Molecular Results and Potential Biomarkers Identified from the Phase 3 MILO/ENGOT-ov11 Study of Binimetinib versus Physician Choice of Chemotherapy in Recurrent Low-Grade Serous Ovarian Cancer.

Purpose: We present the results of a post hoc tumor tissue analysis from the phase 3 MILO/ENGOT-ov11 study (NCT01849874).

Patients And Methods: Mutation/copy-number analysis was performed on tissue obtained pre-randomization. The Kaplan-Meier method was used to estimate progression-free survival (PFS).

MILO/ENGOT-ov11: Binimetinib Versus Physician's Choice Chemotherapy in Recurrent or Persistent Low-Grade Serous Carcinomas of the Ovary, Fallopian Tube, or Primary Peritoneum.

Purpose: Low-grade serous ovarian carcinomas (LGSOCs) have historically low chemotherapy responses. Alterations affecting the MAPK pathway, most commonly KRAS/BRAF, are present in 30%-60% of LGSOCs. The purpose of this study was to evaluate binimetinib, a potent MEK1/2 inhibitor with demonstrated activity across multiple cancers, in LGSOC.

Afatinib vs Placebo as Adjuvant Therapy After Chemoradiotherapy in Squamous Cell Carcinoma of the Head and Neck: A Randomized Clinical Trial.

Importance: Locoregionally advanced head and neck squamous cell cancer (HNSCC) is treated curatively; however, risk of recurrence remains high among some patients. The ERBB family blocker afatinib has shown efficacy in recurrent or metastatic HNSCC.

Objective: To assess whether afatinib therapy after definitive chemoradiotherapy (CRT) improves disease-free survival (DFS) in patients with HNSCC.

Niraparib Maintenance Therapy in Patients With Recurrent Ovarian Cancer After a Partial Response to the Last Platinum-Based Chemotherapy in the ENGOT-OV16/NOVA Trial.

Purpose: In the ENGOT-OV16/NOVA trial (ClinicalTrials.gov identifier: NCT01847274), maintenance therapy with niraparib, a poly(ADP-ribose) polymerase inhibitor, prolonged progression-free survival in patients with platinum-sensitive, recurrent ovarian cancer who had a response to their last platinum-based chemotherapy. The objective of the study was to assess the clinical benefit and patient-reported outcomes in patients who had a partial response (PR) and complete response (CR) to their last platinum-based therapy.

Trebananib or placebo plus carboplatin and paclitaxel as first-line treatment for advanced ovarian cancer (TRINOVA-3/ENGOT-ov2/GOG-3001): a randomised, double-blind, phase 3 trial.

Background: Angiopoietin 1 and 2 regulate angiogenesis and vascular remodelling by interacting with the tyrosine kinase receptor Tie2, and inhibition of angiogenesis has shown promise in the treatment of ovarian cancer. We aimed to assess whether trebananib, a peptibody that inhibits binding of angiopoietin 1 and 2 to Tie2, improved progression-free survival when added to carboplatin and paclitaxel as first-line therapy in advanced epithelial ovarian, primary fallopian tube, or peritoneal cancer in a phase 3 clinical trial.

Methods: TRINOVA-3, a multicentre, multinational, phase 3, double-blind study, was done at 206 investigational sites (hospitals and cancer centres) in 14 countries.

Quality of life in patients with recurrent ovarian cancer treated with niraparib versus placebo (ENGOT-OV16/NOVA): results from a double-blind, phase 3, randomised controlled trial.

Background: Quality of life (QOL) has become an important complementary endpoint in cancer clinical studies alongside more traditional assessments (eg, tumour response, progression-free survival, overall survival). Niraparib maintenance treatment has been shown to significantly improve progression-free survival in patients with recurrent ovarian cancer. We aimed to assess whether the benefits of extending progression-free survival are offset by treatment-associated toxic effects that affect QOL.

Pembrolizumab in recurrent advanced cervical squamous carcinoma.

No definitive cure is known for recurrent, persistent or metastatic cervical carcinoma. Chemotherapy remains the standard of care, although available options are scarce and do not provide satisfactory results. Immune checkpoint inhibitors have shown a strong and prolonged response in several types of cancer, although only in a subset of patients.

Randomized Phase II Trial of Seribantumab in Combination With Paclitaxel in Patients With Advanced Platinum-Resistant or -Refractory Ovarian Cancer.

Purpose Seribantumab is a fully human immunoglobulin G2 monoclonal antibody that binds to human epidermal growth factor receptor (HER) 3 (ErbB3), blocking heregulin (HRG) -mediated ErbB3 signaling and inducing ErbB3 receptor downregulation. This open-label randomized phase II study evaluated progression-free survival (PFS) with seribantumab in combination with once-per-week paclitaxel compared with paclitaxel alone in patients with platinum-resistant or -refractory ovarian cancer. A key secondary objective was to determine if any of five prespecified biomarkers predicted benefit from seribantumab.

Double-Blind, Placebo-Controlled, Randomized Phase III Trial Evaluating Pertuzumab Combined With Chemotherapy for Low Tumor Human Epidermal Growth Factor Receptor 3 mRNA-Expressing Platinum-Resistant Ovarian Cancer (PENELOPE).

Purpose: The AGO-OVAR 2.29/ENGOT-ov14/PENELOPE prospectively randomized phase III trial evaluated the addition of pertuzumab to chemotherapy in patients with platinum-resistant ovarian carcinoma with low tumor human epidermal growth factor receptor 3 (HER3) mRNA expression. We report the results of the primary efficacy analysis.

Pertuzumab Plus Chemotherapy for Platinum-Resistant Ovarian Cancer: Safety Run-in Results of the PENELOPE Trial.

Objective: In platinum-resistant ovarian cancer, adding pertuzumab to gemcitabine improved progression-free survival in the subgroup with low tumor HER3 messenger RNA expression. The 2-part PENELOPE trial (NCT01684878) is prospectively investigating pertuzumab plus chemotherapy in this population.

Patients And Methods: Part 1 evaluated pertuzumab plus either topotecan or paclitaxel.

A randomized phase II non-comparative study of PF-04691502 and gedatolisib (PF-05212384) in patients with recurrent endometrial cancer.

Objective: PF-04691502 and gedatolisib (PF-05212384) are potent, dual PI3K/mTOR inhibitors. This phase II study (B1271004) was conducted in patients with recurrent endometrial cancer following platinum-containing chemotherapy. The primary endpoint was to assess clinical benefit response (complete or partial response, or stable disease for ≥16weeks) following treatment with PF-04691502 or gedatolisib.

Volasertib Versus Chemotherapy in Platinum-Resistant or -Refractory Ovarian Cancer: A Randomized Phase II Groupe des Investigateurs Nationaux pour l'Etude des Cancers de l'Ovaire Study.

Purpose: Volasertib is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase. This phase II trial evaluated volasertib or single-agent chemotherapy in patients with platinum-resistant or -refractory ovarian cancer who experienced failure after treatment with two or three therapy lines.

Patients And Methods: Patients were randomly assigned to receive either volasertib 300 mg by intravenous infusion every 3 weeks or an investigator's choice of single-agent, nonplatinum, cytotoxic chemotherapy.

BRCA1/2 mutations associated with progression-free survival in ovarian cancer patients in the AGO-OVAR 16 study.

Objective: AGO-OVAR 16 demonstrated that pazopanib maintenance therapy significantly increased progression-free survival (PFS) in patients with ovarian cancer whose disease had not progressed after first-line therapy. In a sub-study, we evaluated the effect of clinically important germline BRCA1 and BRCA2 mutations on PFS.

Methods: Of 940 AGO-OVAR 16 participants, 664 had BRCA1/2 exon sequencing data (pazopanib, n=335; placebo, n=329).

Progression-free survival by local investigator versus independent central review: comparative analysis of the AGO-OVAR16 Trial.

Background: Analysis of progression-free survival (PFS) as the primary endpoint in advanced epithelial ovarian, fallopian tube, and primary peritoneal cancer (AEOC) trials may be confounded by the difficulty of radiologic evaluation of disease progression and the potential for discrepancy between investigator and blinded independent central assessments. PFS as assessed by local investigator (INV) was the primary endpoint of AGO-OVAR16, a randomized, double-blind trial of pazopanib maintenance therapy in AEOC. To confirm the robustness of the primary analysis, PFS was also evaluated by blinded independent central review (BICR).

Incorporation of pazopanib in maintenance therapy of ovarian cancer.

Purpose: 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.

MicroRNAs as prognostic markers in ovarian cancer.

Ovarian cancer (OC) is the most lethal gynecological malignancy among women. Over 70% of women with OC are diagnosed in advanced stages and most of these cases are incurable. Although most patients respond well to primary chemotherapy, tumors become resistant to treatment.

Genomic analyses across six cancer types identify basal-like breast cancer as a unique molecular entity.

To improve our understanding of the biological relationships among different types of cancer, we have characterized variation in gene expression patterns in a set of 1,707 samples representing 6 human cancer types (breast, ovarian, brain, colorectal, lung adenocarcinoma and squamous cell lung cancer). In the unified dataset, breast tumors of the Basal-like subtype were found to represent a unique molecular entity as any other cancer type, including the rest of breast tumors, while showing striking similarities with squamous cell lung cancers. Moreover, gene signatures tracking various cancer- and stromal-related biological processes such as proliferation, hypoxia and immune activation were found expressed similarly in different proportions of tumors across the various cancer types.

Intravenous aflibercept in patients with platinum-resistant, advanced ovarian cancer: results of a randomized, double-blind, phase 2, parallel-arm study.

Background: In this randomized phase 2 study, the authors assessed the efficacy and safety of intravenous aflibercept at 2 different doses (2 mg/kg or 4 mg/kg) in patients with recurrent, platinum-resistant ovarian, peritoneal, or fallopian tube cancer who developed disease progression after receiving topotecan and/or pegylated liposomal doxorubicin.

Methods: Patients were randomized to receive intravenous aflibercept at a dose of either 2 mg/kg or 4 mg/kg every 2 weeks until they developed disease progression or significant toxicity. The primary endpoint was to evaluate Response Evaluation Criteria in Solid Tumor response rates (overall response rate [ORR] = complete responses plus partial responses) and to test the null hypothesis (ORR, >5%).

A Bayesian hierarchical model for DCE-MRI to evaluate treatment response in a phase II study in advanced squamous cell carcinoma of the head and neck.

Object: Pharmacokinetic parameters from dynamic contrast-enhanced MRI (DCE-MRI) were used to assess the perfusion effects due to treatment response using a tyrosine kinase inhibitor. A Bayesian hierarchical model (BHM) is proposed, as an alternative to voxel-wise estimation procedures, to test for a treatment effect while explicitly modeling known sources of variability.

Materials And Methods: Nine subjects from a randomized, blinded, placebo-controlled, multicenter, phase II study of lapatinib were examined before and after treatment.

Trabectedin combined with liposomal doxorubicin in women with relapsed ovarian cancer.

In the absence of a curative treatment for patients with recurrent ovarian cancer, many agents have shown different levels of activity in the control of this disease. Trabectedin is an antineoplastic agent originally derived from the Caribbean marine tunicate Ecteinascidia turbinate. This drug has a new mechanism of action based on DNA minor-groove binding.

Update on novel therapeutic agents for cervical cancer.

Effective cytotoxic treatment options for advanced cervical cancer are exceedingly limited. Cisplatin-based combination chemotherapy, the most commonly used cytotoxic therapy, has produced response rates ranging from 20% to 30% and overall survival of less than 10 months. Because of the minimal degree of success with cytotoxic therapies and the poor prognosis of patients with this disease, interest has increased in targeted therapeutics for the treatment of cervical cancer.