Showing papers by "Jonathan A. Ledermann published in 2018"

Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial

Abstract: Summary Background Although women with endometrial cancer generally have a favourable prognosis, those with high-risk disease features are at increased risk of recurrence. The PORTEC-3 trial was initiated to investigate the benefit of adjuvant chemotherapy during and after radiotherapy (chemoradiotherapy) versus pelvic radiotherapy alone for women with high-risk endometrial cancer. Methods PORTEC-3 was an open-label, international, randomised, phase 3 trial involving 103 centres in six clinical trials collaborating in the Gynaecological Cancer Intergroup. Eligible women had high-risk endometrial cancer with FIGO 2009 stage I, endometrioid-type grade 3 with deep myometrial invasion or lymph-vascular space invasion (or both), endometrioid-type stage II or III, or stage I to III with serous or clear cell histology. Women were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or radiotherapy and chemotherapy (consisting of two cycles of cisplatin 50 mg/m 2 given during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m 2 ) using a biased-coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage of cancer, and histological type. The co-primary endpoints were overall survival and failure-free survival. We used the Kaplan-Meier method, log-rank test, and Cox regression analysis for final analysis by intention to treat and adjusted for stratification factors. The study was closed on Dec 20, 2013, after achieving complete accrual; follow-up is ongoing. PORTEC-3 is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov, number NCT00411138. Results 686 women were enrolled between Nov 23, 2006, and Dec 20, 2013. 660 eligible patients were included in the final analysis, of whom 330 were assigned to chemoradiotherapy and 330 were assigned to radiotherapy. Median follow-up was 60·2 months (IQR 48·1–73·1). 5-year overall survival was 81·8% (95% CI 77·5–86·2) with chemoradiotherapy versus 76·7% (72·1–81·6) with radiotherapy (adjusted hazard ratio [HR] 0·76, 95% CI 0·54–1·06; p=0·11); 5-year failure-free survival was 75·5% (95% CI 70·3–79·9) versus 68·6% (63·1–73·4; HR 0·71, 95% CI 0·53–0·95; p=0·022). Grade 3 or worse adverse events during treatment occurred in 198 (60%) of 330 who received chemoradiotherapy versus 41 (12%) of 330 patients who received radiotherapy (p vs one [1%] at 3 years; p Interpretation Adjuvant chemotherapy given during and after radiotherapy for high-risk endometrial cancer did not improve 5-year overall survival, although it did increase failure-free survival. Women with high-risk endometrial cancer should be individually counselled about this combined treatment. Continued follow-up is needed to evaluate long-term survival. Funding Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council Project Grant and Cancer Australia, L'Agenzia Italiana del Farmaco, and Canadian Cancer Society Research Institute.

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes

Abstract: Olaparib (Lynparza™) is a PARP inhibitor approved for advanced BRCA-mutated (BRCAm) ovarian cancer. PARP inhibitors may benefit patients whose tumours are dysfunctional in DNA repair mechanisms unrelated to BRCA1/2. We report exploratory analyses, including the long-term outcome of candidate biomarkers of sensitivity to olaparib in BRCA wild-type (BRCAwt) tumours. Tumour samples from an olaparib maintenance monotherapy trial (Study 19, D0810C00019; NCT00753545) were analysed. Analyses included classification of mutations in genes involved in homologous recombination repair (HRR), BRCA1 promoter methylation status, measurement of BRCA1 protein and Myriad HRD score. Patients with BRCAm tumours gained most benefit from olaparib; a similar treatment benefit was also observed in 21/95 patients whose tumours were BRCAwt but had loss-of-function HRR mutations compared to patients with no detectable HRR mutations (58/95). A higher median Myriad MyChoice® HRD score was observed in BRCAm and BRCAwt tumours with BRCA1 methylation. Patients without BRCAm tumours derived benefit from olaparib treatment vs placebo although to a lesser extent than BRCAm patients. Ovarian cancer patients with tumours harbouring loss-of-function mutations in HRR genes other than BRCA1/2 may constitute a small, molecularly identifiable and clinically relevant population who derive treatment benefit from olaparib similar to patients with BRCAm.

Long-term efficacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy

Abstract: BACKGROUND: In Study 19, maintenance monotherapy with olaparib significantly prolonged progression-free survival vs placebo in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer. METHODS: Study 19 was a randomised, placebo-controlled, Phase II trial enrolling 265 patients who had received at least two platinum-based chemotherapy regimens and were in complete or partial response to their most recent regimen. Patients were randomised to olaparib (capsules; 400 mg bid) or placebo. We present long-term safety and final mature overall survival (OS; 79% maturity) data, from the last data cut-off (9 May 2016). RESULTS: Thirty-two patients (24%) received maintenance olaparib for over 2 years; 15 (11%) did so for over 6 years. No new tolerability signals were identified with long-term treatment and adverse events were generally low grade. The incidence of discontinuations due to adverse events was low (6%). An apparent OS advantage was observed with olaparib vs placebo (hazard ratio 0.73, 95% confidence interval 0.55‒0.95, P = 0.02138) irrespective of BRCA1/2 mutation status, although the predefined threshold for statistical significance was not met. CONCLUSIONS: Study 19 showed a favourable final OS result irrespective of BRCA1/2 mutation status and unprecedented long-term benefit with maintenance olaparib for a subset of platinum-sensitive, recurrent ovarian cancer patients.

Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: Interim results from the phase 2 KEYNOTE-100 study.

Abstract: 5511Background: Data from the KEYNOTE-028 study (NCT02054806) suggested that pembrolizumab (pembro) has clinical activity in patients (pts) with PD-L1+ advanced ovarian cancer (AOC). We assessed th...

STATEC: A randomised trial of non-selective versus selective adjuvant therapy in high risk apparent stage 1 endometrial cancer.

Abstract: TPS5615Background: The benefit of lymphadenectomy on survival in stage 1 endometrial cancer remains uncertain. STATEC is a surgical trial designed to evaluate the use of nodal status after lymph no...

Abstract LB-A12: Results from the phase 3 study ARIEL3: mutations in non-BRCA homologous recombination repair genes confer sensitivity to maintenance treatment with the PARP inhibitor rucaparib in patients with recurrent platinum-sensitive high-grade ovarian carcinoma

Abstract: Background: High-grade ovarian carcinomas (HGOC) with a mutation in BRCA1/2 or other core homologous recombination repair (HRR) genes are sensitive to treatment with the PARP inhibitor rucaparib. To study whether HRR gene mutations confer sensitivity to rucaparib in the maintenance setting, we performed next-generation sequencing (NGS) on carcinomas from a double-blind, placebo-controlled, phase 3 study of rucaparib in patients with HGOC following response to platinum-based chemotherapy (ARIEL3, NCT01968213). Materials and Methods: Archival ovarian carcinoma specimens were required for all 564 patients who were randomized in ARIEL3 and were sequenced using Foundation Medicine’s NGS-based assay to identify deleterious mutations in a prespecified list of HRR genes (BRCA1/2 and 28 non-BRCA HRR genes, including ATM, BARD1, BRIP1, CHEK2, RAD51C, RAD51D, RAD54L, and FANC family genes). Patients were randomized 2:1 to receive oral rucaparib 600 mg twice daily or placebo. The randomization was stratified by HRR gene mutation status (BRCA, non-BRCA HRR, no mutation in BRCA or HRR gene), progression-free interval of the penultimate platinum-based regimen, and best response to most recent platinum regimen. The primary endpoint for ARIEL3 was investigator-assessed progression-free survival (PFS) per RECIST v1.1. Exploratory analysis of confirmed response was conducted for the subgroup of patients with measurable disease at study entry. Results: Deleterious mutations in non-BRCA HRR genes were detected in ovarian carcinoma specimens from 7.6% (43/564) of randomized patients. In these patients, PFS was significantly longer with rucaparib than with placebo (hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.09-0.50; P=0.0005), with a median PFS of 11.1 mo and 5.5 mo, respectively. This HR is similar to that found in women with carcinomas containing a BRCA1/2 mutation (0.23; 95% CI, 0.16-0.34). The most commonly found non-BRCA HRR gene mutations among the 28 patients in the rucaparib arm were RAD51C (n=6) and RAD51D (n=4) and among the 15 patients in the placebo arm were BRIP1 (n=5) and RAD51C (n=2). A diverse set of mutation types were detected, including frameshift insertions/deletions, homozygous deletions, and nonsense and splice site mutations. All 10 RAD51C/D mutations were homozygous within the carcinomas, indicating biallelic loss. Additionally, all RAD51C/D-mutant carcinomas exhibited high genomic loss of heterozygosity, which is a type of genomic scar characteristic of HRR deficiency. At the visit cutoff date (15 April 2017), only 2 of the 10 RAD51C/D cases in the rucaparib arm had disease progression; 7 had a PFS duration of at least 1 y (median PFS, 16.4 mo; range 5.4+ to 30.4+ mo). Three of the RAD51C/D cases were in the subgroup of patients who had measurable disease at baseline, and all achieved a confirmed response (1 complete response and 2 partial responses). In comparison, the 3 RAD51C/D cases in the placebo arm had a median PFS of 5.4 mo (range, 3.9 to 5.5 mo). Conclusions: Patients with recurrent platinum-sensitive HGOC harboring a deleterious mutation in non-BRCA HRR genes (including RAD51C/D) had significantly longer PFS with rucaparib maintenance treatment than with placebo. Citation Format: David M. O9Malley, Robert L. Coleman, Amit M. Oza, Domenica Lorusso, Carol Aghajanian, Ana Oaknin, Andrew Dean, Nicoletta Colombo, Iain A. McNeish, Elizabeth M. Swisher, Clare L. Scott, Gottfried E. Konecny, Heidi Giordano, Terri Cameron, Lara Maloney, Sandra Goble, James Sun, Thomas C. Harding, Kevin K. Lin, Jonathan A. Ledermann. Results from the phase 3 study ARIEL3: mutations in non-BRCA homologous recombination repair genes confer sensitivity to maintenance treatment with the PARP inhibitor rucaparib in patients with recurrent platinum-sensitive high-grade ovarian carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A12.

Clear cell ovarian cancer (CCOC): 115 patient (pt) series showing access to experimental therapy may improve response rates in recurrent disease.

Abstract: 5581Background: 10 year survival for ovarian cancer (OC) in the UK has improved from 18% (1971) to a predicted survival of 35% (2011). Historical data show pts with advanced CCOC have worse surviva...

Abstract PR06: ARIEL3: A phase 3, randomized, double-blind study of rucaparib vs placebo following response to platinum-based chemotherapy for recurrent ovarian cancer (OC)

Abstract: Background: Rucaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, is approved in the United States for treatment of women with deleterious BRCA mutation (germline and/or somatic) associated advanced OC who have been treated with two or more chemotherapies. Rucaparib has also demonstrated antitumor activity in the treatment setting in patients (pts) with BRCA wild-type associated recurrent OC whose tumor has high genomic loss of heterozygosity (LOH). ARIEL3 evaluated rucaparib vs placebo as maintenance treatment in pts with recurrent platinum-sensitive OC. Methods: Eligible pts received ≥2 prior platinum-based therapies, had platinum-sensitive OC (disease progression ≥6 mo after penultimate platinum), and achieved a complete response (RECIST v1.1) or partial response (RECIST v1.1 or Gynecologic Cancer InterGroup CA-125 criteria) to their most recent platinum. All pts were required to have CA-125 less than the upper limit of normal. Pts were randomized 2:1 to receive oral rucaparib 600 mg BID or placebo. Investigator-assessed progression-free survival (PFS) (primary endpoint) was assessed in a step-down procedure for 3 nested cohorts: (1) BRCA mutant (deleterious germline or somatic BRCA mutation); (2) homologous recombination deficient (HRD) (BRCA mutant or BRCA wild type/LOH high); and (3) intent-to-treat (ITT) population. PFS was also assessed by blinded independent central review (BICR) (secondary endpoint) and LOH status in pts with BRCA wild type OC (exploratory endpoint). Adverse events (AEs) were summarized descriptively. Results: ARIEL3 enrolled 564 pts (375, rucaparib; 189, placebo). Nearly 200 pts (n=196) had BRCA mutation-associated OC. Of these pts, 130 had a germline BRCA mutation (82 [21.9%], rucaparib; 48 [25.4%], placebo), 56 had a somatic BRCA mutation (40 [10.7%], rucaparib; 16 [8.5%], placebo), and 10 pts had tumors with germline and/or somatic BRCA status unknown (8 [2.1%], rucaparib; 2 [1.1%], placebo). Median investigator-assessed PFS in the BRCA-mutant cohort (130, rucaparib; 66 placebo) was 16.6 mo vs 5.4 mo (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.16-0.34; P Conclusion: Rucaparib significantly improved PFS vs placebo in pts with platinum-sensitive, recurrent OC in all primary analysis groups of pts with platinum-sensitive, recurrent OC. Additionally, rucaparib significantly improved PFS vs placebo in pts with BRCA wild-type OC (LOH high and LOH low). Clinical trial identification: NCT01968213. This abstract is also being presented as Poster A47. Citation Format: Robert L. Coleman, Amit M. Oza, Domenica Lorusso, Carol Aghajanian, Ana Oaknin, Andrew Dean, Nicoletta Colombo, Johanne I. Weberpals, Andrew Clamp, Giovanni Scambia, Alexandra Leary, Robert W. Holloway, David M. O’Malley, Terri Cameron, Lara Maloney, Sandra Goble, Kevin Lin, James Sun, Heidi Giordano, Jonathan A. Ledermann. ARIEL3: A phase 3, randomized, double-blind study of rucaparib vs placebo following response to platinum-based chemotherapy for recurrent ovarian cancer (OC). [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr PR06.

Exploratory analysis of percentage of genomic loss of heterozygosity (LOH) in patients with platinum-sensitive recurrent ovarian carcinoma (rOC) in ARIEL3.

Abstract: 5545Background: In ARIEL3, rucaparib significantly improved progression-free survival (PFS) vs placebo in all randomized patients, including patients with BRCA-mutant, BRCA wild-type/high-LOH (pres...

Evaluation of rucaparib in platinum-sensitive recurrent ovarian carcinoma (rOC) in patients (pts) with or without residual bulky disease at baseline in the ARIEL3 study.

Abstract: 5537Background: In ARIEL3, pts were randomized 2:1 (oral rucaparib 600 mg or placebo). Rucaparib significantly improved progression-free survival (PFS) vs placebo in all primary analysis groups (Co...

Locus-specific loss of heterozygosity (LOH) in BRCA1/2 mutated (mBRCA) ovarian tumors from the SOLO2 (NCT01874353) and Study 19 (NCT00753545) clinical trials.

Abstract: 5563Background: The PARP inhibitor olaparib is approved in the US for patients with mBRCA (germline) advanced ovarian cancer, and in the EU for platinum-sensitive relapsed mBRCA (germline or somati...

METRO-BIBF: Phase II, randomised, placebo controlled, multicentre, trial of low dose (metronomic) cyclophosphamide (MCy) with or without nintedanib in relapsed ovarian cancer (ROC).

Abstract: 5551Background: ROC patients (pts), heavily pretreated with IV chemotherapy (CT) are a heterogenous group, median OS 3-9 mo. Oral MCy is well tolerated, avoids IV CT and has been shown to have clin...