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Backround: Patients with metastatic endometrial carcinoma have a poor prognosis and PIK3CA mutations and amplifications are common in these cancers. This study evaluated the efficacy and safety of the pure PI3K inhibitor BKM120 in advanced or recurrent endometrial carcinoma. Methods: This phase II, multicentre, single-arm, double strata (histological low grade (LG) or high grade (HG)) open-label study enrolled patients with histologically confirmed advanced or recurrent endometrial carcinoma who had received not more than one prior chemotherapy regimen. Patients received initially BKM120 100 mg tablets once daily. Primary end points were proportion of patients free of progression at 2 months (HG strata) or at 3 months (LG strata), objective response rate (ORR), and safety. Results: A total of 40 patients were enrolled, of whom 16 patients had received BKM120 at 100 mg. Because of high toxicities (cutaneous rash (54%), depressive events (47%), and anxiety (40%), the IDMC has proposed to stop recruitment at 100 mg and to continue the clinical trial with a lower dose of 60 mg per day. In addition, 24 patients (median age 67 years old) were newly enrolled (14 in the LG strata and 10 in the HG strata). Rate of nonprogression at 2 months in the HG strata was 70% and at 3 months was 60% in the LG strata. Median progression-free survival (PFS) for all patients is 4.5 months (CI 95% 2.8–6.1), and the median PFS for LG strata is 8.3 months compared with 3.8 months for the HG strata. No response was reported. At 60 mg per day, the most commonly reported treatment-related adverse events (AEs) were hyperglycaemia (58%), cognitive (31%), digestive (28%), hepatic liver functions (26%), and rash (23%). The most commonly reported treatment-related grade ⩾3 AEs were HTA (17%), hyperglycaemia (17%), and increased alanine aminotransferase (24%). Five patients (21%) stopped BKM120 for toxicity. Conclusions: The BKM120 was associated with an unfavourable safety profile and minimal antitumour activity in monotherapy in advanced or recurrent endometrial carcinoma. The clinical trial was stopped before end of recruitment for toxicity.

Introduction/BackgroundDetecting tumor-specific genetic alterations in cell-free DNA (cfDNA) obtained from cancer patients allows for a quantification of the tumoral fraction, i.e. the circulating tumor DNA (ctDNA). Previous studies in metastatic cancer patients showed that early changes of this fraction during therapy are indicative of therapeutic response. We tested this hypothesis on cfDNA samples collected in the GANNET53 clinical trial (FP7, funded by the European Commission, grant no 602602).MethodologyPatients with high-grade serous/endometrioid and/or undifferentiated PROC were recruited for treatment with weekly paclitaxel with or without Hsp90-inhibitor ganetespib. Archival biopsy samples were used for tumor TP53 genotyping. CfDNA was prospectively collected prior to treatment at baseline (cycle 1 day 1, C1D1), 24 hours later (cycle 1 day 2, C1D2) and after 4 and 8 weeks, at day 1 of cycle 2 (C2D1) and 3 (C3D1) respectively. Targeted TP53 resequencing was performed on cfDNA and allelic frequencies of the known TP53 variant (TP53 VAF) were quantified and correlated with clinical outcome.ResultsFor 125 of the 133 randomized patients, at least 1 C1D1 cfDNA sample was available. For 119 tumor samples, TP53 genotyping was successful and identified deleterious TP53 mutations in 106 patients (89.1%). The median ctDNA level was 1.82% (IQR:0.17–8.34%) at C1D1 which decreased significantly after 4–8 weeks of therapy. Overall, ctDNA was detectable in 64.6% (64/99) of baseline samples. Baseline CA125 did not differ between cases with and without detectable ctDNA at C1D1. Detection of ctDNA at C1D1 (HR 2.3; 95%CI:1.4–3.9), C1D2 (HR 2.2; 95%CI:1.3–3.9) and C2D1 (HR 2.8; 95%CI:1.6–4.9) predicted a worse overall survival. A subgroup of patients for whom TP53 ctDNA was undetectable at C2D1 or C3D1 (14/64) had a high overall response rate of 64.2%.ConclusionQuantification of TP53 mutations in cfDNA of PROC patients has prognostic value at baseline. Favorable early changes during treatment may predict therapeutic response.DisclosureThe presenting author, A.Vanderstichele, has no conflict of interest.

Introduction/Background*Endometrial cancer (EC) patients (Pts) with advanced and recurrent disease relapse despite treatment with combination chemotherapy and have a short progression-free survival (PFS). Nintedanib (N) is a potent, orally available triple receptor tyrosine kinase inhibitor targeting VEGFR 1–3, PDGFR α/β, and FGFR 1–3. This study explored the preliminary efficacy of nintedanib in EC.MethodologyThe primary objective of this placebo-controlled, randomized study was to evaluate efficacy defined by median PFS of concomitant and maintenance N against placebo (P) in combination with chemotherapy. Patients with histologically confirmed stage IIIC2 or IVA & B or relapsed after adjuvant therapy for stage I-III disease; prior surgery; adjuvant chemotherapy; radiation therapy; hormonal therapy in metastatic setting; with measurable/non-measurable disease were permitted. Pts were randomized 1:1 to receive N 200mg or P, twice daily days 2–21 during chemotherapy (six cycles of Carboplatin (AUC5) and paclitaxel (175mg/m2) every 21 days) and continuously in maintenance phase. N/P was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Stratification by stage of disease, prior adjuvant chemotherapy and measurable/non-measurable disease. This is an ENGOT Model A study. Clinical trial information: NCT02730416.Result(s)*146 of 148 pts were eligible for PFS: 72N/74P; mean age 66yrs; FIGO stage III 18%, IV 42%, recurrent 40%; follow-up 30 mo. N added to chemotherapy did not improve PFS (119 events) as compared to chemotherapy plus P: median for N 8.3 vs. for P 7.2 mo; hazard ratio (HR) adjusted for stratification factors 1.03; 95% confidence interval (CI),[0.71 to 1.48]; p0.879. Median overall survival (85 events) for N 20 vs. for P 22 mo; HR: 1.10; CI: 0.72–1.69; p0.665. Treatment-emerged grade 3–4 adverse events were higher in N vs P arm: liver function tests 13%/0%; diarrhea 12%/6%; neutropenia 21%/14%; asthenia 4%/1%. Patient-reported outcomes will be reported.Conclusion*Addition of nintedanib to chemotherapy did not improve PFS nor OS. This regimen cannot be recommended to undergo further testing in a phase III trial.

Background: It can be hypothesised that inherited polymorphisms in the drug-transporter ABCB1 gene may interfere with interindividual variations in drug response in breast cancer patients. Docetaxel is a substrate for ABCB1 whose function has been shown to be modulated by oestrogen and progesterone. Methods: Whether ABCB1 polymorphisms including T-129C, A61G, C1236T, G2677T/A and C3435T polymorphisms could account for variations in the disposition of docetaxel and whether menopausal status at the time of diagnosis might interact with this effect were analysed in women receiving neoadjuvant chemotherapy for breast cancer ( n =86). Results: A highly significant association was observed, but restricted to premenopausal women ( n =53), between the pharmacokinetics of docetaxel and C3435T polymorphism, as patients with CC genotype had lower mean values of the area under the plasma concentration-time curve (AUC) of docetaxel than patients with CT and TT genotypes ( P <0.0001). Comparison between pre- and postmenopausal women with the same C3435T genotype yielded a significant difference in docetaxel AUC only for CC genotype ( P <0.0001). Conclusion: These results suggest that C3435T polymorphism genotyping and menopausal status at the time of diagnosis might be useful when considering chemotherapy regimens including docetaxel in breast cancer patients.

Introduction/BackgroundSurgery is the cornerstone of ovarian Granulosa Cell Tumor (GCT). Complete resection with adequate staging is the gold standard in 1st line setting.The aim of this study is to assess the impact of an appropriate surgery according to the guidelines.MethodologyThis is a nationwide five-year retrospective study, including 463 patients (of the 639 included patients) with a definitive diagnosis of GCT between 2011 and 2016. Medical and surgical practices were analyzed for conformity. Conformity to guidelines was defined by a conservative (unilateral salpingo-oophorectomy) or radical surgery (hysteretomy and bilateral salpingo-oophorectomy) including surgical staging (omentectomy, peritoneal biopsy and peritoneal cytology) according to the FIGO classification.ResultsMedian age at diagnosis was 49 years old (range 10–89). The median size of tumor was 94 mm (range 5–400). Radical surgery was performed in 240 patients (51,8%), while a fertility-sparing surgery was performed in 98 cases (21,2%). A complete surgical staging was performed in only 76 cases (16,4%). 289 (62.4%) patients received an evaluation of the endometrium (hysterectomy or endometrial curettage).Surgery was fully compliant with the guidelines in 65 patients (14%), partially compliant in 213 patients (46%), non-compliant in 137 patients (29,6%) and not assessable in 48 cases (10,4%) respectively. A statistically significant improvement in the surgical management was observed among patients treated after 2012 compared to those treated before 2012. This Improvement included: endometrial evaluation (p=0,026), tumour rupture rate during surgery (p=0,010) and the global compliance of the surgery (p<0,001). Survival data will be reported.ConclusionStaging surgery provides a better assessment and an appropriate treatment of this rare tumors. According to this study, the implementation of a national network and guidelines dedicated to rare gynaecologic tumors seems to significantly improve the surgical management of the patients with GCT.DisclosureNothing to disclose.Abstract EP1225 Figure 1Progression free survival compared to the surgical conformityAbstract EP1225 Figure 2Overall survival compared to the surgical conformity

The addition of bevacizumab to chemotherapy (15 mg/kg for six cycles) followed by extended therapy with bevacizumab every 3 weeks for a total of 15 months of treatment improved progression-free survival by 4 months in incompletely resected stage III or IV ovarian cancer. Ovarian cancer is the fourth most common cause of cancer-related deaths in women, with an estimated 200,000 cases and 125,000 deaths occurring annually worldwide. For the past decade, the standard treatment for women with advanced ovarian cancer has been surgery and platinum-based chemotherapy. Attempts to improve this standard two-drug chemotherapy by adding a third cytotoxic drug failed to affect either progression-free survival or overall survival and resulted in an increase in toxic effects. 1 – 4 Although intraperitoneal chemotherapy has extended overall survival by 12 to 17 months, it is an option only for women with advanced ovarian cancer who have a . . .

BackgroundIn Study 19, maintenance monotherapy with olaparib significantly prolonged progression-free survival vs placebo in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer.MethodsStudy 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).ResultsThirty-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.ConclusionsStudy 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.

Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug. In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB–IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0–2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m2 on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m2 on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin–carboplatin, or 15 mg/kg every 21 days combined with gemcitabine–carboplatin or paclitaxel–carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17. Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4–9·3) in the standard chemotherapy group and 11·8 months (10·8–12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41–0·65; log-rank p<0·0001). Most common grade 3–4 adverse events were hypertension (20 [10%] in the standard chemotherapy group vs 58 (29%) in the bevacizumab group), neutrophil count decrease (81 [41%] vs 80 [40%]), and platelet count decrease (43 [22%] vs 61 [30%]). 68 patients (33%) died in the standard chemotherapy group and 79 (39%) died in the bevacizumab group; two deaths (1%) in the standard chemotherapy group and one death (<1%) in the bevacizumab group were deemed to be treatment-related. Continuing bevacizumab beyond progression combined with chemotherapy in patients with platinum-sensitive recurrent ovarian cancer improves progression-free survival compared with standard chemotherapy alone and might be considered in clinical practice. Hoffmann–La Roche and Associazione Italiana per la Ricerca sul Cancro.

This open-label, non-comparative, 2:1 randomized, phase II trial (NCT03275506) in women with stage IIIC/IV high-grade serous carcinoma (HGSC) for whom upfront complete resection was unachievable assessed whether adding pembrolizumab (200 mg every 3 weeks) to standard-of-care carboplatin plus paclitaxel yielded a complete resection rate (CRR) of at least 50%. Postoperatively patients continued assigned treatment for a maximum of 2 years. Postoperative bevacizumab was optional. The primary endpoint was independently assessed CRR at interval debulking surgery. Secondary endpoints were Completeness of Cytoreduction Index (CCI) and peritoneal cancer index (PCI) scores, objective and best response rates, progression-free survival, overall survival, safety, postoperative morbidity, and pathological complete response. The CRR in 61 pembrolizumab-treated patients was 74% (one-sided 95% CI = 63%), exceeding the prespecified ≥50% threshold and meeting the primary objective. The CRR without pembrolizumab was 70% (one-sided 95% CI = 54%). In the remaining patients CCI scores were ≥3 in 27% of the standard-of-care group and 18% of the investigational group and CC1 in 3% of the investigational group. PCI score decreased by a mean of 9.6 in the standard-of-care group and 10.2 in the investigational group. Objective response rates were 60% and 72%, respectively, and best overall response rates were 83% and 90%, respectively. Progression-free survival was similar with the two regimens (median 20.8 versus 19.4 months in the standard-of-care versus investigational arms, respectively) but overall survival favored pembrolizumab-containing therapy (median 35.3 versus 49.8 months, respectively). The most common grade ≥3 adverse events with pembrolizumab-containing therapy were anemia during neoadjuvant therapy and infection/fever postoperatively. Pembrolizumab was discontinued prematurely because of adverse events in 23% of pembrolizumab-treated patients. Combining pembrolizumab with neoadjuvant chemotherapy is feasible for HGSC considered not completely resectable; observed activity in some subgroups justifies further evaluation to improve understanding of the role of immunotherapy in HGSC. Immune checkpoint blockade could improve the complete cytoreduction rate with standard-of-care neoadjuvant chemotherapy (NACT) in patients with ovarian cancer. Here the authors report the results of a randomized phase II trial of NACT alone or in combination with pembrolizumab (anti-PD1) in patients with advanced high-grade serous carcinoma.

In the phase 3 SOLO1 trial, maintenance olaparib provided a significant progression-free survival benefit versus placebo in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation in response after platinum-based chemotherapy. We analysed health-related quality of life (HRQOL) and patient-centred outcomes in SOLO1, and the effect of radiological disease progression on health status. SOLO1 is a randomised, double-blind, international trial done in 118 centres and 15 countries. Eligible patients were aged 18 years or older; had an Eastern Cooperative Oncology Group performance status score of 0–1; had newly diagnosed, advanced, high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian tube cancer with a BRCA mutation; and were in clinical complete or partial response to platinum-based chemotherapy. Patients were randomly assigned (2:1) to either 300 mg olaparib tablets or placebo twice per day using an interactive voice and web response system and were treated for up to 2 years. Treatment assignment was masked for patients and for clinicians giving the interventions, and those collecting and analysing the data. Randomisation was stratified by response to platinum-based chemotherapy (clinical complete or partial response). HRQOL was a secondary endpoint and the prespecified primary HRQOL endpoint was the change from baseline in the Functional Assessment of Cancer Therapy–Ovarian Cancer Trial Outcome Index (TOI) score for the first 24 months. TOI scores range from 0 to 100 (higher scores indicated better HRQOL), with a clinically meaningful difference defined as a difference of at least 10 points. Prespecified exploratory endpoints were quality-adjusted progression-free survival and time without significant symptoms of toxicity (TWiST). HRQOL endpoints were analysed in all randomly assigned patients. The trial is ongoing but closed to new participants. This trial is registered with ClinicalTrials.gov, NCT01844986. Between Sept 3, 2013, and March 6, 2015, 1084 patients were enrolled. 693 patients were ineligible, leaving 391 eligible patients who were randomly assigned to olaparib (n=260) or placebo (n=131; one placebo patient withdrew before receiving any study treatment), with a median duration of follow-up of 40·7 months (IQR 34·9–42·9) for olaparib and 41·2 months (32·2–41·6) for placebo. There was no clinically meaningful change in TOI score at 24 months within or between the olaparib and placebo groups (adjusted mean change in score from baseline over 24 months was 0·30 points [95% CI −0·72 to 1·32] in the olaparib group vs 3·30 points [1·84 to 4·76] in the placebo group; between-group difference of −3·00, 95% CI −4·78 to −1·22; p=0·0010). Mean quality-adjusted progression-free survival (olaparib 29·75 months [95% CI 28·20–31·63] vs placebo 17·58 [15·05–20·18]; difference 12·17 months [95% CI 9·07–15·11], p<0·0001) and the mean duration of TWiST (olaparib 33·15 months [95% CI 30·82–35·49] vs placebo 20·24 months [17·36–23·11]; difference 12·92 months [95% CI 9·30–16·54]; p<0·0001) were significantly longer with olaparib than with placebo. The substantial progression-free survival benefit provided by maintenance olaparib in the newly diagnosed setting was achieved with no detrimental effect on patients' HRQOL and was supported by clinically meaningful quality-adjusted progression-free survival and TWiST benefits with maintenance olaparib versus placebo. AstraZeneca and Merck Sharp & Dohme.