Second-line targeted therapies after nivolumab-ipilimumab failure in metastatic renal cell carcinoma

Correction: Volume: 119 Pages: 200-201 DOI: 10.1016/j.ejca.2019.04.012 Published: SEP 2019Background: Nivolumab-ipilimumab demonstrated a survival benefit over sunitinib in first-line setting for metastatic renal cell carcinomas (mRCCs) and is becoming a new standard of care for naive patients with intermediate or poor risk prognosis (International mRCC Database Consortium). The efficacy of subsequent vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs) after nivolumab-ipilimumab failure remains unclear. Methods: Medical records of mRCC patients treated with nivolumab-ipilimumab, who received subsequent TKI, as part of Checkmate 214 study were reviewed in 13 institutions. Baseline characteristics, outcome data including progression-free survival (PFS), response, overall survival (OS) and toxicities were retrospectively collected. Results: Overall 33 patients received subsequent TKI after nivolumab-ipilimumab failure. Median follow-up from start of subsequent TKI is 22 months (19-NR). Best response was assessed in 30 patients: 12 partial responses (36%), 13 stable diseases (39%) and five progressive diseases (15%). Median PFS from start of TKI was 8 months [5-13]. Median PFS with first-generation (sunitinib/pazopanib) and second-generation TKI (axitinib/cabozantinib) was 8 months [5-16] and 7 months (5-NA), respectively. PFS in second line was significantly longer in patients with a long first-line duration of response to the double immune checkpoint blockade (>= 6 months) with 8 versus 5 months for short responder (= 3. Conclusion: This is the first report of outcomes with TKI, after first-line nivolumab-ipilimumab failure. Median PFS suggests a sustained benefit of TKI and supports trials investigating the optimal sequence. (C) 2018 Published by Elsevier Ltd.Peer reviewe

Caractérisation du micro-environnement des carcinomes rénaux à cellules claires et détermination des marqueurs de réponse aux inhibiteurs de checkpoints immunologiques

Le cancer du rein à cellules claires (ccRCC) a bénéficié ces dernières années d'avancées thérapeutiques majeures. Le nivolumab, inhibiteur du point de contrôle immunitaire Programmed Cell Death-1 (PD-1), permettant de restaurer l'immunité adaptative anti-tumorale via l'activation des lymphocytes T (LT) CD8, est devenu depuis 2017 un standard de traitement en situation métastatique après échec d'un TKI anti-VEGFR. Cependant, seuls un quart des patients répondent au traitement et nous ne disposons pas à l'heure actuel de biomarqueur robuste prédictif d'efficacité. L'arrivée imminente de la combinaison nivolumab-ipilimumab en 1ère ligne de RCC métastatique suivi de la combinaison TKI anti-VEGFR plus anti-PD-1 pose d'autant plus la question du biomarqueur de sélection, sachant les toxicités potentiellement graves et le cout financier pour la société. La composition du microenvironnement tumoral et les interactions cellules immunitaires - cellules tumorales sont les pistes explorées les plus solides pour prédire la réponse aux immunothérapies. Mon travail de thèse s'inscrit dans la continuité des travaux menés par mon équipe d'accueil sur la caractérisation du microenvironnement immunitaire des ccRCC. A l'aide plusieurs cohortes distinctes de patients avec un ccRCC, nous avons rapporté dans 3 études publiées que : 1) une forte densité de LT CD8+ (immunohistochimie (IHC)) était associée à un mauvais pronostic à l'inverse de la plupart des autres tumeurs solides. Nous avons montré que ces CD8 avaient un phénotype « épuisé » potentiellement du fait de l'absence de coordination de la réponse immunitaire par des cellules dendritiques (DC) majoritairement immatures, situées en dehors des structures lymphoïdes tertiaires (TLS) ; 2) par l'analyse des lymphocytes infiltrant les tumeurs (TIL), nous identifions 3 groupes aux profil immunitaires distincts, « immuno-activé », « immuno-silencieux » et « immuno-régulé ». Ce dernier groupe caractérisé par une population lymphocytaire polyclonale, faiblement cytotoxique CD8+PD-1+Tim-3+Lag-3+ ainsi qu'une population de T régulateurs (Treg) ICOS+ avait un risque de récidive significativement plus important que les deux autres dans l'année suivant la néphrectomie. L'analyse du phénotype des LT circulants identifiait 2 groupes dont le groupe immuno-régulé ; 3) la voie classique du complément jouait un rôle pro-inflammatoire clé dans la progression tumorale, via la coopération entre les cellules tumorales et les macrophages associés à la tumeur (TAM). Les résultats préliminaires d'un 4ème travail en cours montrent des proportions/phénotypes de populations de LT, DC et de Treg différentes dans le sang circulant entre 24 patients avec une tumeur localisé et 17 patients métastatiques débutant du nivolumab. Nous identifions également des phénotypes immunitaires associés à la réponse au nivolumab. Enfin, ces travaux se concluent par la conduite de l'essai clinique de phase II académique BIONIKK (NCT NCT02960906, promoteur ARTIC) dans lequel les patients avec un ccRCC métastatique sont traités soit par TKI anti-VEGFR, soit par nivolumab soit par nivolumab-ipilimumab en fonction de leur groupe moléculaire (de 1 à 4), déterminé à l'inclusion sur tissu tumoral congelé à partir d'une signature d'expression de 35 gènes co-développé par mon équipe d'accueil. L'objectif principal est d'étudier la réponse au traitement en fonction du groupe moléculaire. De nombreuses analyses ancillaires sont associées à cette étude incluant analyses transcriptomiques, quantification des infiltrats immunitaires et de leur phénotype (PD-1, PD-L1, Tim-3...) par IHC, analyse des populations immunitaires circulantes etc. Au 1er juillet 2019, l'ensemble des patients prévus ont été randomisés (N=200) et des premiers résultats de l'analyse intermédiaire seront présentés lors de la soutenance (confidentiel).Clear cell renal cell carcinomas (ccRCC) has benefited from major therapeutic advance in recent years. Since 2017, nivolumab, an immune checkpoint inhibitor targeting the Programmed Cell Death-1 (PD-1) allowing to restore the adaptive anti-tumour immunity via the CD8 T cell activation, has become a standard treatment for metastatic patients with ccRCC after failure of an anti-VEGFR TKI. However, only a quarter of patients respond to treatment and we do not currently have a robust biomarker that predicts efficacy. The imminent arrival of the nivolumab-ipilimumab combination in the first line of metastatic ccRCC followed by the arrival of anti-VEGFR TKI and anti-PD-1 combination further raises the question of a selection biomarker, given the potentially severe toxicities and the financial cost for the society. The composition of the tumour microenvironment and immune cell-tumour cell interactions are the most promising issues explored to predict the response to immunotherapies. My thesis work is in line with the work carried out by my host team on the characterization of the ccRCC immune microenvironment. Using several separate cohorts of patients with ccRCCs, we reported in 3 published studies that: 1) high CD8+ T-cell (LT) density (immunohistochemistry (IHC)) was associated with a poor prognosis unlike most other solid tumours. We showed that these CD8 had an "exhausted" phenotype potentially due to a lack of immune response coordination by immature dendritic cells (DC) located outside the tertiary lymphoid structures (TLS); 2) by the analysis of tumour infiltrating lymphocytes (TIL), we identified 3 groups with distinct immune profiles, "immune-activated", "immune-silent" and "immune-regulated". The latter group, characterized by a polyclonal, low cytotoxic CD8+PD-1+Tim-3+Tim-3+Lag-3+ population as well as an ICOS+ T regulators (Treg) one, had a significantly higher risk of recurrence than the two other groups in the year following nephrectomy. Analysis of the phenotype of circulating LT identified 2 groups including the immune-regulated group; 3) the classical complement pathway played a key pro-inflammatory role in tumour progression, via cooperation between tumour cells and tumour associated macrophages (TAM). Preliminary results of our 4th ongoing study show different LT, DC and Treg population proportions and/or phenotypes in circulating blood between 24 patients with localized tumour and 17 metastatic patients starting nivolumab. We also identify immune phenotypes associated with response to nivolumab. Finally, this work is concluded with the conduct of the BIONIKK academic Phase II clinical trial (NCT02960906, sponsor: ARTIC) in which patients with metastatic ccRCC are treated either with anti-VEGFR TKI, or nivolumab alone or nivolumab-ipilimumab depending on their molecular group (from 1 to 4), determined at inclusion on frozen tumour tissue from a 35-gene expression signature previously co-developed by my host team. The main objective is the response to treatment according to the molecular group. Many ancillary analyses are associated including transcriptomic analyses, quantification of immune infiltrates and their phenotype (PD-1, PD-L1, Tim-3...) by IHC, analysis of circulating immune populations etc. As of July 1st 2019, all planned patients have been randomized (N=200) and initial results of the interim analysis will be presented during the thesis defense (confidential)

Valeur pronostique de la réponse précoce dans les cancers broncho-pulmonaires non à petites cellules localement avancés, traité par radiochimiothérapie

NICE-BU Médecine Odontologie (060882102) / SudocSudocFranceF

Enhance the Immune Checkpoint Inhibitors Efficacy with Radiotherapy Induced Immunogenic Cell Death: A Comprehensive Review and Latest Developments

International audienceThe immunogenic cell death (ICD) is defined as a regulated cell death able to induce an adaptive immunity. It depends on different parameters including sufficient antigenicity, adjuvanticity and favorable microenvironment conditions. Radiation therapy (RT), a pillar of modern cancer treatment, is being used in many tumor types in curative, (neo) adjuvant, as well as metastatic settings. The anti-tumor effects of RT have been traditionally attributed to the mitotic cell death resulting from the DNA damages triggered by the release of reactive oxygen species. Recent evidence suggests that RT may also exert its anti-tumor effect by recruiting tumor-specific immunity. RT is able to induce the release of tumor antigens, to act as an immune adjuvant and thus to synergize with the anti-tumor immunity. The advent of new efficient immunotherapeutic agents, such as immune checkpoint inhibitors (ICI), in multiple tumor types sheds new light on the opportunity of combining RT and ICI. Here, we will describe the biological and radiobiological rationale of the RT-induced ICD. We will then focus on the interest to combine RT and ICI, from bench to bedside, and summarize the clinical data existing with this combination. Finally, RT technical adaptations to optimize the ICD induction will be discussed

Tumor Microenvironment Features as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors (ICI) in Metastatic Clear Cell Renal Cell Carcinoma (mccRCC)

Renal cell carcinoma (RCC) is the seventh most frequently diagnosed malignancy with an increasing incidence in developed countries. Despite a greater understanding of the cancer biology, which has led to an increase of therapeutic options, metastatic clear cell renal cell carcinoma (mccRCC) still have a poor prognosis with a median five-years survival rate lower than 10%. The standard of care for mccRCC has changed dramatically over the past decades with the emergence of new treatments: anti-VEGFR tyrosine kinase inhibitors, mTOR Inhibitors and immune checkpoint inhibitors (ICI) such as anti-Programmed cell-Death 1 (PD-1) and anti-anti-Programmed Death Ligand-1 (PD-L1) used as monotherapy or as a combination with anti CTLA-4 or anti angiogenic therapies. In the face of these rising therapeutic options, the question of the therapeutic sequences is crucial. Predictive biomarkers are urgently required to provide a personalized treatment for each patient. Disappointingly, the usual ICI biomarkers, PD-L1 expression and Tumor Mutational Burden, approved in melanoma or non-small cell lung cancer (NSCLC) have failed to distinguish good and poor mccRCC responders to ICI. The tumor microenvironment is known to be involved in ICI response. Innovative technologies can be used to explore the immune contexture of tumors and to find predictive and prognostic biomarkers. Recent comprehensive molecular characterization of RCC has led to the development of robust genomic signatures, which could be used as predictive biomarkers. This review will provide an overview of the components of the RCC tumor microenvironment and discuss their role in disease progression and resistance to ICI. We will then highlight the current and future ICI predictive biomarkers assessed in mccRCC with a major focus on immunohistochemistry markers and genomic signatures

Resistance to cancer immunotherapy in metastatic renal cell carcinoma

The prognosis of metastatic clear cell renal cell carcinoma (mccRCC) has changed dramatically over the years with the emergence of immune checkpoint inhibitors (ICI) used alone, or in combination with another ICI, or with vascular endothelial growth factor receptor tyrosine kinase inhibitor. Although major response rates have been observed with ICI, many patients do not respond, reflecting primary resistance, and durable responses remain exceptional, reflecting secondary resistance. Factors contributing to primary and acquired resistance are manifold, including patient-intrinsic factors, tumor cell-intrinsic factors and factors associated with the tumoral microenvironment (TME). While some mechanisms of resistance are common to several tumor types, others are specific to mccRCC. Predictive biomarkers and alternative strategies are needed to overcome this resistance. This review provides an overview of the major ICI resistance mechanisms, highlights the potential of the TME to induce resistance to ICI, and discusses the predictive biomarkers available to guide therapeutic choice

Tumor Microenvironment Features as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors (ICI) in Metastatic Clear Cell Renal Cell Carcinoma (mccRCC)

Renal cell carcinoma (RCC) is the seventh most frequently diagnosed malignancy with an increasing incidence in developed countries. Despite a greater understanding of the cancer biology, which has led to an increase of therapeutic options, metastatic clear cell renal cell carcinoma (mccRCC) still have a poor prognosis with a median five-years survival rate lower than 10%. The standard of care for mccRCC has changed dramatically over the past decades with the emergence of new treatments: anti-VEGFR tyrosine kinase inhibitors, mTOR Inhibitors and immune checkpoint inhibitors (ICI) such as anti-Programmed cell-Death 1 (PD-1) and anti-anti-Programmed Death Ligand-1 (PD-L1) used as monotherapy or as a combination with anti CTLA-4 or anti angiogenic therapies. In the face of these rising therapeutic options, the question of the therapeutic sequences is crucial. Predictive biomarkers are urgently required to provide a personalized treatment for each patient. Disappointingly, the usual ICI biomarkers, PD-L1 expression and Tumor Mutational Burden, approved in melanoma or non-small cell lung cancer (NSCLC) have failed to distinguish good and poor mccRCC responders to ICI. The tumor microenvironment is known to be involved in ICI response. Innovative technologies can be used to explore the immune contexture of tumors and to find predictive and prognostic biomarkers. Recent comprehensive molecular characterization of RCC has led to the development of robust genomic signatures, which could be used as predictive biomarkers. This review will provide an overview of the components of the RCC tumor microenvironment and discuss their role in disease progression and resistance to ICI. We will then highlight the current and future ICI predictive biomarkers assessed in mccRCC with a major focus on immunohistochemistry markers and genomic signatures

Optimal cut-off for neutrophil-to-lymphocyte ratio: Fact or Fantasy? A prospective cohort study in metastatic cancer patients

<div><p>This study assessed the prognostic value of pre-treatment neutrophil-to-lymphocyte ratio (NLR) in patients with metastatic solid tumors. Clinical and biological data for patients with metastatic solid tumors treated in an oncology outpatient department and prospectively followed by a call center (PROCHE program) between January 2008 and December 2011 were analyzed. All patients with an NLR value within 28 days before the first cycle of first-line of chemotherapy were included (cohort 1). To assess influence of chemotherapy line on NLR prognostic value, data from patients treated with later chemotherapy lines were also analyzed (cohort 2). Adjusted multivariate Cox regressions with or without non-linear and time-dependent effects were performed. Optimal NLR cut-off was investigated by time-dependent sensitivity analysis using several indices. There were 317 and 134 patients in cohorts 1 and 2, respectively. Elevated NLR was associated with worse survival (hazard ratio [HR] for death, 1.35 [95% confidence interval 1.19–1.54]; p<0.0001). The optimal NLR cut-off in cohort 1 was dependent on index used and time of assessment: HR values were non-significant at a cut-off of 3.0 (1.34 [0.99–1.32], but significant when the cut-off was 4.0 (1.53 [1.11–2.10]). NLR was linearly related to mortality risk; in subgroup analysis, no significant interaction was found with co-variables or tumor localization overall (cohorts 1+2). Pre-treatment NLR is a useful prognostic tool in patients with metastatic solid tumors, irrespective of primary tumor site, chemotherapy line, age, gender and performance status. However, using an NLR cut-off value for clinical decision-making requires extreme caution.</p></div