Investigational drugs for recurrent or primary advanced metastatic cervical cancer: what is in the clinical development pipeline?

Recurrent cervical cancer; Combination therapy; ImmunotherapyCáncer cervical recurrente; Terapia de combinación; InmunoterapiaCàncer cervical recurrent; Teràpia combinada; ImmunoteràpiaIntroduction: Recurrent or primary advanced metastatic cervical cancer (R/M CC) has a poor prognosis with a 5-year-survival rate of 16.5%, demanding novel and improved therapies for the treatment of these patients. The first-line standard of care for R/M CC now benefits from the addition of the immune checkpoint inhibitor, pembrolizumab, to platinum-based chemotherapy with paclitaxel and bevacizumab. Additionally, new options for second-line treatment have become available in recent years. Areas covered: Here, we review current investigational drugs and discuss their relative targets, efficacies, and potential within the R/M CC treatment landscape. This review will focus on recently published data and key ongoing clinical trials in patients with R/M CC, covering multiple modes of action, including immunotherapies, antibody-drug conjugates, and tyrosine kinase inhibitors. We searched clinicaltrials.gov for ongoing trials and pubmed.ncbi.nih.gov for recently published trial data, as well as recent years' proceedings from the annual conferences of the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), European Society of Gynaecological Oncology (ESGO), and the International Gynecologic Cancer Society (IGCS). Expert opinion: Therapeutics currently attracting attention include novel immune checkpoint inhibitors, therapeutic vaccinations, antibody-drug conjugates, such as tisotumab vedotin, tyrosine kinase inhibitors targeting HER2, and multitarget synergistic combinations

Emerging treatment strategies in recurrent platinum-sensitive ovarian cancer: focus on trabectedin.

Ovarian cancer (OC) is the leading cause of death from gynecological malignancies. In spite of high response rates to the standard front-line treatment for advanced disease with cytoreductive surgical debulking, followed by platinum/taxane-based chemotherapy, most patients eventually relapse developing drug-resistant disease. Owing to the molecular heterogeneity, genetic instability and mutagenicity of OC, increases in survival might be achieved by translating recent insights at the morpho-molecular levels to individual therapeutic strategies. Several emerging treatments have been shown to be active in platinum-sensitive (PS) recurrent OC (ROC), but an optimal strategy still has not been established. Based on the recent results, it is likely that the introduction of novel non-platinum based chemotherapies and molecular targeted therapies will have a major impact on the management of ROC. Some current strategies are focused on the extension of platinum-free interval (PFI) in patients with PS, particularly in those with partially PS disease. Apparently, the PFI extension by an effective non-platinum intervention, such as trabectedin plus pegylated liposomal doxorubicin (PLD), may reduce cumulative platinum-induced toxicities leading to longer survival after the reintroduction of subsequent platinum. The introduction of novel therapies, such as the antiangiogenic monoclonal antibody bevacizumab, opens a new field of targeted therapies in this indication. In this review, we aim to outline the therapeutic potential of new emerging approaches, particularly the role of non-platinum therapy with trabectedin in combination with PLD in patients with PS ROC. © 2013 The Authors

Le territoire, générateur d’inégalités face aux cancers

Agir efficacement contre les inégalités géographiques face aux cancers implique une meilleure compréhension du processus aboutissant à ces inégalités. Une méthodologie interdisciplinaire, traitant conjointement les multiples dimensions par lesquelles le territoire impacte la santé et retraçant l’évolution pronostique des patients, permettrait de répondre à ce besoin. La cohorte EMS, retraçant la prise en charge de patients atteints de sarcomes (cancers rares) en Rhône-Alpes, a été analysée suivant ces principes méthodologiques. L’analyse de 15 variables géographiques ayant une influence sur la santé a permis de distinguer six types de territoires rhônalpins. Cette typologie a ensuite été croisée avec les données de la cohorte EMS pour étudier les pertes de chances propres à chaque type de territoire. La surmortalité des pôles urbains est liée à l’incidence plus importante des sarcomes, quand celle des quartiers populaires et des espaces ruraux s’expliquent davantage par des pertes de chances de survie au cours de la prise en charge.Cancers inequalities in France are among the highest in developed countries and these gaps seem to be growing in the last decades. Territorial inequalities of cancers are analyzed by mapping, which showed higher mortality rates in the North-East Regions of France. At the local scale, standardized mortality rates are two times higher in some areas in the North as other areas in the South-East. Epidemiological studies, mostly based on multilevel analysis, evidence the impact of physical environment, deprivation or health care access on health outcomes. But to identify contextual effects are not sufficient to understand how cancer inequalities are built and how patient’s life context contributes to this process. As epidemiological approach is splitting contextual effects according to health outcomes, geographical approach may have to explain how these contextual effects lead to cancer inequalities, by using territorial typology to summarize these contextual effects. Comparing health outcomes according to this territorial classification may help to understand territory’s ability to generate health inequalities. Several stages across the cancer continuum are implied in the building of the cancer inequalities. This medical process has to be reconstructed to determine whether mortality inequalities are generated by a higher incidence or a lower survival. Moreover, lower survival may be linked to the worse prognosis of patients at diagnosis or to the lower quality of management according to cancer care facilities. Evolution of patients’ prognosis may be reconstructed, thanks to clinical data, in order to identify the most influent steps during this medical process. As a result, to understand the way geographical inequalities of cancers are building requires a multidisciplinary methodology, considering the territory’s contribution as a whole and using longitudinal clinical data. But to reconstitute this medical process is quite difficult actually because few longitudinal and exhaustive data are available. The EMS cohort represents an opportunity to test and discuss this methodological approach. This cohort includes all sarcoma (rare cancer) patients diagnosed in 2005 and 2006, in the Rhône-Alpes Region, and collects clinical data from the diagnosis to the patient follow-up. For this geographical analysis of the EMS cohort, we used a territorial typology generated thanks to multivariate analysis of 15 geographical variables known for their impact on health. Strong differences are noticed in terms of environment exposures, deprivation and health care access between the six types of territory (metropolitan neighborhoods, working-class neighborhoods, urban districts, residential areas, periurban areas, rural areas). This typology seems to be relevant to study geographical inequalities because it enables to distinguish populations which are not exposed to the same risks through their life context. A logistic regression including stage, age and histological subtype, as clinical factors influencing prognosis, estimates the patients’ prognosis at diagnosis. This prognosis score seems to be quite predictive because only 7% of “good prognosis” patients will be dead five years later, whereas this five years death rate raises to 80% for the worse prognosis patients. Analysis of geographical inequalities for sarcoma patients in the Rhône-Alpes Region shows the diversity of situations leading to inequalities of mortality. Indeed, the higher mortality in three types of territories has to be attributed to three different processes. In the case of the urban hub, this high mortality is linked to the higher incidence of sarcoma, as survival rate for patients of these districts is very close to the regional average. As incidence and prognosis risk in the working-class neighborhoods are quite similar to the regional average, higher mortality is due to the loss of survival odds in the course of treatments, probably because of a less optimal management. Despite the second lower incidence among the six types of territories, the worse prognosis of patients (more late-stage diagnosis) and the loss of survival odds during cancer management explained the high mortality rated in the rural areas. Thanks to the EMS cohort’s analysis, we assess the potential of a multidisciplinary methodology studying the territory’s ability to generate geographical inequalities of cancers. Territorial typology, produced without health outcomes data, may be used for every health studies as a synthetic index of the territory and also evidence strong inequalities of health according to people’s life contexts. As public policies struggle to be successful on this issue, to identify key events in the medical process leading to cancer inequalities may improve the territorialization and the efficiency of these policies. Territories with high risk before diagnosis would be focused on prevention and early diagnosis, whereas those more disadvantage during the management would lean towards cancer care quality, access to hospitals and cancer expertise and patient compliance

The Changing Landscape of Systemic Treatment for Cervical Cancer: Rationale for Inhibition of the TGF-β and PD-L1 Pathways

Cervical cancer; Tumor microenvironmentCáncer de cuello uterino; Microambiente tumoralCàncer de coll uterí; Microambient tumoralCervical cancer is one of the most common and lethal cancers among women worldwide. Treatment options are limited in patients with persistent, recurrent, or metastatic cervical cancer, with 5 years. Persistent human papillomavirus (HPV) infection has been implicated in almost all cases of cervical cancer. HPV infection not only causes normal cervical cells to transform into cancer cells, but also creates an immunosuppressive environment for cancer cells to evade the immune system. Recent clinical trials of drugs targeting the PD-(L)1 pathway have demonstrated improvement in overall survival in patients with cervical cancer, but only 20% to 30% of patients show overall survival benefit beyond 2 years, and resistance to these treatments remains common. Therefore, novel treatment strategies targeting HPV infection–associated factors are currently being evaluated in clinical trials. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human immunoglobulin G1 monoclonal antibody that blocks PD-L1. Early clinical trials of bintrafusp alfa have shown promising results in patients with advanced cervical cancer.This work was funded by Merck (CrossRef Funder ID: 10.13039/100009945) and was previously part of an alliance between Merck and GlaxoSmithKline

Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2)

Càncer d'ovaris; Biomarcadors tumoralsCáncer de ovarios; Biomarcadores tumoralesOvarian cancer; Tumour biomarkersARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity

Factors of interrupting chemotherapy in patients with Advanced Non-Small-Cell Lung Cancer

<p>Abstract</p> <p>Background</p> <p>Little is known about prognosis of metastatic patients after receiving a first-line treatment and failure. Our group already showed in pre-treated patients enrolled in phase I clinical trials that a performance status (PS) > 2 and an LDH > 600 UI/L were independent prognostic factors. In this prospective study, which included 45 patients, we identified clinical and biological variables as outcome predictors in metastatic Non-Small Cell lung cancer after first line chemotherapy were identified.</p> <p>Findings</p> <p>Forty-five patients that were previously treated for metastatic disease from 12/2000 to 11/2005 in the comprehensive cancer centre (Centre Léon Bérard). Clinical assessment and blood parameters were recorded and considered. Patient prognostic factors for overall survival (OS) with a 0.05-significance level in univariate analysis were entered in a multivariate Cox model for further analysis.</p> <p>Patients' median age was 58.5 years (range: 37 - 76). Sixty two percent of the patients were PS = 0 or 1. After inclusion, nine patients received second-line (22.5%), and two received third-line chemotherapy (5%). Univariate analysis showed that the factors associated with reduced OS were: PS > 2, weight loss >10%, more than one line of chemotherapy treatment and abnormal blood parameters (hemoglobin (Hb), platelet and neutrophils counts). Multiple regression analysis confirmed that PS > 2 and abnormal hemoglobin were independent predictors for low overall survival. According to the presence of none (33%), 1 (37%) and 2 (30%) prognostic factors, median OS were 12, 5 and 2 months respectively.</p> <p>Conclusion</p> <p>From this prospective study, both PS and anemia were found as independent determinants of survival, we found that both PS and anemia were independent determinants of survival. The combination of poor PS and anemia is an effective strategy to predict survival in the case of patients with metastatic NSCLC receiving further treatment after the first line.</p

European Network of Gynaecological Oncological Trial Groups’ requirements for trials between academic groups and industry partners – a new Model D for drug and medical device development

No abstract available

First-line PARP inhibitors in ovarian cancer: summary of an ESMO Open - Cancer Horizons round-table discussion

Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is the latest breakthrough in the management of newly diagnosed advanced ovarian cancer. The results of the SOLO-1 trial in 2018 led to European Medicines Agency and Food and Drug Administration approval of olaparib as first-line maintenance therapy in patients with BRCA1/2 mutation, establishing a new standard of care. Subsequently, the results of three phase III trials (PRIMA, PAOLA-1, VELIA) evaluating the use of first-line PARP inhibitors beyond patients with BRCA1/2 mutations and as combination strategies were presented in 2019, leading to the recent approval of maintenance niraparib irrespective of biomarker status and olaparib in combination with bevacizumab in homologous recombination deficiencypositive-associated advanced ovarian cancer. An ESMO Open - Cancer Horizons round-table expert panel discussed the four phase III trials of first-line PARP inhibitor therapy and how they are changing the clinical management of advanced ovarian cancer

Short-Term cost impact of compliance with clinical practice guidelines for initial sarcoma treatment

Background: The impact of compliance to clinical practice guidelines (CPG) on outcomes and/or costs of care has not been completely clarified.Objective: To estimate relationships between medical expenditures and compliance to CPG for initial sarcoma treatment.Research design: Selected cohorts of patients diagnosed with sarcoma in 2005 and 2006, and treated at the University hospital and/or the cancer centre of the Rhône-Alpes region, France (n=90). Main outcome measurements were: patient characteristics, compliance with CPG, health outcomes, and costs. Data were mainly extracted from patient records. The logarithm of treatment costs was modelled using linear and Tobit regressions.Results: Rates of compliance with CPG were 86%, 66%, 88%, 89%, and 95% for initial diagnosis, primary surgical excision, wide surgical excision, chemotherapy, and radiotherapy, respectively. Total average costs reached €24,439, with €1,784, €11,225, €10,360, and €1,016 for diagnosis, surgery (primary and wide surgical excisions), chemotherapy, and radiotherapy, respectively. Compliance of diagnosis with CPG decreased the cost of diagnosis, whereas compliance of primary surgical excision increased the cost of chemotherapy. Compliance of chemotherapy with CPG decreased the cost of radiotherapy.Conclusion: Since chemotherapy is one of the major cost drivers, these results support that compliance with guidelines increases medical care expenditures in short term.Oncology; Sarcoma; Cost; Clinical guidelines; Efficacy; Medical Practices; Government Policy; Regulation; Public Health