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Background: Immune checkpoint blockade has shown mixed results in advanced/recurrent gynecologic malignancies. Efficacy may be improved through costimulation with OX40 and 4‐1BB agonists. The authors sought to evaluate the safety and efficacy of avelumab combined with utomilumab (a 4‐1BB agonist), PF‐04518600 (an OX40 agonist), and radiotherapy in patients with recurrent gynecologic malignancies. Methods: The primary end point in this six‐arm, phase 1/2 trial was safety of the combination regimens. Secondary end points included the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors and immune‐related Response Evaluation Criteria in Solid Tumors, the disease control rate (DCR), the duration of response, progression‐free survival, and overall survival. Results: Forty patients were included (35% with cervical cancer, 30% with endometrial cancer, and 35% with ovarian cancer). Most patients (n = 33; 83%) were enrolled in arms A–C (no radiation). Among 35 patients who were evaluable for efficacy, the ORR was 2.9%, and the DCR was 37.1%, with a median duration of stable disease of 5.4 months (interquartile range, 4.1–7.3 months). Patients with cervical cancer in arm A (avelumab and utomilumab; n = 9 evaluable patients) achieved an ORR of 11% and a DCR of 78%. The median progression‐free survival was 2.1 months (95% CI, 1.8–3.5 months), and overall survival was 9.4 months (95% CI, 5.6–11.9 months). No dose‐limiting toxicities or grade 3–5 immune‐related adverse events were observed. Conclusions: The findings from this trial highlight that, in heavily pretreated patients with gynecologic cancer, even multidrug regimens targeting multiple immunologic pathways, although safe, did not produce significant responses. A DCR of 78% in patients with cervical cancer who received avelumab and utomilumab indicates that further research on this combination in select patients may be warranted. In a phase 1/2 trial of heavily pretreated patients who had recurrent gynecologic cancers, avelumab in combination with a 4‐1BB agonist, an OX40 agonist, and/or radiation was safe and had a similar rate of immune‐related adverse events compared with single‐agent immune checkpoint blockade. The combination of multiple immune‐modulating agents, however, did not result in increased efficacy. [ABSTRACT FROM AUTHOR]

Background: Tumor‐based next‐generation sequencing is used inconsistently as a tool to tailor treatment of ovarian cancer, yet beyond detection of somatic BRCA1 and BRCA2 mutations, the clinical benefit is not well established. This study aimed to assess the clinical relevance of tumor‐based next‐generation sequencing (tbNGS) in patients with ovarian cancer. Methods: This retrospective study included patients with high‐grade epithelial ovarian carcinoma. tbNGS results were identified in the electronic medical record using optical character recognition and natural language processing. Genetic, clinical, and demographic information was collected. Progression‐free survival (PFS) and overall survival were calculated and compared using log‐rank tests. Multivariate Cox regression and clustering analyses were used to identify patterns of genetic alterations associated with survival. Results: Of 1092 patients in the described population, 409 (37.5%) had tbNGS results. Nearly all (96.1% [393/409]) had one or more genetic alterations. In 25.9% (106/409) of patients, an alteration that aligned with a targeted treatment was identified, and in an additional 48.7% (199/409), tbNGS results suggested eligibility for an investigational agent or clinical trial. The most frequent alterations were TP53, PIK3CA, and NF1 mutations, and CCNE1 amplification. Together, BRCA1 and BRCA2 mutations were associated with longer PFS (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.42–0.92; p =.02), whereas AKT2 amplification was associated with shorter PFS (HR, 3.86; 95% CI, 1.002–14.88; p <.05). Multivariate Cox regression and clustering analyses identified several combinations of genetic alterations that corresponded to outcomes in patients with high‐grade serous carcinoma. Conclusions: tbNGS often yields clinically relevant information. Detailed analysis of population‐level tumor genomics may help to identify therapeutic targets and guide development of clinical decision support tools. Plain Language Summary: Although more and more patients with ovarian cancer are undergoing tumor‐based next‐generation sequencing to identify genetic mutations in their tumors, the benefits of such testing are not well established.In a group of over 400 patients with ovarian cancer who underwent tumor‐based next‐generation sequencing in the course of their treatment, nearly all patients had one or more genetic alterations detected, and one out of four patients had a mutation that qualified them for a personalized treatment option. In a large cohort of women with high‐grade epithelial ovarian cancer, one out of four patients who underwent tumor‐based next‐generation sequencing (tbNGS) was found to harbor a mutation that warranted consideration of a targeted therapeutic. tbNGS often reveals relevant information that may improve clinical outcomes when used to match patients with targeted therapies or clinical trials. [ABSTRACT FROM AUTHOR]

Immunotherapies targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) have showed substantial therapeutic benefit in patients with clinically advanced solid malignancies. However, autoimmune toxicities are common and often significant adverse events with these agents. While rash and pruritus remain the most common cutaneous complications in treated patients, novel dermatologic toxicities related to immune checkpoint blockade continue to emerge as the number of patients exposed to immunotherapy increases. Here, we describe 2 patients treated with combination immunotherapy with ipilimumab and nivolumab who developed painful subcutaneous nodules. Although the findings were clinically concerning for disease recurrence, histopathologic examination of biopsies from the lesions revealed a subcutaneous mixed septal and lobular erythema nodosum-like panniculitis. Notably, neither patient received immunosuppressive therapy for these lesions, which subsequently remained stable, and both patients' cancer remained controlled. These cases show that the dermatologic toxicity profile of immune checkpoint blockade is diverse and continues to expand, and illustrates that recognition of such toxicities is critical to optimal patient management. [ABSTRACT FROM AUTHOR]

Recent success of immunotherapy and other targeted therapies in cancer treatment has led to an unprecedented surge in the number of novel therapeutic agents that need to be evaluated in clinical trials. Traditional phase II clinical trial designs were developed for evaluating one candidate treatment at a time and thus not efficient for this task. We propose a Bayesian phase II platform design, the multi-candidate iterative design with adaptive selection (MIDAS), which allows investigators to continuously screen a large number of candidate agents in an efficient and seamless fashion. MIDAS consists of one control arm, which contains a standard therapy as the control, and several experimental arms, which contain the experimental agents. Patients are adaptively randomized to the control and experimental agents based on their estimated efficacy. During the trial, we adaptively drop inefficacious or overly toxic agents and 'graduate' the promising agents from the trial to the next stage of development. Whenever an experimental agent graduates or is dropped, the corresponding arm opens immediately for testing the next available new agent. Simulation studies show that MIDAS substantially outperforms the conventional approach. The proposed design yields a significantly higher probability for identifying the promising agents and dropping the futile agents. In addition, MIDAS requires only one master protocol, which streamlines trial conduct and substantially decreases the overhead burden. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: BRCA1 and BRCA2 germline mutations account for the majority of hereditary ovarian cancers and comprise 10% of total cases. Ovarian cancers arising from these mutations exhibit both overlapping and distinct clinical and molecular features. The expression profiles of sporadic ovarian cancers show similarities to those of BRCA1 and BRCA2-related tumors suggesting that BRCA-related pathways may be involved in their development as well. The purpose of this review is to consider the available data on ovarian cancers in the context of other investigations of BRCA-related transcriptional alterations, and highlight areas for future research. [Copyright &y& Elsevier]