Cyclins are proteins that activate cyclin-dependent kinases (CDKs) and are required for normal cell cycle transitions. Palbociclib is an oral selective inhibitor of the CDKs 4 and 6. EC endometrioid adenocarcinoma is hormone dependent and endocrine therapy with aromatase inhibitors is well established. This is the first randomised trial of a CDK4/6 inhibitor (P) vs placebo combined with L in pts with advanced or recurrent ER+ EC.
Eligible pts had ECOG PS 0/1, histologically confirmed endometrioid EC that was ER+ and measurable or evaluable per RECIST v1.1 and had received no prior CDK4/6 inhibitor therapy. Prior surgery, radiation therapy, chemotherapy or ≤1 line of endocrine therapy (MPA/megestrol acetate) was permitted. Pts were stratified according to number of prior chemotherapy lines, prior endocrine therapy and measurable vs evaluable disease. Pts were randomised 1:1 to receive L 2.5 mg OD orally d1–28 with either palbociclib 125 mg or placebo OD orally d1–21 in a 28-d cycle until progression. Tumours were assessed every 12 weeks. The primary endpoint was progression-free survival (PFS).
Of 77 enrolled pts, 73 were evaluable (2 received no trial drug; 1 had brain metastases; 1 withdrew consent before starting treatment): 37 randomised to L + placebo and 36 to L + palbociclib combination. Major comorbidity: diabetes in 12%, hypertension in 41%. 88% had relapsed disease and only 15% had prior MPA/megestrol acetate. Palbociclib/placebo was interrupted in 25/ 8 pts and in 14 pts the dose of palbociclib was reduced. L + palbociclib significantly improved PFS compared with L + placebo: median 8.3 vs. 3.0 months, respectively; hazard ratio 0.56 (95% CI 0.32 to 0.98; p0.041). Disease control rate at 24 weeks: 64% vs. 38%. Treatment-emergent grade 3/4 adverse events were significantly more frequent with L + palbociclib (anaemia 8% vs 3%; neutropenia 42% vs 0%). Patient-reported outcomes were similar in the two treatment arms.
The L + palbociclib combination demonstrated clinically meaningful improvement in PFS with manageable toxicity, meriting phase III investigation.
NCT02730429.
NSGO-CTU (Nordic Society of Gynaecological Oncology - Clinical Trial Unit).
Pfizer.
M.R. Mirza: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy: Biocad; Advisory/Consultancy, Research grant/Funding (institution): Clovis Oncology; Honoraria (self): Genmab; Advisory/Consultancy, Leadership role, Board of Directors: Karyopharm Therapeutics; Advisory/Consultancy: Merck; Advisory/Consultancy: Oncology Adventure; Research grant/Funding (institution): Pfizer; Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy: Seattle Genetics; Honoraria (self), Advisory/Consultancy: Sera Prognostics; Advisory/Consultancy: Sotio; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): GSK; Advisory/Consultancy: Zailab; Research grant/Funding (institution): Boehringer. All other authors have declared no conflicts of interest.
The management of patients with intraoperatively detected positivity of pelvic lymph nodes (LN) remains controversial. Namely, a combination of extensive surgical dissection in the pelvis followed by pelvic radiotherapy is associated with higher morbidity. Goal of ABRAX multicentric, retrospective, cohort study was to determine whether the completion of radical hysterectomy improves oncological outcome of such patients.
A total of 515 cervical cancer patients, who intraoperatively turned to be LN positive, referred for primary surgery with a curative intent between 2005 and 2015 (stage IA-IIB, common tumour types) were retrospectively analysed in 51 institutions from 19 countries. LNs with metastasis ≥2 mm were considered positive (N1). Completion (COMPL group, n=361) or abandonment (ABAND group, n=154) of planned uterine surgery stratified the cohort in two subgroups in which oncological outcomes and major prognostic factors were evaluated. 91.4% of COMPL group underwent adjuvant chemoradiation, 100% of ABAND group were treated with primary chemoradiation.
Disease free survival reached 74% (381/515) in the whole cohort with the median follow-up of 48.9 months. Both groups (ABAND and COMPL) were balanced in main prognostic factors (tumour size, tumour type, stage of disease). No significant difference was found between the groups in the risk of recurrence (HR=1.154; p=0.446), local recurrence (HR=0.836; p=0.557), or death (HR=1.064; p=0.779). Subgroup analyses did not identify any cohort with survival benefit from radical surgery completion. Increasing FIGO stage and tumour size ≥4 cm were identified as major prognostic factors for recurrence and survival in the whole cohort.
ABRAX trial revealed that completion of radical hysterectomy in patients with intraoperative detection of positive lymph node does not improve the survival; recurrence risk is not decreased irrespective of tumour size or tumour type. Therefore, if pelvic LN involvement is diagnosed at surgery, abandonment of planned uterine procedure should be considered and the patient should be referred to definitive chemoradiation.
NCT04037124; July 30, 2019.
The authors.
Charles University in Prague (UNCE 204065 and PROGRES Q28/LF1), and the Czech Research Council (No 16-31643A).
All authors have declared no conflicts of interest.
Post-hoc analysis of NOVA study suggested that patients with low body weight (< 77 kg) or low platelet count (< 150,000/μL) may benefit from an initial starting dose of niraparib 200 mg without compromising efficacy. We aimed to prospectively assess the efficacy and safety of niraparib with an individualized starting dose (ISD) in Chinese patients.
NORA trial was conducted in 32 hospitals in China. Eligible patients were women with PSROC who had either germline
From September 26 2017 to February 2 2019, 265 patients were randomized to niraparib (n=177) or placebo (n=88); 16 patients received fixed starting dose of 300 mg and 249 patients received an ISD (300 mg, n=14; 200 mg, n=235) under the amended protocol. The median PFS was significantly longer for patients on niraparib versus placebo; 18.3 (95% CI, 10.9, not evaluable) versus 5.4 (95% CI, 3.7, 5.7) months (HR=0.32; 95% CI, 0.23–0.45; p <0.0001). Grade ≥3 treatment emergent adverse events (TEAE) occurred in 50.8% and 19.3% of patients (niraparib vs placebo), especially for hematological TEAE reported in the Table. Hematology TEAE of Grade ≥ 3 # Include PTs of platelet count decreased & thrombocytopenia.
TEAEs, n (%) Niraparib (n=177) Placebo (n=88) Neutrophil count decreased 36 (20.3) 7 (8.0) Platelet count decreased # 20 (11.3) 1 (1.1) Anaemia 26 (14.7) 2 (2.3)
This is the first study to demonstrate the efficacy and safety of niraparib in Chinese patients with PSROC. ISD of niraparib is effective and safe and should be considered a standard clinical practice in this patient population.
NCT03705156.
Zai Lab (Shanghai) Co., Ltd.
Zai Lab (Shanghai) Co., Ltd., Shanghai, China. National Major Scientific and Technological Special Project for “Significant New Drugs Development” in 2018 (No. 2018ZX09736019), China.
All authors have declared no conflicts of interest.
The INOVATYON trial aimed at demonstrating an improvement in overall survival (OS) for the trabectedin/PLD (TP) regimen followed, at relapse, by platinum re-challenge, over carboplatin/PLD (CP).
Patients (pts) with recurrent ovarian cancer (ROC) and a platinum-free interval (TFIp) between 6-12 months (mos) were randomized to the combination of trabectedin (1.1 mg/m2) and PLD (30 mg/ m2) or carboplatin (AUC 5) and PLD (30 mg/ m2).
From 2014 to 2017, we enrolled 617 pts from 117 European sites (306 CP arm, 311 TP arm). The median TFIp was 8.4 mos and 30% of pts received 2 previous platinum lines. The treatment was interrupted before the sixth cycle in 28% of pts in CP arm (70% for progression/death, 15% for toxicity and 5% for patient refusal) and in 46% in TP arm (54% for progression/death, 19% for toxicity and 13% for patient refusal). 75% and 74% of pts received a subsequent therapy (ST) in CP and TP arm respectively; in TP arm 86% of ST was platinum-based. At a median follow-up of 44 mos, 466 deaths were observed. The median OS was 21.3 and 21.5 mos in CP and TP arm (HR=1.10; 95%CI: 0.92-1.32; p=0.284). The median progression free survival (PFS) was 9.0 and 7.5 mos in CP and TP arm (HR=1.26 95%CI: 1.07-1.49; p=0.005). In pts receiving a ST, the HR for PFS from the ST was 0.84 (95%CI: 0.70-1.02, p=0.086) in favor of TP. Subgroup analyses (according to BRCA status, extent of the disease, number of previous lines, histology, ST) did not identify subsets of pts with a clear benefit from TP. Grade 3-5 (g3-5) adverse reactions (ARs) occurred in 36% and 69% of pts in CP and TP arm. G3-5 most frequent ARs were hematological (28% CP, 45% TP), gastrointestinal (7% CP, 18% TP), hepatic (1% CP, 18% TP); any grade neurotoxicity was 16% for both arms.
This study did not meet its primary endpoint of improving OS with the TP regimen followed by platinum over CP regimen. However, as TP reached similar OS, it can still be considered in pts who need a longer recovery time from platinum specific toxicities.
NCT01379989.
Istituto di Ricerche Farmacologiche Mario Negri IRCCS - Milan.
PharmaMar.
N. Colombo: Honoraria (institution), Advisory/Consultancy: roche; Honoraria (self), Advisory/Consultancy: pharmaMar; Honoraria (self), Advisory/Consultancy: AstaZeneca; Honoraria (self), Advisory/Consultancy: Clovis; Honoraria (self), Advisory/Consultancy: Tesaro/GSK; Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: biocad; Honoraria (self), Advisory/Consultancy: Immunogen; Honoraria (self), Advisory/Consultancy: Takeda; Honoraria (self), Advisory/Consultancy: Advaxis. J. Sehouli: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: Clovis; Advisory/Consultancy, Travel/Accommodation/Expenses: GSK/Tesaro; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): PharmaMar; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Novocure; Advisory/Consultancy: Eisai; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Roche Diagnostics; Leadership role: NOGGO; Leadership role: ESGO; Leadership role: PARSGO; Leadership role: AGO. E. Biagioli: Research grant/Funding (institution): Roche; Research grant/Funding (institution): GSK/Tesaro; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): PharmaMar. N. Ottevanger: Research grant/Funding (institution): PharmaMar. A.G. G. Zeimet: Honoraria (self), Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: PharmaMar; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca. I.B. Vergote: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Amgen (Europe) GmBH; Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy: Clovis; Advisory/Consultancy: Carrick Therapeutics; Advisory/Consultancy: Debiopharm International; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Contracted research: Genmab; Advisory/Consultancy: GSK; Advisory/Consultancy: Immunogen; Advisory/Consultancy: Medical University of Vienna; Advisory/Consultancy: Millenium Pharmaceuticals; Advisory/Consultancy, Travel/Accommodation/Expenses: MSD Belgium; Advisory/Consultancy: Octimet Oncology; Advisory/Consultancy, Contracted research: Oncoinvent AS; Advisory/Consultancy: PharmaMar; Advisory/Consultancy: Roche NV; Advisory/Consultancy: Sotio A.S.; Advisory/Consultancy, Travel/Accommodation/Expenses: Tesaro; Advisory/Consultancy: Deciphera Phramaceuticals; Advisory/Consultancy: Verastem Oncology; Travel/Accommodation/Expenses: MSD/Merck Zurich + USA. J. Maenpaa: Honoraria (self): Roche; Honoraria (self): GSK; Honoraria (self): AstraZeneca; Honoraria (self): Clovis; Honoraria (self): Orion Pharma. R. Fossati: Research grant/Funding (institution): Roche; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): GSK/Tesaro; Research grant/Funding (institution): PharmaMar. A. Poveda: Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy: Clovis; Advisory/Consultancy, Travel/Accommodation/Expenses: PharmaMar; Advisory/Consultancy: GSK. All other authors have declared no conflicts of interest.