Delphine Loirat

Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma

Background Pembrolizumab and nivolumab are immune checkpoint inhibitors targeting PD-1 that have recently been approved in pretreated recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients. In the clinic, some patients seem not only not to benefit from anti-PD-L1/PD-1 agents but rather to experience an acceleration of tumor growth kinetics (TGK). Patients and methods We retrospectively compared TGK on immunotherapy and TGK on last treatment in patients with R/M HNSCC treated with PD-1/PD-L1 inhibitors in four French centers. The TGK ratio (TGKR, ratio of the slope of tumor growth before treatment and the slope of tumor growth on treatment) was calculated. Hyperprogression was defined as a TGKR ≥ 2. Results From September 2012 to September 2015, 34 patients were identified. Patterns of recurrence included exclusive loco-regional recurrence in 14 patients, exclusive distant metastases in 11 patients, and both in 9 patients. No pseudo-progression was observed. Hyperprogression was observed in 10 patients (29%), including 9 patients with at least a locoregional recurrence, and only 1 patient with exclusively distant metastases. Hyperprogression significantly correlated with a regional recurrence (TGKR ≥ 2: 90% versus TGKR < 2: 37%, P = 0.008), but not with local or distant recurrence. Hyperprogression was associated with a shorter progression-free survival (PFS) according to RECIST (P = 0.003) and irRECIST (P = 0.02), but not with overall survival (P = 0.77). Conclusions Hyperprogression was observed in 29% of patients with R/M HNSCC treated with anti-PD-L1/PD-1 agents and correlated with a shorter PFS. It occurred in 39% of patients with at least a locoregional recurrence and 9% of patients with exclusively distant metastases. No pseudo-progressions were reported. Mechanisms and causality of hyperprogression should further be assessed through prospective controlled studies.

Loss of immune tolerance to IL-2 in type 1 diabetes.

Type 1 diabetes (T1D) is characterized by a chronic, progressive autoimmune attack against pancreas-specific antigens, effecting the destruction of insulin-producing β-cells. Here we show interleukin-2 (IL-2) is a non-pancreatic autoimmune target in T1D. Anti-IL-2 autoantibodies, as well as T cells specific for a single orthologous epitope of IL-2, are present in the peripheral blood of non-obese diabetic (NOD) mice and patients with T1D. In NOD mice, the generation of anti-IL-2 autoantibodies is genetically determined and their titre increases with age and disease onset. In T1D patients, circulating IgG memory B cells specific for IL-2 or insulin are present at similar frequencies. Anti-IL-2 autoantibodies cloned from T1D patients demonstrate clonality, a high degree of somatic hypermutation and nanomolar affinities, indicating a germinal centre origin and underscoring the synergy between cognate autoreactive T and B cells leading to defective immune tolerance.

Cost analysis of adverse events associated with non-small cell lung cancer management in France

Background Adverse events (AEs) related to medical treatments in non-small cell lung cancer (NSCLC) are frequent and need an appropriate costing in health economic models. Nevertheless, data on costs associated with AEs in NSCLC are scarce, particularly since the development of immunotherapy with specific immune-related AEs. Objective To estimate the costs of grades 3 and 4 AEs related to NSCLC treatments including immunotherapy in France. Methods Grades 3 and 4 AEs related to treatment and reported in at least 1% of patients in Phase III clinical trials for erlotinib, ramucirumab plus docetaxel, docetaxel, pemetrexed plus carboplatin plus bevacizumab, platinum-based chemotherapies, nivolumab and pembrolizumab were identified. When no cost evaluation was reported in literature, estimates on standard treatments and medical resource use for each AE were obtained thanks to an expert panel. Total cost per AE was calculated from a French national health insurance perspective and updated in 2017 Euros. Hospital stay costs were estimated based on public and private weighted tariffs and data from the French Medical Information System (Programme de Médicalisation des Systèmes d’Information). Costs of tests, consultations and treatments were calculated based on national reimbursement tariffs. Results Overall, costs of grades 3 and 4 AEs related to treatment ranged from €46 per event to €7,742 per year. Fourteen out of 24 AEs identified had a mean estimated cost over €2,000. The highest mean costs were related to type 1 diabetes (€7,742 per year) followed by pneumonitis (€5,786 per event), anemia (€5,752 per event), dehydration (€5,207 per event) and anorexia (€4,349 per event). Costs were mostly driven by hospitalization costs. Conclusion Among the AEs identified, a majority appeared to have an important economic impact, with a management cost of at least €2,000 per event mainly driven by hospitalization costs. This study may be of interest for economic evaluations of new interventions in NSCLC.

Comparative analysis of durable responders on immune checkpoint inhibitors (ICI) versus other systemic therapies: A meta-analysis of phase III trials.

3070Background: Durable responses have been reported with ICI. We aimed at quantifying the proportion of patients experiencing a durable response on ICI, and comparing it to the proportion observed...

Relevance of a molecular tumour board (MTB) for patients’ enrolment in clinical trials: experience of the Institut Curie

Background High throughput molecular screening techniques allow the identification of multiple molecular alterations, some of which are actionable and can be targeted by molecularly targeted agents (MTA). We aimed at evaluating the relevance of using this approach in the frame of Institut Curie Molecular Tumor Board (MTB) to guide patients with cancer to clinical trials with MTAs. Patients and methods We included all patients presented at Institut Curie MTB from 4 October 2014 to 31 October 2017. The following information was extracted from the chart: decision to perform tumour profiling, types of molecular analyses, samples used, molecular alterations identified and those which are actionable, and inclusion in a clinical trial with matched MTA. Results 736 patients were presented at the MTB. Molecular analyses were performed in 442 patients (60%). Techniques used included next-generation sequencing, comparative genomic hybridisation array and/or other techniques including immunohistochemistry in 78%, 51% and 58% of patients, respectively. Analyses were performed on a fresh frozen biopsy in 91 patients (21%), on archival tissue (fixed or frozen) in 326 patients (74%) and on both archival and fresh frozen biopsy in 25 patients (6%). At least one molecular alteration was identified in 280 analysed patients (63%). An actionable molecular alteration was identified in 207 analysed patients (47%). Forty-five analysed patients (10%) were enrolled in a clinical trial with matched MTA and 29 additional patients were oriented and included in a clinical trial based on a molecular alteration identified prior to the MTB analysis. Median time between date of specimen reception and molecular results was 28 days (range: 5–168). Conclusions The implementation of an MTB at Institut Curie enabled the inclusion of 10% of patients into a clinical trial with matched therapy.

Abstract CT108: A phase I dose escalation study of intra-tumoral LTX-315 as monotherapy or in combination with either ipilimumab or pembrolizumab in patients with transdermally accessible tumors (NCT01986426)

This Phase I clinical study is evaluating the safety and tolerability of intra-tumoral doses of LTX-315 in patients with advanced/metastatic solid tumors. Intratumoral administration results in growth inhibition, complete regression and long lasting tumor specific immune responses in multiple pre-clinical tumor models. LTX-315 treatment results in increased CD8+ T cell infiltration, increased CD8+ T cell/Treg ratio and enhanced T cell clonality. The oncolytic effect of LTX-315 involves immunogenic cell death as shown by disintegration of cytosolic organelles with subsequent release of DAMPs (Damage-Associated Molecular Pattern molecules) such as ATP, cytochrome C and HMGB1. Multi-domain proteins from the BCL-2 family seem to be partially involved in LTX-315 mediated killing. The membranolytic effect of LTX-315 also facilitates effective release of tumor antigens. In preclinical tumor models, combination of LTX-315 and immune checkpoint inhibitors demonstrates significant synergy. In this phase I study a recommended Phase II dose as monotherapy and in combination with immune checkpoint inhibitors will be determined. Post-treatment biopsies are also being collected to assess changes in the tumor microenvironment resulting from LTX-315 treatment. Patients are being recruited to one of 4 arms. Arm A: LTX-315 monotherapy single tumor lesion treatment; Arm B: LTX-315 monotherapy single or multiple lesion treatment; Arm C: LTX-315 and ipilimumab in patients with unresectable/metastatic malignant melanoma previously treated with an anti-PD-1 antibody; Arm D: LTX-315 and pembrolizumab in patients with triple negative breast cancer. Patients are receiving LTX-315 in transdermally accessible lesions on days 1, 2, 8, 9, 15 and 16. Ipilimumab and pembrolizumab are administered at standard dose and schedule. As of January 2017, 28 of 60 planned patients have been recruited. Immune responses are assessed by analysis of T lymphocyte subsets in (peripheral blood) and in tumor tissue. In Arm B PD-L1 expression is assessed in bystander (non-injected) tumor biopsies. Anti-tumor activity is assessed by the immune-related response criteria (irRC) for measureable lesions (irCR, irPR, overall response duration, progression free survival (PFS), time to response and disease control rate (irPR, irCR and stable disease (irSD)). Citation Format: Jean-Francois Baurain, Ahmad Awada, Paal F. Brunsvig, Rebecca Kristeleit, Delphine Loirat, Dag Eirik Jossang, Laurence Zitvogel, Guido Kroemer, Aurilien Marabelle, Oystein Rekdal, Baldur Sveinbjornsson, Hedda Wold, Berit Nicolaisen, Andrew Saunders, James Spicer. A phase I dose escalation study of intra-tumoral LTX-315 as monotherapy or in combination with either ipilimumab or pembrolizumab in patients with transdermally accessible tumors (NCT01986426) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT108. doi:10.1158/1538-7445.AM2017-CT108

Immunothérapie anticancer : les molécules immunomodulatrices en développement clinique

RésuméLes réponses immunitaires sont le plus souvent insuffisantes pour contrôler le développement tumoral soit du fait d’une activation lymphocytaire inefficace ou de mécanismes de tolérisation ou d’inactivation. Les immunothérapies ont pour finalité d’inverser le déséquilibre entre la réponse immune et le développement tumoral. Une des stratégies consiste à jouer sur les mécanismes d’activation ou d’inhibition des réponses immunitaires en ciblant les molécules immunomodulatrices. Cette approche thérapeutique a montré son efficacité dans le mélanome métastatique avec l’ipilimumab, anticorps anti-CTLA4 et plus récemment avec les anti-PD-1 dans le mélanome, mais également dans de multiples autres types tumoraux. Cette nouvelle classe thérapeutique est en plein essor, notamment du fait de l’élargissement de ses applications à différentes localisations tumorales mais aussi par la diversité des cibles potentielles. Les thérapies ciblant les voies de modulation inhibitrice du système immunitaire ayant pour cibles principalement les membres de la famille B7 (CTLA4, PD-1, PD-L1/2…) sont les plus avancées en termes de développement, mais la voie qui consiste à stimuler les molécules activatrices de la famille des récepteurs au TNF (OX40, CD40, GITR, CD137…) semble prometteuse. Nous présentons dans cet article une synthèse des différentes voies de modulation du système immunitaire ainsi que les molécules en cours de développement les ciblant.AbstractImmune response often fails to control tumor development due to the activation of inefficient lymphocyte or tolerization mechanisms. The goal of immunotherapeutics is to reverse the balance between the immune response and tumor growth. Targeting immune checkpoints involved in the activation or inhibition pathways of specific immune response is an emerging strategy. It has shown promising results for metastatic melanoma with antibodies targeting CTLA4, and more recently with antibodies targeting PD- 1/PD-L1 in melanoma and also other types of tumor. Therapies targeting B7 family members (CTLA4, PD-1, PD-L1/2, etc.) are the most advanced in clinical development, but molecules belonging to TNF-R family (OX40, CD40, GITR, CD137, etc.) also appear to be promising. In this article, we present a review of the different pathways involved in immune response modulation and corresponding therapeutic agents under clinical development.

Anti-Cancer immunotherapy: Immunomodulating agents in clinical development

RésuméLes réponses immunitaires sont le plus souvent insuffisantes pour contrôler le développement tumoral soit du fait d’une activation lymphocytaire inefficace ou de mécanismes de tolérisation ou d’inactivation. Les immunothérapies ont pour finalité d’inverser le déséquilibre entre la réponse immune et le développement tumoral. Une des stratégies consiste à jouer sur les mécanismes d’activation ou d’inhibition des réponses immunitaires en ciblant les molécules immunomodulatrices. Cette approche thérapeutique a montré son efficacité dans le mélanome métastatique avec l’ipilimumab, anticorps anti-CTLA4 et plus récemment avec les anti-PD-1 dans le mélanome, mais également dans de multiples autres types tumoraux. Cette nouvelle classe thérapeutique est en plein essor, notamment du fait de l’élargissement de ses applications à différentes localisations tumorales mais aussi par la diversité des cibles potentielles. Les thérapies ciblant les voies de modulation inhibitrice du système immunitaire ayant pour cibles principalement les membres de la famille B7 (CTLA4, PD-1, PD-L1/2…) sont les plus avancées en termes de développement, mais la voie qui consiste à stimuler les molécules activatrices de la famille des récepteurs au TNF (OX40, CD40, GITR, CD137…) semble prometteuse. Nous présentons dans cet article une synthèse des différentes voies de modulation du système immunitaire ainsi que les molécules en cours de développement les ciblant.AbstractImmune response often fails to control tumor development due to the activation of inefficient lymphocyte or tolerization mechanisms. The goal of immunotherapeutics is to reverse the balance between the immune response and tumor growth. Targeting immune checkpoints involved in the activation or inhibition pathways of specific immune response is an emerging strategy. It has shown promising results for metastatic melanoma with antibodies targeting CTLA4, and more recently with antibodies targeting PD- 1/PD-L1 in melanoma and also other types of tumor. Therapies targeting B7 family members (CTLA4, PD-1, PD-L1/2, etc.) are the most advanced in clinical development, but molecules belonging to TNF-R family (OX40, CD40, GITR, CD137, etc.) also appear to be promising. In this article, we present a review of the different pathways involved in immune response modulation and corresponding therapeutic agents under clinical development.

Abstract P5-15-12: Clinico-biological characteristics of patients surviving more than two years with metastatic breast cancer (MBC): Results of a transversal national multicentric survey

Introduction: MBC cancer patients may have prolonged survival, and MBC cancers can be considered as a chronic disease. The main goal of the present study was to describe the clinico-biological features of patients surviving more than two years with MBC. Method: During 4 months, we conducted a national multicentric survey about patients aged ≥ 18 in metastatic setting (all solid tumors) for more than 24 months. Clinico-biological data from 200 patients were collected in 39 French centers. Preliminary results of MBC patients (N=88, 87 women/one man) are presented. Results: Most of them were ductal carcinoma (88%), expressing hormonal receptor HR (77%). 43% of tumors overexpressed HER2 (HER2+ tumors: 43%; Triple negative tumors: 6%). Median age at MBC diagnosis was 53 years [29-85]. 18% had metastatic disease at diagnosis and 82 % were localized with a disease-free survival of 65 months [4-312]. Median time of MBC disease was 4,5 years [2-20]. At the time of MBC diagnosis, 64% of patients were not single; 55% were working while 30% were retired. At data collection, 89% of non-single patients were not separated, and 43 % of working patients at diagnosis were still working. Mean number of treatment lines in advanced disease was 4.7 [1-13]. 89% of MBC patients received at least one chemotherapy, 68% hormonotherapy, 70% targeted therapy and 38% had been included in at least one clinical trial. 97% of patients had a local treatment of their primary tumor. Concerning metastasis, 23% had a surgical treatment and 40% radiotherapy treatment. 80% of patients remain with PS of 0 or 1. Only 9% of patients were followed by a palliative care team, 24% by a psychologist and 23% by a nutritionist. Conclusion: Our preliminary results of suggest that an important proportion of MBC cancer patients who live more than 2 years are young, have been treated with chemotherapy, hormonal and targeted therapy, have participated to clinical trials and still have good performance status. No change in marital status was observed. Half of working patients at MBC diagnosis continue to work. Few of them received palliative care. This study may help to better describe long-term survivors with MBC, and socio-medical burden as cancer became a chronic disease. Citation Format: Delphine Loirat, Camille Tlemsani, Jennifer Arrondeau, Audrey Bellesoeur, Christophe Le Tourneau, Benoit Rousseau. Clinico-biological characteristics of patients surviving more than two years with metastatic breast cancer (MBC): Results of a transversal national multicentric survey [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-15-12.

Abstract P4-03-01: Role of disseminated tumor cell (DTC) in bone marrow (BM) detected at primary diagnosis on overall survival and central nervous system (CNS) recurrences in a cohort of 620 early breast cancer patients after 11 years follow up

Background: BM DTC detection is known to be a prognostic factor for distant metastasis and overall survival in early breast cancer. However, distant relapses may occur in patients with no DTC detected at time of primary cancer. In this study, we studied the impact of early breast cancer pathological features (including BM DTC status) on the incidence of CNS metastases. Methods: In a cohort (1998-2005) of 620 early breast cancer patients in whom BM DTC were detected using an anti-cytokeratin antibody (A45B/B3) (Bidard et al., 2008, Clinical Cancer Research, outcome updating (median follow up 11y) on overall survival (OS) and distant metastasis free survival (DMFS) was assessed by log rank test and uni- and multivariate analyses. 137 patients of this cohort have a later metastatic relapse. Chi2 test were performed to compare patient with CNS metastasis and patients with other metastases locations. CNS metastasis survivals were estimated using Kaplan-Meier method and compared by log-rank test. Results: At eleven-year median follow-up, the prognostic value of DTC detection was confirmed in the 620 patients cohort for OS (p=0.03 in multivariate analysis), but DTC were probably less involved in late metastatic events. Distant metastases were diagnosed in 137 (22%) patients. In the course of the metastatic disease, 55 of these patients (40%) have been diagnosed with CNS metastases (parenchymal=30, leptomeningeal=10, both localizations=15), as first metastatic or later event. Patients with CNS metastasis were mostly less than 50 years old (60% vs 38%, p=0.01), pN0 (31% vs 10%, p=0.002), hormonal receptor status negative (54% vs 30%, p=0.007) and HER2 status positive (50% vs 22%, p=0.01). Strikingly, although DTC detection was associated with development of distant metastasis in the whole cohort, the occurrence of CNS metastasis was found to be higher in patients who had no DTC detected at primary diagnosis (p=0.016). From CNS metastasis, median survival was 7.8 months (8.3 months for parenchymal and 2.4 months for leptomeningeal recurrences). For HER2+ patients, the median survival after diagnosis of CNS metastasis was 16.6 months (N=15) and 4.1 months for Her2- patients (N=15). Conclusions: After a long-term follow up, DTC remain an adverse prognostic factor in early breast cancer. Our study suggests that cancer cells with epithelial differentiation, as detected in the BM, are less prone to CNS dissemination. This study also confirmed previously reported determinants of CNS metastases (age, RH-, HER2+) in the pre-adjuvant trastuzumab era, but also showed that the outcome of HER2+ patients with CNS relapse was longer, probably due to HER2 targeted therapy during metastatic course. Citation Format: Delphine Loirat, Francois-Clement Bidard, Leonor Chaltiel, Frederique Berger, Veronique Dieras, Yann de Rycke, Severine Alran, Youlia Kirova, Paul Cottu, Anne Vincent- Salomon, Xavier Sastre-Garau, Jean-Yves Pierga. Role of disseminated tumor cell (DTC) in bone marrow (BM) detected at primary diagnosis on overall survival and central nervous system (CNS) recurrences in a cohort of 620 early breast cancer patients after 11 years follow up [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-03-01.