Lurbinectedin (L) is a new anticancer agent that blocks transcriptional transactivation, induces DNA double-strand breaks, and modulates the tumor microenvironment. L showed activity in platinum-resistant ovarian cancer (PROC) patients (pts) in a randomized phase II trial in comparison to topotecan (Ann Oncol 2017; 28:1280).
Pts with PROC [platinum-free interval [PFI] 1-6 months (mo) after last platinum chemotherapy (CT)] treated with ≤3 prior CT lines and ECOG PS 0-2 were eligible. Enrolled pts were randomly assigned (1:1) to receive L 3.2 mg/m2 q3wk (Arm A), or investigator choice of PLD (P) 50 mg/m2 q4wk or topotecan (T) 1.5 mg/m2/day D1-5 q3wk (Arm B) until progression or discontinuation due to toxicity. Pts were stratified by ECOG PS (0 vs ≥ 1), PFI (1-3 vs > 3-6 mo) and prior CT lines (1-2 vs 3). The primary endpoint was PFS by independent review committee (IRC). Sample size was calculated to demonstrate a 30% reduction in the relative risk of progression or death. The secondary endpoints of ORR, OS, and patient-reported outcomes are also reported.
442 pts were randomized; 221 in each arm. Baseline characteristics were well balanced including median prior CT (n = 2) with the following differences (Arm A/B): median age 63/59 years; serous histology 82/90%; ascites 41/50%; and use of prior bevacizumab 40/46%. Median (95% CI) PFS by IRC was 3.5 mo in arm A vs 3.6 mo in arm B (HR 1.04, 95% CI 0.84-1.29). ORR by IRC was 14.0% (9.7-19.3%) in arm A vs 12.2% (8.2-17.3%) for arm B (p=NS). Interim OS was 11.2 mo in arm A vs 11.1 mo in arm B (HR 0.97, 95% CI 0.77-1.23). Related adverse events (AEs) were reported in 201/219 pts (92%) in Arm A vs 198/213 (93%) in Arm B; grade ≥ 3 AEs in 105 (48%) vs 136 (64%) (p = 0.001), respectively. In arm B, T accounted for a higher percentage of AEs than P. Treatment-related dose reductions, delays and discontinuations were more frequent in Arm B. Global QoL scores were not different between the arms.
Although the primary endpoint (30% of reduction in PFS) was not met, the similar efficacy results between arms and the favorable safety profile indicate a potential role for Lurbinectedin in the difficult-to-treat PROC setting.
Has not received any funding.
S. Gaillard: Consulting or advisory role: Pfizer, Genentech/Roche, Merck, Tesaro; Patents, royalties, other intellectual property: Sermonix Pharmaceuticals; Honoraria: Merck; Research funding: TetraLogic Pharmaceuticals, PharmaMar, Bristol-Myers Squibb, Gradalis, Merck, Genentech/Roche, Iovance Biotherapeutics. I.L. Ray-Coquard: Consulting or advisory role: Pfizer, Abbvie, Amgen Honoraria: Roche, PharmaMar, AstraZeneca. I.B. Vergote: Consulting or advisory role: AstraZeneca, Amgen, Array Biopharma, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Lilly, GE Healthcare, Genentech, GlaxoSmithKline, Intuitive Surgical, Janssen-Cilag, MedImmune, Menarini, Merck Sharp & Dohme, Morphotek, Nektar, Novo Nordisk, Oasmia Pharmaceutical AB, PharmaMar, Phillips Gilmore Oncology, Roche, Sanofi, Schering-Plough; Travel, accommodations, expenses: GCI Health, Roche, Oasmia Pharmaceutical AB, PharmaMar, AstraZeneca; Research funding: Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Exelixis, Fresenius Biotech, GlaxoSmithKline, Ipsen, Janssen-Cilag, Merck Sharp & Dohme, Merrimack, Morphotek, Nektar, Nerviano Medical, Sciences, Novartis, Pfizer, Quintiles, Roche, Sandoz, Sanofi, Schering-Plough, Vifor Pharma, Wyeth, MedImmune, Genmab, Karyopharm Therapeutics, Tesaro. N. Colombo: Consulting or advisory role: Roche/Genentech, PharmaMar, Amgen, AstraZeneca, Clovis Oncology, Pfizer, MSD Oncology. S.A. Ghamande: Consulting or advisory role: Advaxis; Speakers' bureau: Advaxis; Research funding: Advaxis, GlaxoSmithKline, AstraZeneca, Tesaro, PharmaMar, Teueda, Merck and Co Inc. A. Soto-Matos, C. Kahatt, J. Gomez, A. Nieto: Employee and stock: PharmaMar. C.M. Fernandez, N. Torres: Employee PharmaMar. R.S. Kristeleit: Consulting or advisory role: Clovis Oncology, Roche/Genentech, Sotio, Cerulean Pharma, Basilea; Travel, accommodations, expenses: Clovis Oncology, Basilea, Valirx; Honoraria: Clovis Oncology, Roche/Genentech, AstraZeneca, Tesaro. D.M. O'Malley: Honoraria: Clovis Oncology; Consulting or advisory role: Janssen Oncology, AstraZeneca, Clovis Oncology, Amgen, Tesaro, Novocure, Myriad Genetics, Abbvie; Research funding: Amgen, VentiRx, AstraZeneca, Genentech/Roche, Regeneron, ImmunoGen, Janssen; Research & Development: Clovis Oncology, EMD Serono, Ergomed, Ajinomoto, ImmunoGen, Janssen, Cerulean Pharma, Array BioPharma, Agenus, Tesaro, Tracon Pharma, Stem CentRx, Bristol Myers Squibb, PharmaMar. All other authors have declared no conflicts of interest.
In patients with recurrent ovarian cancer (ROC) suitable for platinum-based retreatment (PBT), standard includes CG-BEV and Carboplatin(C)/pegylated-liposomal- Doxorubicin (D). CG-BEV significantly increases progression-free-survival (PFS) over CG alone whilst CD has one of the best therapeutic indices for ROC-PBT. The aim of this trial was to evaluate whether CD is superior to CG when given in combination with BEV with investigator-determined PFS as primary objective (NCT01837251).
Between 2013/08 and 2015/07 682 pts. with ROC-PBT were randomized to standard CG-BEV (n = 337) or experimental CD-BEV (n = 345). Secondary objectives were overall survival (OS), biological progression-free survival (PFSBIO) by serum CA125, quality of life (QoL) assessed by EORTC-QLQ-C30 and QLQ-OV28, safety and tolerability. The trial was designed to have 80% power (two-sided logrank-test, alpha level 5%) to show a 26.6% change in PFS (Hazard Ratio (HR) 0.79; 564 PFS events).
At data cut-off 571 events occurred. Mean age was 61.1 (SD 10.3) years, 87.4% had serous histology, 83.1% were high grade, 41.5% were pretreated with BEV as part of first-line treatment. CG-BEV was associated with 359 (53,3%) serious adverse events vs. 314 (46,7%) for CD-BEV (p = 0.083). Median PFS in the standard arm CG-BEV was 11.7 months (95% CI 11.1-12.8) vs. 13.3 months (95% CI 11.7-14.3) in the experimental arm CD-BEV (HR 0.80; 95% CI 0.68-0.96, p = 0.0128). In the stratum with previous anti-angiogenic treatment (N = 309) median PFS was 10.1 months (95% CI 8.5-11.2) for CG-BEV vs. 11.3 months (95% CI 10.1-13.8) for CD-BEV (HR 0.73; 95% CI 0.57-0.94, p = 0.0126).
CD-BEV provided a significant PFS improvement compared to CG-BEV in patients with ROC suitable for PBT. A significant PFS improvement was also seen in the subgroup of patients with previous anti-angiogenic treatment. CD-BEV was associated with fewer serious adverse events. Thus CD-BEV might be an important addition to the therapeutic options in these patients.
AGO Research GmbH.
Hoffmann La Roche.
J. Pfisterer: Consulting or Advisory role: Roche; Research funding: Roche; Travel, Accomodations, Expenses: Roche. A.P. Dean: Honoraria: Baxalta, Astra Zeneca; Consulting or Advisory role: Baxalta, specialized Therapeutics; Speakers' bureau: Baxalta; Travel, Accomodations, Expenses: Amgen. P. Harter: Consulting or Advisory role: AstraZeneca, Roche/Genentech, Tesaro, Clovis, PharmaMar, Lilly, Sotio; Travel, Accommodations, Expenses: Medac. F. Joly: Consulting or Advisory role: Roche, Janssen; Travel, Accomodations, Expenses: Roche, Janssen. J. Sehouli: Honoraria: Roche, AstraZeneca, Tesaro, PharmaMar; Consulting or Advisory role: Clovis, Roche, AstraZeneca, Tesaro, Novartis; Research funding: Amgen, Novartis, Lilly, Bayer. U. Canzler: Honoraria: AstraZeneca, Roche Consulting or Advisory role: Roche. B. Schmalfeldt: Consulting or Advisory role: Roche, AstraZeneca, Tesaro; Travel, Accomodations, Expenses: Roche, AstraZeneca. C. Shannon: Consulting or Advisory role: AstraZeneca, Roche. D.U. Reimer: Consulting or Advisory role: AstraZeneca, PharmaMar; Travel, Accomodations, Expenses: AstraZeneca, Amgen, PharmaMar, Roche Patents, Royalties, other intellectual property: yes. L.C. Hanker: Consulting or Advisory role: Roche, Tesaro; Travel, Accomodations, Expenses: Roche, AstraZeneca. T. Petit: Consulting or Advisory role: Roche, Pfizer; Travel, Accomodations, Expenses: Roche, Pierre Fabre. F. Marme´: Honoraria: Roche, Amgen, AstraZeneca, Eisai, Celgene, Novartis, Pfizer, Genomic Health; Consulting or Advisory Role: roche, AstraZeneca, Novartis; Travel, Accomodations, Expenses: Roche, Amgen, AstraZeneca, Eisai, Celgene, Novartis, Pfizer, PharmaMar. A. El-Balat: Honoraria: Roche, AstraZeneca, Tesaro; Consulting or Advisory role: Roche, AstraZeneca, PharmaMar; Travel, Accomodations, Expenses: PharmaMar, Tesaro, Clovis. R. Glasspool: Consulting or Advisory role: Tesaro, Roche, Clovis Oncology, Clovis; Research Funding: Ignyta, Boehringer Ingelheim, Roche; Travel, Accomodations, Expenses: AstraZeneca, Roche, Tesaro. N. de Gregorio: Consulting or Advisory role: Roche, AstraZeneca, Tesaro; Travel, Accomodations, Expenses: Tesaro. S. Mahner: Honoraria: Roche/Genentech, AstraZeneca, PharmaMar, Medac, Jenapharm, Janssen-Cilag, Teva, GlaxoSmithKline; Consulting or Advisory role: Roche, AstraZeneca, Merck Sharp & Dohme, Janssen-Cilag, Tesaro, Medac; Research funding: Roche, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Janssen-Cilag, Medac, PharmaMar, Tesaro, Bayer. J-E. Kurtz: Consulting or Advisory role: Tesaro, AstraZeneca; Travel, Accomodations, Expenses: Roche, PharmaMar. All other authors have declared no conflicts of interest.
Ovarian SCT tend to respond poorly to chemotherapy (CT). We explored the efficacy of wP with or w/o bev in a randomized 1:1 phase II trial in patients (pts) with relapse who were not candidate to surgery & after > 1 line of platinum based CT.
Primary endpoint is the PFS rate at 6 months (PFR-6). Pts in the wP arm were allowed to receive bev alone at progression. A Bayesian approach allowed continuous monitoring PFR-6 with sequential analyses planned every 20 pts to allow early stopping for efficacy. wP+Bev will be considered interesting if the probability is > 0.9 to show that the estimated PFR-6 in wP+Bev is higher than in wP arm.
From 02/13 to 10/16, 60 pts with SCT (52 AGCT (Adult Granulosa cell tumor), 2 SLT (Sertoli Leydig tumor), 6 other) were randomized. All pts had recurrent disease and were previously treated with CT (47 pts received ≤2 lines). Baseline characteristics were well balanced between the 2 arms. 17 pts (28%) received prior hormonal therapy. Platinum-free interval (PFI) was ≥ 12 months in 21 pts (66%) and 22 (79%) in the wP and wP +bev group, respectively. The PFR-6 [95% CI] was 71% [55%; 84%] vs 72% [55%; 87%] in wP arm (arm A) and wP+bev (arm B). Median PFS were 14.7 and 14.9 months, in arm A and B respectively. In wP arm 50% of pts received bev alone at cross over, with median PFS of 7.3 months. Median TFST were 28.5, 33.6 and 33.6 months, in arm A + cross over bev, arm A w/o crossover and arm B respectively. Most frequent AE (all grade) were: hypertension in 78% of pts wP vs 93% of pts wP+Bev, fatigue (63% vs 78%), neuropathy (56% vs 74%), proteinuria (13% vs 63%), bleeding (16% vs 59%), alopecia (34% vs 56%), vomiting (16% vs 7%). Grade 3/4 AEs were reported in 10 arm wP vs 12 pts in arm wP+Bev.
Arms ORR SD PD wP 8(25%) 17(53%) 7(22%) wP+Bev 12(44%) 12(44%) 3(11%)
A randomized trial is feasible in rare cancer with a strong international collaboration. wP confirmed as active drug in SCT. Bev added to wP tends to increase ORR compared to wP alone but failed to significantly improve PFR-6 nor PFS in relapsed SCT pts.
Thanks to all the patients and their families, the investigators, study nurses, pharmacists, pathologists and all study team.
Thanks to Roche laboratory for their financial support.
P. Harter: Honoraria: Roche, Astrazeneca, Tesaro; Consulting: Roche, AstraZeneca, Tesaro, Clovis, Pharmamar. I.B. Vergote: Consulting role: GCI Health, Oncoinvent AS, Rocje NV, Genmab A/S, Advaxis Inc, Morphotec Inc, F. Hoffmann-La Roche Ltd, Cerulean Pharma Inc, Novocure GMBH, AstraZeneca LP, Mateon Therapeutics Inc, Immunogen Inc, Eli Lilly benelux NV, Amgen INc, Theradex Europe Limited, Pfizer Inc, Debiopharma International SA, Vifor Pharma Belgie NV, Novartis Pharma AG, MSD Belgium BVBA, Oxigene Inc, Janssen-Cilag, Nektar Therapeutics, Bayer Pharma AG; Grant: Amgen, Roche; Travel accomodations: Tesaro, Theradex, Elsevier. K. Fujiwara: Honoraria: Chugai, Roche. L. Gladieff: Honoraria: AstraZeneca, Tesaro, Clovis, Roche; Travel accommodations: Roche, Pharmamar. H-J. Lueck: Honoraria: Tesaro, Roche, Amgen, AstraZeneca; Consulting: Tesaro, Roche, Pfizer, Novartis; Speakers' bureau: Roche, Novartis, Pfizer, Amgen; Travel accommodations: AstraZeneca, Tesaro. A. Floquet: Travel accommodations: Roche. A. Schnelzer: Consulting: Roche S. Pignata: Honoraria, Consulting, Travel accommodations: Roche. F. Selle: Consulting: MSD, Roche, AstraZeneca, Tesaro; Travel accommodations: MSD, Roche. J. Sehouli: Honoraria: Roche, AstraZeneca, Tesaro, Pharmamar; Consulting: Novartis, Clovis, Roche, AstraZeneca, Tesaro; Research fundings: Amgen, Novartis, Lilly, Bayer. G. Mangili: Speakers' bureau: Astrazeneca; Research fundings: Ipsen; Travel accommodations: Roche, PharmaMar. P. Pautier: Consulting role: Roche, Tesaro, AstraZeneca, Lilly. U. De Giorgi: Honoraria: BMS, AstraZeneca, Sanofi, Pfizer, Ipsen. P-E. Heudel: Consulting role: AstreZeneca, Pfizer, Novartis; Research fundings: AstrasZeneca; Travel and accommodation: Pfizer, Novartis. All other authors have declared no conflicts of interest.
Ovarian cancer (OC) treatment is associated with psychological morbidity. We prospectively studied the impact of a brief course of psychological support on self-reported depression, fear of progression (FoP) and quality of life (QOL) in patients (pts) following chemotherapy for primary or recurrent OC.
Pts consented at their first post-chemotherapy appointment and were eligible if they scored from 5-19 on PHQ9 questionnaire. They were randomised 1:1 to Intervention or Control. Intervention comprised 3 standardised 90-minute sessions of psychological support given 6 -12 weeks after chemotherapy. Control was standard of care in which support was provided where indicated; unblinded block randomisation was used for primary or recurrent OC and 3 levels of PHQ9 as stratification factors. Pts completed PHQ9, FoP-Q-SF, EORTC QLQ C30 and OV28 questionnaires up to 2 years. Primary endpoint was change in PHQ9 score at 3 months compared to baseline.
Oct 2015 - Nov 2017: 182 pts were registered; 107 were eligible and randomised; 54 to Intervention and 53 to Control; mean age of 59 yrs; 75 (70%) primary and 32 (30%) relapsed disease; 63 pts completed baseline and 3-month questionnaires and were included in the analysis: 31 control, 32 intervention. At 3 months there was an improvement in the PHQ9 and the Global Health Status/QOL scale for pts in both arms compared to baseline but no significant difference between Intervention and Control. However, there was a significant improvement on FoP-Q-SF scores in the Intervention arm whilst, for pts in the Control arm, FoP-Q-SF scores deteriorated at 3 months (Intervention effect = -5.2, 95%CI (-8.45-1.9) p = 0.003).
Overall, although symptoms of depression improved following completion of chemotherapy for patients in both arms of the study, Fear of Progression did not. This is the first randomised trial of a survivorship intervention in OC and demonstrates that Fear of Progression is a prominent concern for pts but it can be overcome with provision of psychological support immediately after chemotherapy.
UKCRN ID 15363.
Imperial College London.
Imperial College Healthcare Charity, Maggie's Centres.
S. Blagden: Advisor: Ellipses; Director of RNA Guardian Ltd, Ad boards: Clovis, Novartis; Research funding: Nucana plc. R.M. Glasspool: Advisory boards: Clovis, Tesaro, Roche, AstraZeneca; Institution receives research funding: Ignyta, Boehringer Ingelheim, AstraZeneca, Tesaro. S. Nicum: Advisory boards: Roche, Tesaro, Clovis, AstraZeneca; Research funding: AstraZeneca. All other authors have declared no conflicts of interest.