improvement in progression-free survival (a primary endpoint) with weekly chemotherapy compared with standard 3-weekly treatment among patients with epithelial ovarian cancer All ICON8 patients were eligible to take part in the accompanying health-related quality-of-life study, which measured the effect of treatment on self-reported wellbeing, reported here Methods In this open-label, randomised, controlled, phase 3, three-arm, Gynecologic Cancer Intergroup (GCIG) trial done at 117 hospital sites in the UK, Australia, New Zealand, Mexico, South Korea, and Republic of Ireland, women (aged at least 18 years) with newly diagnosed, histologically confirmed International Federation of Gynecology and Obstetrics stage IC–IV ovarian cancer and an Eastern Cooperative Oncology Group performance status of 0–2 were randomly assigned (1:1:1) centrally using minimisation to group 1 (intravenous carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 intravenous paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 weekly and 80 mg/m2 paclitaxel weekly) Randomisation was stratified by GCIG group, disease stage, and outcome and timing of surgery Patients and clinicians were not masked to treatment assignment Patients underwent immediate or delayed primary surgery according to clinicians' choice Patients were asked to complete European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-OV28 questionnaires at enrolment, before each chemotherapy cycle, then 6-weekly up to 9 months, 3-monthly up to 2 years, and 6-monthly up to 5 years Quality of life was a prespecified secondary outcome of the ICON8 study Within the quality-of-life study, the co-primary endpoints were QLQ-C30 global health score at 9 months (cross-sectional analysis) and mean QLQ-C30 global health score from randomisation to 9 months (longitudinal analysis) Data analyses were done on an intention-to-treat basis The trial is registered on ClinicalTrialsgov , NCT01654146 and ISRCTN Registry, ISRCTN10356387, and is currently in long-term follow up Findings Between June 6, 2011, and Nov 28, 2014, 1566 patients were recruited into ICON8 (522 were included in group 1, 523 in group 2, and 521 in group 3) Baseline quality-of-life questionnaires were completed by 1438 (92%) of 1566 patients and 9-month questionnaires by 882 (69%) of 1280 patients We observed no significant difference in global health score at 9 months (cross-sectional analysis) between study groups (group 2 vs group 1, difference in mean score 2·3, 95% CI −0·4 to 4·9, p=0·095; group 3 vs group 1, −0·8, −3·8 to 2·2, p=0·61) Using longitudinal analysis, we found lower global health scores for those receiving weekly paclitaxel than for those receiving 3-weekly chemotherapy (group 2 vs group 1, mean difference −1·8, 95% CI −3·6 to −0·1, p=0·043; group 3 vs group 1, −2·9, −4·7 to −1·1, p=0·0018) Interpretation We found no evidence of a difference in global quality of life between treatment groups at 9 months; however, patients receiving weekly treatment reported lower mean quality of life across the 9-month period after randomisation Taken together with the lack of progression-free survival benefit, these findings do not support routine use of weekly paclitaxel-containing regimens in the management of newly diagnosed ovarian cancer Funding Cancer Research UK, Medical Research Council, Health Research Board Ireland, Irish Cancer Society, and Cancer Australia
21 citations
Harvard University1, Sheba Medical Center2, Yale University3, Katholieke Universiteit Leuven4, Netherlands Cancer Institute5, University of Alabama at Birmingham6, Free University of Berlin7, European Institute of Oncology8, University of Navarra9, Hebron University10, Radboud University Nijmegen11, Vilnius University12, Merck & Co.13, University College London14
TL;DR: Pembrolizumab showed modest clinical activity in patients with recurrent advanced ovarian cancer with recurrent AOC after a median follow-up of 16.9 mo in an interim analysis of patients treated with the drug.
Abstract: 6005Background: Pembrolizumab (pembro) showed modest clinical activity in patients (pts) with recurrent advanced ovarian cancer (AOC) after a median follow-up of 16.9 mo in an interim analysis of K...
21 citations
New Generation University College1, University of Sydney2, Institut Gustave Roussy3, University College London4, Harvard University5, Princess Margaret Cancer Centre6, Sheba Medical Center7, Pomeranian Medical University8, European Institute of Oncology9, Hannover Medical School10, Netherlands Cancer Institute11, Peter MacCallum Cancer Centre12
18 citations
TL;DR: Nintedanib did not improve outcomes when added to oral cyclophosphamide, and more patients than expected remained on treatment for ≥6 months, which may reflect a higher proportion of patients with more indolent disease or the higher dose of cycloph phosphamide used.
15 citations
European Institute of Oncology1, Princess Margaret Cancer Centre2, Memorial Sloan Kettering Cancer Center3, St John of God Subiaco Hospital4, Ottawa Hospital Research Institute5, University of Manchester6, Institut Gustave Roussy7, Auckland City Hospital8, Royal Brisbane and Women's Hospital9, Ohio State University10, Johns Hopkins University11, The Royal Marsden NHS Foundation Trust12, University of Washington13, University College London14, University of Texas MD Anderson Cancer Center15
TL;DR: Efficacy, patient-centered outcomes, and safety of rucaparib were similar between age subgroups, indicating that all eligible women with recurrent ovarian cancer should be offered this therapeutic option, irrespective of age.
13 citations
Institut Gustave Roussy1, Katholieke Universiteit Leuven2, University of Marburg3, Hospital Universitario La Paz4, Oslo University Hospital5, University Hospital of Basel6, University of Graz7, Charité8, Dresden University of Technology9, Ludwig Maximilian University of Munich10, University College London11
TL;DR: The addition of atezolizumab to standard non-platinum combination of chemotherapy and bevacizumAB improves median overall survival from 15 to 20 months and overall survival and progression-free survival are co-primary endpoints.
Abstract: Background Improvement in clinical outcomes of patients with platinum-resistant disease is an unmet medical need and trials in this population are urgently needed Checkpoint-inhibitors have already shown activity in multiple other tumor entities and ovarian cancer, especially in the combination with anti-angiogenic treatment Primary objective To test if the activity of non-platinum-based chemotherapy and bevacizumab could be improved by the addition of atezolizumab Study hypothesis The addition of atezolizumab to standard non-platinum combination of chemotherapy and bevacizumab improves median overall survival from 15 to 20 months Trial design Patients are randomized to chemotherapy (paclitaxel weekly or pegylated liposomal doxorubicin) + bevacizumab + placebo vs chemotherapy + bevacizumab + atezolizumab Stratification factors are: number of prior lines, planned type of chemotherapy, prior use of bevacizumab, and tumor programmed death-ligand 1 (PD-L1) status Major inclusion/exclusion criteria Recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer with up to three prior therapies and a treatment-free interval after platinum of less than 6 months Patients with three prior lines of chemotherapy are eligible irrespective of the platinum free-interval A de novo tumor tissue sample biopsy for determination of PD-L1 status prior to randomization for stratification is mandatory Major exclusion criteria consider bevacizumab-specific and immunotherapy-specific criteria Primary endpoint Overall survival and progression-free survival are co-primary endpoints Sample size It is planned to randomize 664 patients Trial registration NCT03353831
TL;DR: Clinical data support the use of PARP inhibitor maintenance therapy beyond BRCA patients and current HRD tests lack negative predictive value and more research is required to develop a composite HRD assay that provides a dynamic readout of HRD status.
Abstract: Purpose of review:
PARP inhibitors have transformed the management of BRCA mutant (BRCAmut) high-grade serous and endometroid ovarian cancer (HGOC). However, it is clear that the benefit can be extended beyond this subgroup, particularly to those cancers with homologous recombination repair deficiency (HRD). We review emerging molecular and clinical data to support the use of PARP inhibitors in HRD HGOC and discuss the advantages and disadvantages of different HRD assays.
Recent findings:
Several phase 3 trials support the use of PARP inhibitor maintenance therapy beyond those patients with BRCAmut in the first-line and platinum-sensitive relapse setting. Many of these studies included HRD testing and it is clear, regardless of the assay used, that an incremental reduction in benefit is observed from BRCAmut tumours to HRD to homologous recombination proficient tumours. However, although currently available HRD assays predict the magnitude of benefit from PARP inhibitors, they consistently fail to identify a subgroup of patients who do not benefit.
Summary:
Clinical data support the use of PARP inhibitor maintenance therapy beyond BRCAmut patients. Current HRD tests lack negative predictive value and more research is required to develop a composite HRD assay that provides a dynamic readout of HRD status.
St George's Hospital1, National Health and Medical Research Council2, University College London3, Harvard University4, Princess Margaret Cancer Centre5, Sheba Medical Center6, Pomeranian Medical University7, New Generation University College8, Yonsei University9, European Institute of Oncology10, Saitama Medical University11, Netherlands Cancer Institute12, Katholieke Universiteit Leuven13, Paris Descartes University14
TL;DR: Almost half the patients without CA-125 progression had RECIST progression, and most of these hadCA-125 within the normal range, and regular computed tomography imaging should be considered as part of surveillance in patients treated with or without maintenance olaparib rather than relying on CA- 125 alone.
TL;DR: Baseline HRQL is simple to measure, is predictive of PFS and OS and when used in conjunction with clinicopathological prognostic factors, can assist with clinical decision making and treatment recommendations for women with PPSROC≥3.
University of Milan1, Princess Margaret Cancer Centre2, Saitama Medical University3, University of Alabama at Birmingham4, Virginia Commonwealth University5, I.M. Sechenov First Moscow State Medical University6, Agostino Gemelli University Polyclinic7, University Health System8, Pfizer9, University of Arizona10
TL;DR: The JAVELIN Ovarian 100 trial as discussed by the authors showed that avelumab (anti-PD-L1) in combination with chemotherapy or as maintenance did not improve progression-free survival (PFS) vs chemotherapy followed by observation in treatment-naive patients with epithelial ovarian cancer (EOC).
Abstract: Introduction In the JAVELIN Ovarian 100 trial (NCT02718417), avelumab (anti–PD-L1) in combination with chemotherapy or as maintenance did not improve progression-free survival (PFS) vs chemotherapy followed by observation in treatment-naive patients with epithelial ovarian cancer (EOC; hazard ratios [95% CI] were 1.14 [0.832, 1.565] and 1.43 [1.051, 1.946], respectively). The trial was terminated when prespecified futility boundaries were crossed at the interim analysis, and study treatment was subsequently discontinued. Here we report biomarker analyses. Methods Women with stage III-IV EOC (post debulking/cytoreductive surgery or candidates for neoadjuvant chemotherapy) were randomized 1:1:1 to receive carboplatin/paclitaxel chemotherapy (6 cycles) followed by avelumab every 2 weeks as maintenance (CTx→Ave), chemotherapy + avelumab (10 mg/kg every 3 weeks) followed by avelumab every 2 weeks as maintenance (CTx+Ave→Ave), or chemotherapy followed by observation (CTx→O; control arm). The primary endpoint was PFS by blinded independent central review per RECIST version 1.1. Pretreatment tumor tissue was analyzed by immunohistochemistry (CD8 and PD-L1) and next-generation DNA and RNA sequencing. Results 998 patients were randomized. Subgroup analyses based on PD-L1, CD8, and germline BRCA1/2 status did not identify subsets with clear PFS benefit in either avelumab arm vs control (table 1). Whole-exome and RNA sequencing analyses will be presented. Conclusions In the JAVELIN Ovarian 100 trial, PD-L1, CD8, and germline BRCA1/2 status did not predict differential clinical benefit with the addition of avelumab to chemotherapy in treatment-naive patients with EOC.
Ohio State University1, Princess Margaret Cancer Centre2, Memorial Sloan Kettering Cancer Center3, University of Milan4, Ottawa Hospital Research Institute5, University of Manchester6, Institut Gustave Roussy7, Royal Brisbane and Women's Hospital8, Johns Hopkins University9, The Royal Marsden NHS Foundation Trust10, University of Washington Medical Center11, University College London12, University of Texas at Austin13
TL;DR: This year’s recipients include David M. O’Malley, Domenica Lorusso, Carol Aghajanian, Ana Oaknin, Nicoletta Colombo, Johanne I. Weberpals, and Robert L. Coleman.
Abstract: David M. O’Malley,1 Amit M. Oza,2 Domenica Lorusso,3 Carol Aghajanian,4 Ana Oaknin,5 Andrew Dean,6 Nicoletta Colombo,7 Johanne I. Weberpals,8 Andrew R. Clamp,9 Giovanni Scambia,3 Alexandra Leary,10 Robert W. Holloway,11 Margarita Amenedo Gancedo,12 Peter C. Fong,13 Jeffrey C. Goh,14 Deborah K. Armstrong,15 Susana Banerjee,16 Jesus García-Donas,17 Elizabeth M. Swisher,18 Terri Cameron,19 Lara Maloney,20 Sandra Goble,20 Kevin K. Lin,20 Jonathan A. Ledermann,21 Robert L. Coleman22
University College London1, Sheba Medical Center2, Yale University3, Katholieke Universiteit Leuven4, Netherlands Cancer Institute5, University of Arkansas for Medical Sciences6, Université de Montréal7, Free University of Berlin8, European Institute of Oncology9, University of Navarra10, Hebron University11, Merck & Co.12, Harvard University13
Ottawa Hospital Research Institute1, Princess Margaret Cancer Centre2, Memorial Sloan Kettering Cancer Center3, Hebron University4, European Institute of Oncology5, University of Manchester6, Institut Gustave Roussy7, University of Auckland8, Royal Brisbane and Women's Hospital9, Ohio State University10, Johns Hopkins University School of Medicine11, The Royal Marsden NHS Foundation Trust12, University of Washington13, University College London14
TL;DR: Rucaparib maintenance for recurrent ovarian cancer (rOC) significantly improved investigator-assessed PFS and postprogression efficacy outcomes versus placebo regardless of biomarker status and there was a trend for better outcomes across all endpoints in patients with BRCA1 and BRCa2 mutations.
Abstract: Introduction In ARIEL3 (NCT01968213), rucaparib maintenance for recurrent ovarian cancer (rOC) significantly improved investigator-assessed PFS and postprogression efficacy outcomes versus placebo regardless of biomarker status. PFS was also improved in patients with rOC associated with either BRCA1 or BRCA2 mutations (HR, 0.32 [95% CI, 0.19–0.53] and 0.12 [0.06–0.26], respectively). This exploratory analysis further examined the subgroup of patients with rOC associated with BRCA1 or BRCA2 mutations to assess the durability of the clinical benefit of rucaparib maintenance following disease progression. Methods Patients were randomised 2:1 to oral rucaparib (600 mg twice daily) or placebo. Postprogression efficacy endpoints were assessed in patients with germline or somatic BRCA1 or BRCA2 mutations. Results Investigator-assessed postprogression efficacy endpoints for patients with either BRCA1 or BRCA2 mutations are presented in the table 1. There was a trend for better outcomes across all endpoints in patients with BRCA1 and BRCA2 mutations, with larger differences between the median values among patients with a BRCA2 mutation. The treatment-by-mutation group interaction test reached statistical significance for TFST and CFI. Among rucaparib-treated patients, the most common treatment-emergent adverse events (any grade) in the BRCA1 and BRCA2 subgroups were nausea (81.0% and 78.0%) and asthenia/fatigue (74.7% and 80.0%). Conclusions/Implications All postprogression efficacy endpoints were longer with rucaparib maintenance than with placebo in both BRCA-mutant subgroups. Safety data for the two subgroups were similar and were consistent with the overall safety population.
University of Sydney1, University College London2, Harvard University3, Princess Margaret Cancer Centre4, Sheba Medical Center5, Pomeranian Medical University6, Hannover Medical School7, Saitama Medical University8, Netherlands Cancer Institute9, Katholieke Universiteit Leuven10, Seoul National University11, Paris Descartes University12
TL;DR: There are no data to support CA-125 as a surrogate biomarker for ovarian cancer PD in patients on maintenance therapy with a PARPi, and the concordance of PD by CA-12 is assessed.
Abstract: 6014Background: There are no data to support CA-125 as a surrogate biomarker for ovarian cancer PD in patients on maintenance therapy with a PARPi. We aimed to assess the concordance of PD by CA-12...