Olaparib has shown significant clinical benefit as maintenance therapy in women with newly diagnosed advanced ovarian cancer with a
mutation. The effect of combining maintenance olaparib and ...bevacizumab in patients regardless of
mutation status is unknown.
We conducted a randomized, double-blind, international phase 3 trial. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were having a response after first-line platinum-taxane chemotherapy plus bevacizumab. Patients were eligible regardless of surgical outcome or
mutation status. Patients were randomly assigned in a 2:1 ratio to receive olaparib tablets (300 mg twice daily) or placebo for up to 24 months; all the patients received bevacizumab at a dose of 15 mg per kilogram of body weight every 3 weeks for up to 15 months in total. The primary end point was the time from randomization until investigator-assessed disease progression or death.
Of the 806 patients who underwent randomization, 537 were assigned to receive olaparib and 269 to receive placebo. After a median follow-up of 22.9 months, the median progression-free survival was 22.1 months with olaparib plus bevacizumab and 16.6 months with placebo plus bevacizumab (hazard ratio for disease progression or death, 0.59; 95% confidence interval CI, 0.49 to 0.72; P<0.001). The hazard ratio (olaparib group vs. placebo group) for disease progression or death was 0.33 (95% CI, 0.25 to 0.45) in patients with tumors positive for homologous-recombination deficiency (HRD), including tumors that had
mutations (median progression-free survival, 37.2 vs. 17.7 months), and 0.43 (95% CI, 0.28 to 0.66) in patients with HRD-positive tumors that did not have
mutations (median progression-free survival, 28.1 vs. 16.6 months). Adverse events were consistent with the established safety profiles of olaparib and bevacizumab.
In patients with advanced ovarian cancer receiving first-line standard therapy including bevacizumab, the addition of maintenance olaparib provided a significant progression-free survival benefit, which was substantial in patients with HRD-positive tumors, including those without a
mutation. (Funded by ARCAGY Research and others; PAOLA-1 ClinicalTrials.gov number, NCT02477644.).
The majority of patients with advanced ovarian cancer progress after first‐line therapy and require further treatment. Tumor biology, prior chemotherapy, responses to previous therapy, performance ...status, and toxicity are the characteristics that influence treatment choice. These criteria have been linked to the time between relapse and last platinum therapy: the platinum‐free interval. Today, patients are classified as either those who are eligible for a new platinum‐based therapy or those for whom platinum is not an option. A nonplatinum regimen should be administered to patients who are not candidates for platinum re‐treatment. This group includes patients with early relapse after, or progression during, previous platinum‐based chemotherapy and patients with platinum intolerability. A single agent such as weekly paclitaxel, pegylated liposomal doxorubicin (PLD), gemcitabine, or topotecan represents the standard. For patients not treated with bevacizumab in the first line, this drug should be added to chemotherapy. For patients for whom platinum rechallenge is an option (because they are potentially platinum‐responsive), different strategies are available with the incorporation of biological drugs targeting angiogenesis or the mechanisms of DNA repair. A BRCA mutation status predicts a better response to platinum and poly(adenosine diphosphate–ribose) polymerase (PARP) inhibition. PARP inhibitors and antiangiogenic drugs have proven efficacy as maintenance therapy after chemotherapy and concurrently with chemotherapy, respectively. These agents have changed current practice, although few biomarkers are available to guide decisions. Patients potentially responsive to platinum who cannot receive the drug again can be treated with a combination of trabectedin and PLD, the most active nonplatinum therapy in this setting.
The treatment of ovarian cancer recurrence is changing. Drugs targeting angiogenesis or the mechanisms of DNA repair have been added to chemotherapy for patients who are candidates to receive platinum again. Patients who are not candidates for platinum should receive single‐agent chemotherapy and bevacizumab if they have not previously been treated with the drug in the first line.
Few effective second-line treatments exist for women with recurrent or metastatic cervical cancer. Accordingly, we aimed to evaluate the efficacy and safety of tisotumab vedotin, a tissue ...factor-directed antibody–drug conjugate, in this patient population.
This multicentre, open-label, single-arm, phase 2 study was done across 35 academic centres, hospitals, and community practices in Europe and the USA. The study included patients aged 18 years or older who had recurrent or metastatic squamous cell, adenocarcinoma, or adenosquamous cervical cancer; disease progression on or after doublet chemotherapy with bevacizumab (if eligible by local standards); who had received two or fewer previous systemic regimens for recurrent or metastatic disease; had measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1); and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 2·0 mg/kg (up to a maximum of 200 mg) tisotumab vedotin intravenously once every 3 weeks until disease progression (determined by the independent review committee) or unacceptable toxicity. The primary endpoint was confirmed objective response rate based on RECIST (version 1.1), as assessed by the independent review committee. Activity and safety analyses were done in patients who received at least one dose of the drug. This study is ongoing with recruitment completed and is registered with ClinicalTrials.gov, NCT03438396.
102 patients were enrolled between June 12, 2018, and April 11, 2019; 101 patients received at least one dose of tisotumab vedotin. Median follow-up at the time of analysis was 10·0 months (IQR 6·1–13·0). The confirmed objective response rate was 24% (95% CI 16–33), with seven (7%) complete responses and 17 (17%) partial responses. The most common treatment-related adverse events included alopecia (38 38% of 101 patients), epistaxis (30 30%), nausea (27 27%), conjunctivitis (26 26%), fatigue (26 26%), and dry eye (23 23%). Grade 3 or worse treatment-related adverse events were reported in 28 (28%) patients and included neutropenia (three 3% patients), fatigue (two 2%), ulcerative keratitis (two 2%), and peripheral neuropathies (two 2% each with sensory, motor, sensorimotor, and neuropathy peripheral). Serious treatment-related adverse events occurred in 13 (13%) patients, the most common of which included peripheral sensorimotor neuropathy (two 2% patients) and pyrexia (two 2%). One death due to septic shock was considered by the investigator to be related to therapy. Three deaths unrelated to treatment were reported, including one case of ileus and two unknown causes.
Tisotumab vedotin showed clinically meaningful and durable antitumour activity with a manageable and tolerable safety profile in women with previously treated recurrent or metastatic cervical cancer. Given the poor prognosis for this patient population and the low activity of current therapies in this setting, tisotumab vedotin, if approved, would represent a new treatment for women with recurrent or metastatic cervical cancer.
Genmab, Seagen, Gynaecologic Oncology Group, and European Network of Gynaecological Oncological Trial Groups.
Summary Background Risk of relapse or progression remains high in the treatment of most patients with epithelial ovarian cancer, and development of a molecular predictor could be a valuable tool for ...stratification of patients by risk. We aimed to develop a microRNA (miRNA)-based molecular classifier that can predict risk of progression or relapse in patients with epithelial ovarian cancer. Methods We analysed miRNA expression profiles in three cohorts of samples collected at diagnosis. We used 179 samples from a Multicenter Italian Trial in Ovarian cancer trial (cohort OC179) to develop the model and 263 samples from two cancer centres (cohort OC263) and 452 samples from The Cancer Genome Atlas epithelial ovarian cancer series (cohort OC452) to validate the model. The primary clinical endpoint was progression-free survival, and we adapted a semi-supervised prediction method to the miRNA expression profile of OC179 to identify miRNAs that predict risk of progression. We assessed the independent prognostic role of the model using multivariable analysis with a Cox regression model. Findings We identified 35 miRNAs that predicted risk of progression or relapse and used them to create a prognostic model, the 35-miRNA-based predictor of Risk of Ovarian Cancer Relapse or progression (MiROvaR). MiROvaR was able to classify patients in OC179 into a high-risk group (89 patients; median progression-free survival 18 months 95% CI 15–22) and a low-risk group (90 patients; median progression-free survival 38 months 24–not estimable; hazard ratio HR 1·85 1·29–2·64, p=0·00082). MiROvaR was a significant predictor of progression in the two validation sets (OC263 HR 3·16, 95% CI 2·33–4·29, p<0·0001; OC452 HR 1·39, 95% CI 1·11–1·74, p=0·0047) and maintained its independent prognostic effect when adjusted for relevant clinical covariates using multivariable analyses (OC179: adjusted HR 1·48, 95% CI 1·03–2·13, p=0·036; OC263: adjusted HR 3·09 2·24–4·28, p<0·0001; and OC452: HR 1·41 1·11–1·79, p=0·0047). Interpretation MiROvaR is a potential predictor of epithelial ovarian cancer progression and has prognostic value independent of relevant clinical covariates. MiROvaR warrants further investigation for the development of a clinical-grade prognostic assay. Funding AIRC and CARIPLO Foundation.
Pazopanib is an oral, multikinase inhibitor of vascular endothelial growth factor receptor (VEGFR) -1/-2/-3, platelet-derived growth factor receptor (PDGFR) -α/-β, and c-Kit. Preclinical and clinical ...studies support VEGFR and PDGFR as targets for advanced ovarian cancer treatment. This study evaluated the role of pazopanib maintenance therapy in patients with ovarian cancer whose disease did not progress during first-line chemotherapy.
Nine hundred forty patients with histologically confirmed cancer of the ovary, fallopian tube, or peritoneum, International Federation Gynecology Obstetrics (FIGO) stages II-IV, no evidence of progression after primary therapy consisting of surgery and at least five cycles of platinum-taxane chemotherapy were randomized 1:1 to receive pazopanib 800 mg once per day or placebo for up to 24 months. The primary end point was progression-free survival by RECIST 1.0 assessed by the investigators.
Maintenance pazopanib prolonged progression-free survival compared with placebo (hazard ratio HR, 0.77; 95% CI, 0.64 to 0.91; P = .0021; median, 17.9 v 12.3 months, respectively). Interim survival analysis based on events in 35.6% of the population did not show any significant difference. Grade 3 or 4 adverse events of hypertension (30.8%), neutropenia (9.9%), liver-related toxicity (9.4%), diarrhea (8.2%), fatigue (2.7%), thrombocytopenia (2.5%), and palmar-plantar erythrodysesthesia (1.9%) were significantly higher in the pazopanib arm. Treatment discontinuation related to adverse events was higher among patients treated with pazopanib (33.3%) compared with placebo (5.6%).
Pazopanib maintenance therapy provided a median improvement of 5.6 months (HR, 0.77) in progression-free survival in patients with advanced ovarian cancer who have not progressed after first-line chemotherapy. Overall survival data to this point did not suggest any benefit. Additional analysis should help to identify subgroups of patients in whom improved efficacy may balance toxicity (NCT00866697).
Summary Background Angiogenesis is a target in the treatment of ovarian cancer. Nintedanib, an oral triple angiokinase inhibitor of VEGF receptor, platelet-derived growth factor receptor, and ...fibroblast growth factor receptor, has shown activity in phase 2 trials in this setting. We investigated the combination of nintedanib with standard carboplatin and paclitaxel chemotherapy in patients with newly diagnosed advanced ovarian cancer. Methods In this double-blind phase 3 trial, chemotherapy-naive patients (aged 18 years or older) with International Federation of Gynecology and Obstetrics (FIGO) IIB–IV ovarian cancer and upfront debulking surgery were stratified by postoperative resection status, FIGO stage, and planned carboplatin dose. Patients were randomly assigned (2:1) via an interactive voice or web-based response system to receive six cycles of carboplatin (AUC 5 mg/mL per min or 6 mg/mL per min) and paclitaxel (175 mg/m2 ) in addition to either 200 mg of nintedanib (nintedanib group) or placebo (placebo group) twice daily on days 2–21 of every 3-week cycle for up to 120 weeks. Patients, investigators, and independent radiological reviewers were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov , number NCT01015118. Findings Between Dec 9, 2009, and July 27, 2011, 1503 patients were screened and 1366 randomly assigned by nine study groups in 22 countries: 911 to the nintedanib group and 455 to the placebo group. 486 (53%) of 911 patients in the nintedanib group experienced disease progression or death compared with 266 (58%) of 455 in the placebo group. Median progression-free survival was significantly longer in the nintedanib group than in the placebo group (17·2 months 95% CI 16·6–19·9 vs 16·6 months 13·9–19·1; hazard ratio 0·84 95% CI 0·72–0·98; p=0·024). The most common adverse events were gastrointestinal (diarrhoea: nintedanib group 191 21% of 902 grade 3 and three <1% grade 4 vs placebo group nine 2% of 450 grade 3 only) and haematological (neutropenia: nintedanib group 180 20% grade 3 and 200 (22%) grade 4 vs placebo group 90 20% grade 3 and 72 16% grade 4; thrombocytopenia: 105 12% and 55 6% vs 21 5% and eight 2%; anaemia: 108 12% and 13 1% vs 26 6% and five 1%). Serious adverse events were reported in 376 (42%) of 902 patients in the nintedanib group and 155 (34%) of 450 in the placebo group. 29 (3%) of 902 patients in the nintedanib group experienced serious adverse events associated with death compared with 16 (4%) of 450 in the placebo group, including 12 (1%) in the nintedanib group and six (1%) in the placebo group with a malignant neoplasm progression classified as an adverse event by the investigator. Drug-related adverse events leading to death occurred in three patients in the nintedanib group (one without diagnosis of cause; one due to non-drug-related sepsis associated with drug-related diarrhoea and renal failure; and one due to peritonitis) and in one patient in the placebo group (cause unknown). Interpretation Nintedanib in combination with carboplatin and paclitaxel is an active first-line treatment that significantly increases progression-free survival for women with advanced ovarian cancer, but is associated with more gastrointestinal adverse events. Future studies should focus on improving patient selection and optimisation of tolerability. Funding Boehringer Ingelheim.
This randomized, multicenter, phase III noninferiority trial was designed to test the efficacy and safety of the combination of pegylated liposomal doxorubicin (PLD) with carboplatin (CD) compared ...with standard carboplatin and paclitaxel (CP) in patients with platinum-sensitive relapsed/recurrent ovarian cancer (ROC).
Patients with histologically proven ovarian cancer with recurrence more than 6 months after first- or second-line platinum and taxane-based therapies were randomly assigned by stratified blocks to CD (carboplatin area under the curve AUC 5 plus PLD 30 mg/m(2)) every 4 weeks or CP (carboplatin AUC 5 plus paclitaxel 175 mg/m(2)) every 3 weeks for at least 6 cycles. Primary end point was progression-free survival (PFS); secondary end points were toxicity, quality of life, and overall survival.
Overall 976 patients were recruited. With median follow-up of 22 months, PFS for the CD arm was statistically superior to the CP arm (hazard ratio, 0.821; 95% CI, 0.72 to 0.94; P = .005); median PFS was 11.3 versus 9.4 months, respectively. Although overall survival data are immature for final analysis, we report here a total of 334 deaths. Overall severe nonhematologic toxicity (36.8% v 28.4%; P < .01) leading to early discontinuation (15% v 6%; P < .001) occurred more frequently in the CP arm. More frequent grade 2 or greater alopecia (83.6% v 7%), hypersensitivity reactions (18.8% v 5.6%), and sensory neuropathy (26.9% v 4.9%) were observed in the CP arm; more hand-foot syndrome (grade 2 to 3, 12.0% v 2.2%), nausea (35.2% v 24.2%), and mucositis (grade 2-3, 13.9% v 7%) in the CD arm.
To our knowledge, this trial is the largest in recurrent ovarian cancer and has demonstrated superiority in PFS and better therapeutic index of CD over standard CP.
Microsatellite instability (MSI) has been identified in several tumors arising from either germline or somatic aberration. The presence of MSI in cancer predicts the sensitivity to immune checkpoint ...inhibitors (ICIs), particularly PD1/PD-L1 inhibitors. To date, the predictive role of MSI is currently used in the selection of colorectal cancer patients for immunotherapy; moreover, the expansion of clinical trials into other cancer types may elucidate the predictive value of MSI for non-colorectal tumors. In clinical practice, several assays are used for MSI testing, including immunohistochemistry (IHC), polymerase chain reaction (PCR) and next-generation sequencing (NGS). In this review, we provide an overview of MSI in various cancer types, highlighting its potential predictive/prognostic role and the clinical trials performed. Finally, we focus on the comparison data between the different assays used to detect MSI in clinical practice.
The prognosis for women with recurrent and metastatic endometrial cancer is poor, and improved therapies are needed. The mammalian target of rapamycin (mTOR) pathway is an important target, and mTOR ...inhibitors show clinical activity in endometrial cancer.
An open-label, multicenter, randomized, phase II trial of oral ridaforolimus compared with progestin or investigator choice chemotherapy (comparator) was undertaken in women with metastatic or recurrent endometrial cancer who had progressive disease following one or two lines of chemotherapy and no hormonal therapy. The primary end point was progression-free survival (PFS) assessed by independent radiologic review.
One hundred thirty patients were enrolled (64 received ridaforolimus and 66 received the comparator), and median age was 66 years. Treatment discontinuation as a result of adverse events was 33% with ridaforolimus versus 6% with the comparator, with common (> 10%) grade 3 toxicities being hyperglycemia, anemia, and diarrhea. Thirty-eight percent (ridaforolimus) versus 71% (comparator) of patients discontinued treatment as a result of disease progression. Median PFS at the protocol prespecified interim analysis with 58 PFS events (primary end point) was 3.6 months (95% CI, 2.7 to 7.3 months) for ridaforolimus and 1.9 months (95% CI, 1.9 to 2.3 months) for the comparator (hazard ratio, 0.53; 95% CI, 0.31 to 0.90; P = .008). PFS rate for ridaforolimus versus comparator was 48% versus 18% at 16 weeks and 38% versus 15% at 24 weeks. Objective response rate for ridaforolimus versus comparator was 0% versus 4% (P = .925), and stable disease was achieved in 35% versus 17% of patients (P = .021).
Oral ridaforolimus shows encouraging activity in advanced endometrial cancer but is associated with significant toxicity. Inhibition of the PI3K/Akt/mTOR pathway may be a viable therapeutic target.
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