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Introduction Pembrolizumab alone (IO-mono) or in combination with platinum-based chemotherapy (CT-IO) is first-line standard of care for advanced non-small cell lung cancer (NSCLC) patients with PD-L1 ≥ 50%. This retrospective multicentre study assessed real-world use and efficacy of both strategies. Methods Patients with advanced NSCLC PD-L1 ≥ 50% from eight hospitals who had received at least one cycle of IO-mono or CT-IO were included. Overall survival (OS) and real-word progression-free-survival were estimated using Kaplan–Meier methodology. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs, and a Cox model with inverse propensity treatment weighting was carried out. Results Among the 243 patients included, 141 (58%) received IO-mono and 102 (42%) CT-IO. Younger patients, those with symptomatic disease and brain metastases were more likely to be proposed CT-IO. With a median follow-up of 11.5 months (95% CI 10.4–13.3), median OS was not reached, but no difference was observed between groups (p = 0.51). Early deaths at 12 weeks were 11% (95% CI 4.6–16.9) and 15.2% (95% CI 9.0–20.9) in CT-IO and IO groups (p = 0.32). After adjustment for age, gender, performance status, histology, brain metastases, liver metastases and tobacco status, no statistically significant difference was found for OS between groups, neither in the multivariate adjusted model [HR 1.07 (95% CI 0.61–1.86), p = 0.8] nor in propensity adjusted analysis [HR 0.99 (95% CI 0.60–1.65), p = 0.99]. Male gender (HR 2.01, p = 0.01) and PS ≥ 2 (HR 3.28, p Conclusion Younger patients, those with symptomatic disease and brain metastases were more likely to be proposed CT-IO. However, sparing the chemotherapy in first-line does not appear to impact survival outcomes, even regarding early deaths.

To investigate the evolution of bone metastases in patients receiving immune checkpoint inhibitors (ICI).A single-center retrospective study included cancer patients with bone metastases treated with ICI at our institution between January 2014 and September 2019. Clinical and biological data were collected from medical records and independent expert review of imaging was performed. Target and non-target lesions were identified and followed up to 1 year. Patients were then classified as bone responder or non-responder. Comparisons between groups were performed with Student's t test or Mann-Whitney test.Among 1108 patients screened, 192 patients had bone metastases and 48 patients were included in the final analysis, with lung cancer, renal carcinoma and melanoma as most represented cancer type. Half of the patients experienced stability, condensation or peripheral sclerosis of bone lesions. Initial progression before stabilization with or without sclerosis of bone lesion occurred for 19% of patients (pseudoprogression). There was an association between bone response and global oncological outcomes. Bone responder patients had a significant decrease in morphine and co-analgesic prescription as well as a significant decrease in alkaline phosphatases compared to non-responder patients.Bone response was observed in half of patients with available imaging and follow-up after 3 months of ICI treatment, with sclerosis observed in one-third of bone lesions at month 3, in all tumor types. Up to 20% of patients experienced a pseudoprogression of bone lesions such as previously described in primary tumor and other metastatic sites. Bone response was associated with improvement of pain and survival.

Introduction Alors que l’immunotherapie prend une place de plus en importante en cancerologie, il y a tres peu de donnees rapportees concernant son effet sur les metastases osseuses. Notre objectif etait d’etudier l’evolution des metastases osseuses chez les patients atteints de cancer et traites par inhibiteurs de checkpoint immunitaire (ICI). Patients et methodes Dans le cadre d’une etude retrospective monocentrique, tous les patients atteints de cancer avec metastases osseuses et traites par ICI entre Janvier 2014 et Septembre 2019 ont ete inclus, si les imageries etaient disponibles. Les donnees cliniques et biologiques ont ete collectees a partir du dossier medical informatise et une relecture des imageries a ete realisee de facon independante par un radiologue specialise en imagerie osteo-articulaire. Des lesions cibles et non-cibles ont ete identifiees lors de la mise sous ICI puis suivies a 3, 6 et 12 mois. Des comparaisons entre les patients avec ou sans reponse osseuse ont ete realisees avec test de Mann-Whitney ou test t de Student. Resultats 48 patients ont pu etre inclus dans les analyses. Pour la moitie des patients, on retrouvait une stabilite des lesions osseuses, avec condensation et/ou apparition d’une sclerose peripherique. Il existait une progression initiale en taille avant d’avoir une stabilite avec ou sans sclerose de la lesion osseuse pour 19 % des patients, phenomene classiquement decrit comme « pseudoprogression ». On retrouvait une correlation entre reponse osseuse et evolution oncologique globale (reponse tumorale evaluee par les criteres RECIST, survie globale et survie sans progression). Pour les patients avec une reponse osseuse, on notait une diminution significative de la consommation en morphine et en co-analgesiques, mais egalement une diminution significative et precoce des phosphatases alcalines en comparaison avec les patients non repondeurs sur leur metastase(s) osseuse(s). En revanche, il n’y avait pas de difference notable sur la survenue d’evenement osseux. Discussion L’evolution des metastases osseuses etait favorable pour la moitie des patients traites par ICI, avec souvent une sclerose peripherique observee des le 3eme mois de traitement, mais possiblement un phenomene de pseudoprogression comme decrit prealablement avec les tumeurs primitives. Cette reponse osseuse s’associait a une meilleure qualite de vie et survie. La relecture specialisee apportait une reelle plus-value comparativement aux comptes-rendus initiaux. Conclusion Les metastases osseuses ont un profil de reponse particulier sous ICI, comme decrit dans les tumeurs primitives, avec une frequente sclerose et possible pseudoprogression.

ObjectivesTo evaluate the prevalence and type of rheumatic immune-related adverse events (irAEs) in patients receiving immune checkpoint inhibitors (ICIs), as well as the correlation with tumour response.MethodsThis was a single-centre prospective observational study including all cancer patients receiving ICIs. The occurrence of irAEs and tumour response was assessed on a regular basis. Patients who experienced musculoskeletal symptoms were referred to the department of rheumatology for clinical evaluation and management.ResultsFrom September 2015 to May 2017, 524 patients received ICIs and 35 were referred to the department of rheumatology (6.6%). All but one of the rheumatic irAEs occurred with anti-programmed cell death protein 1(PD-1)/PD-1 ligand 1(PD-L1) antibodies, with a median exposure time of 70 days. There were two distinct clinical presentations: (1) inflammatory arthritis (3.8%) mimicking either rheumatoid arthritis (n=7), polymyalgia rheumatica (n=11) or psoriatic arthritis (n=2) and (2) non-inflammatory musculoskeletal conditions (2.8%; n=15). One patient with rheumatoid arthritis was anti-cyclic citrullinated peptide (anti-CCP) positive. Nineteen patients required glucocorticoids, and methotrexate was started in two patients. Non-inflammatory disorders were managed with non-steroidal anti-inflammatory drugs, analgesics and/or physiotherapy. ICI treatment was pursued in all but one patient. Patients with rheumatic irAEs had a higher tumour response rate compared with patients without irAEs (85.7% vs 35.3%; PConclusionSince ICIs are used with increasing frequency, knowledge of rheumatic irAEs and their management is of major interest. All patients were responsive either to low-to-moderate doses of prednisone or symptomatic therapies and did not require ICI discontinuation. Furthermore, tumour response was significantly higher in patients who experienced rheumatic irAEs.

Resume La meningite carcinomateuse est une complication tardive et grave du cancer, car elle greve le pronostic vital et fonctionnel. Son incidence, faible actuellement, va augmenter a l’avenir avec l’allongement de la survie des patients et l’amelioration des methodes diagnostiques. Elle est plus frequente dans le cancer du poumon, le cancer du sein et le melanome. Son pronostic reste pourtant mauvais malgre l’avenement de therapies efficaces, avec une survie mediane dans le cancer du poumon de 3 a 4 mois sous traitement. L’heterogeneite clinique et radiologique rend difficile son diagnostic, qui repose essentiellement sur l’IRM cerebrospinale et l’analyse du liquide cephalo-rachidien. Il existe peu de donnees solides concernant les modalites therapeutiques, qui proviennent de cas cliniques ou d’etudes retrospectives. De plus, l’etat general des patients est souvent trop altere pour leur permettre de beneficier d’un traitement ou pour etre inclus dans un essai clinique. C’est pourquoi il n’existe pas de recommandations robustes concernant le traitement des meningites carcinomateuses, en particulier dans le cancer du poumon. Cette revue a donc pour but de faire le point sur la prise en charge diagnostique et therapeutique des meningites carcinomateuses chez les patients atteints de cancers du poumon.

Objective Immune checkpoint inhibitors (ICIs) for cancer therapy frequently induce immune-related adverse effects (IRAEs). Therefore, most patients with preexisting autoimmune diseases have been excluded from clinical trials of ICIs. This study was undertaken to evaluate the safety and efficacy of ICIs in patients with preexisting autoimmune disease and cancer. Methods A retrospective cohort study was conducted from January 2017 to January 2018 via 3 French national networks of experts in oncology and autoimmunity. Adults with preexisting autoimmune disease who were receiving ICIs were assessed for the occurrence of flare of preexisting autoimmune disease, other IRAEs, and cancer response. Results The study included 112 patients who were followed up for a median of 8 months. The most frequent preexisting autoimmune diseases were psoriasis (n = 31), rheumatoid arthritis (n = 20), and inflammatory bowel disease (n = 14). Twenty-four patients (22%) were receiving immunosuppressive therapy at ICI initiation. Autoimmune disease flare and/or other IRAE(s) occurred in 79 patients (71%), including flare of preexisting autoimmune disease in 53 patients (47%) and/or other IRAE(s) in 47 patients (42%), with a need for immunosuppressive therapy in 48 patients (43%) and permanent discontinuation of ICI in 24 patients (21%). The median progression-free survival was shorter in patients receiving immunosuppressive therapy at ICI initiation (3.8 months versus 12 months; P = 0.006), confirmed by multivariable analysis. The median progression-free survival was shorter in patients who experienced a flare of preexisting autoimmune disease or other IRAE, with a trend toward better survival in the subgroup without immunosuppressant use or ICI discontinuation. Conclusion Our findings indicate that flares or IRAEs occur frequently but are mostly manageable without ICI discontinuation in patients with a preexisting autoimmune disease. Immunosuppressive therapy at baseline is associated with poorer outcomes.

Background:Description and initial management of rheumatic immune-related adverse-events (irAEs) from cancer immunotherapies have been reported by several groups but to date, few studies have evaluated the long-term outcomes and management of rheumatic irAEs (1).Objectives:To describe the long-term management and assess the one-year outcomes of patients who experienced rheumatic immune-related adverse events (irAEs) due to immune checkpoint inhibitors (ICI).Methods:This was a single-centre prospective observational study including patients referred for musculoskeletal symptoms while treated with ICI. After baseline rheumatological evaluation defining the clinical entity presented, follow-up visits were organised according to the type and severity of irAE. At one year, persistence of irAE, ongoing treatment, as well as cancer outcomes were assessed.Results:63 patients were included between September 2015 and June 2018. 24 patients (38%) presented with non-inflammatory musculoskeletal conditions managed with short-term symptomatic treatment and did not require specific follow-up. 39 patients (62%) experienced inflammatory manifestations, mimicking either rheumatoid arthritis (RA, n=19), polymyalgia rheumatica (PMR, n=16), psoriatic arthritis (PsA, n=3) and one flare of a preexisting axial spondyloarthritis. Overall, 32 patients (82%) received systemic glucocorticoids, with a median rheumatic dosage of 15mg/day (range: 5-60mg/day). None of the patients had to permanently discontinue ICI therapy for rheumatic irAE. 20 patients (67%) were still receiving glucocorticoids at one year, with a median dosage of 5mg/day (range: 2-20mg/day). Glucocorticoids were more frequently discontinued for patients with RA-like condition (44%) than PMR-like condition (23%), but no other predictive factor of glucocorticoids withdrawal could be identified. At one year, overall survival and progression-free survival were comparable between patients who were still receiving glucocorticoids for rheumatic irAE and patients who have discontinued. Eight patients required csDMARDs.Conclusion:At one year, a majority of patients required long-term low-dose glucocorticoids for chronic rheumatic irAE, which seems not altering oncological control.References:[1]Braaten TJ, Brahmer JR, Forde PM, et al. Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation. Ann Rheum Dis. 2019 Sep 20.Disclosure of Interests:None declared

Background Immune checkpoint inhibitors (ICI) represent a new standard of care for the treatment of selected advanced cancers and are still being investigated in many other tumour types. By enhancing the T-cell activation, a unique spectrum of inflammatory side effects has emerged, also known as immune-related adverse events (irAEs), including various well-described rheumatic manifestations. Data regarding the association between irAEs and patient outcomes are conflicting. Objectives To evaluate the incidence and characteristics of irAEs in patients receiving ICI, as well as the correlation with tumour response and patient survival. Methods This was a single-centre prospective observational study including all cancer patients receiving ICIs. The occurrence of irAEs, tumour response and patient outcomes were assessed on a regular basis. Overall survival has been considered from the start of ICI. Results From May 2015 to September 2017, 636 patients (70% male, mean age 64 years) have been included in this cohort while receiving anti PD-1 (n=435), anti PD-L1 (n=66) or anti CTLA-4 (n=3) as single agent or as sequential (n=100) or combined (n=32) therapies. Cancer types were mainly melanoma (n=293), non-small cell lung cancer (n=150) and renal carcinoma (n=83). Overall, 274/633 patients (43%) experienced irAEs, either 1 irAE (n=162), 2 irAEs (n=78) or ≥3 irAEs (n=34), with a median exposure time of 52 days30–91 for the first irAE. Dermatological irAEs were by far the most frequent (n=160), followed by digestive (n=80), endocrine irAEs (n=67), rheumatic (n=49) and pulmonary irAEs (n=17). So far, evaluation of tumour response was available for 551 patients, including 190 responders (complete response n=36 and partial response n=154), 192 patients with stable disease and 169 with progressive disease. 122/189 responders (65%) and 107/192 with stable disease (56%) experienced at least one irAE while reported only in 40/169 non responders (24%). Patients experiencing at least one irAE had an increased overall survival (median of 1169 days versus 224 days, p Conclusions Although irAE occurrence is not required for treatment benefit, it strongly associates with overall survival. Optimal multidisciplinary management of irAEs, including rheumatologists when needed, is worthwhile to maintain beneficial responses. Disclosure of Interest None declared

Background Immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) axis have been a major advance in cancer immunotherapy. By enhancing T cell activity, unprecedented long-lasting tumour responses are observed in selected cancers but some patients experience immune related adverse events (irAE). Objectives To evaluate the prevalence and type of rheumatic and musculoskeletal disorders in patients receiving ICI at a single institution (University Hospital of Bordeaux, France). Methods All cancer patients with musculoskeletal disorders while receiving ICI were referred to our rheumatology department. For each referred patient, an experienced rheumatologist performed a comprehensive clinical evaluation. Blood tests (inflammatory markers, serum creatine kinase, autoantibodies) and imaging (X-rays, ultrasound) were obtained according to clinical findings. HLA-DR phenotyping was also performed for some patients to search for shared epitope. Results From September 2015 to December 2016, 329 patients received ICI (anti CTLA-4: n=38; anti PD-1: n=251; anti PD-L1: n=29; combination anti CTLA-4/anti PD-1: n=11) and 21 patients were referred to our rheumatology department (6.4%). Mean age was 65 years and cancer types included melanoma (n=10), non small cell lung cancer (n=9), Merkel carcinoma (n=1) and renal carcinoma (n=1). All musculoskeletal disorders occurred in patients receiving anti PD-1 (nivolumab: n=12; pembrolizumab: n=6) or anti PD-L1 (avelumab: n=2; atezolizumab: n=1), with a median exposure time of 90 days (range: 1–650 days). There were two distinct clinical presentations: 1) inflammatory arthritis (IA) mimicking either rheumatoid arthritis (n=5) or polymyalgia rheumatica (n=8) and, 2) non-inflammatory musculoskeletal conditions (n=8). Of note, one patient was anti-CCP positive but negative for RF. Shared epitope HLA-DRB1 *01:01 was present in 4 patients. Eleven patients required corticosteroid therapy with a median dose of 15mg/day (range: 7–30 mg/day). Non-inflammatory disorders were easily managed with NSAIDs, analgesics and/or physiotherapy. ICI treatment was temporarily discontinued in one patient only, in line with the clinical trial protocol. To date, there was a partial or complete tumour response to ICI in 10 patients whereas 3 had stable disease and 7 had progressive disease. Tumour response or stable disease was observed in 11 of 12 patients with IA but only in 2 of 8 patients with non-inflammatory conditions. Conclusions In our series, patients with immune-related IA mimicking rheumatoid arthritis and polymyalgia rheumatica were responsive to low-to-moderate dose of prednisone and did not require ICI discontinuation. Furthermore, tumour response was frequently observed in such patients. Disclosure of Interest None declared

e14166 Background: Evidence suggests that sarcopenia is a significant predictor of worst outcomes and treatment toxicities in metastatic solid tumors patients (pts). We investigated whether sarcopenia was associated with outcomes and severe toxicities (ST) in patients treated with check point inhibitors (CPI). Methods: All consecutive metastatic solid tumors patients treated with CPI from January 2013 to December 2017 in Bordeaux University Hospital (France) were retrospectively reviewed. Sarcopenia was evaluated using computed tomography (CT) obtained within 1 month before treatment initiation. Skeletal muscle mass index (SMI) were measured from axial L3 CT section. Sarcopenia was defined as SMI ≤ 52.4 cm2/m2 for males and SMI ≤ 38.5 cm2/m2 for women. Clinical characteristics included Performance Status (PS) and anthropometric parameters. ST included grade III-IV according to NCI-CTC v4.0 and any grade of toxicity leading to treatment interruption. Results: Among 261 pts included, 179 (69%) had metastatic lung cancer and 151 (58%) had previously received one line of treatment. Median age was 61 years old and there were 198 males (76%). PS status was 1 in 55% of pts. CPI treatment was: anti PD1, anti PD-L1, anti CTLA-4 and CPI combination in 192, 43, 3 and 20 pts, respectively. The prevalence of sarcopenia was 64%. At inclusion, sarcopenia was associated with poor PS (p = 0.002), anorexia (p < 0.001), lower albumin (p = 0.002) and hemoglobin (p < 0.001). Objective Response Rate (ORR) was 28% in sarcopenic pts and 26% in non-sarcopenic pts. Median progression free survival (PFS) was 6.9 and 7.6 months in sarcopenic pts and non-sarcopenic pts respectively (p = 0.5). In multivariate analysis, sarcopenia was not associated with PFS or ORR. Median overall survival (mOS) was 10.2 months in lung cancer, without significant difference between sarcopenic and non-sarcopenic patients (mOS: 9 months and 17 months respectively, p = 0.06). In general population, ST occurred in 36 (14%) pts; among which 23 (64%) presented sarcopenia. In multivariate analysis, sarcopenia was not associated with ST (OR = 1.16, p = 0.71). Conclusions: Sarcopenia was not associated with outcomes or toxicities in metastatic solid tumors patients treated with CPI in this study.

The central nervous system (CNS), through carcinomatous meningitis or solid brain metastases, is the most common site of recurrence in non-small cell lung cancers (NSCLC) with activating mutations. Our retrospective study describes the population of patients with CNS metastases of NSCLC harboring activating mutation with targeted therapy (EGFR, ALK, BRAF, HER2) in 4 French regional reference hospitals. 60 patients were analyzed. The proposed treatments were heterogeneous and included combinations of chemotherapy, targeted therapy and radiotherapy±associated with topical treatments. Median overall survival following CNS metastasis in these patients was 15.8 months for meningitis carcinoma and 26 months for brain metastases. In patients with brain metastases, the addition of targeted therapy treatment allows a significant improvement in median progression free survival from 5.9 months to 10.6 months (HR 0.48 CI95 [0.24 to 0.97] P=0.035). These patients seem therefore benefit from systemic therapy and particularly targeted therapy with better survival than usual.

La frequence des dysthyroidies induites par les inhibiteurs de checkpoint immunitaire (ICPI) entraine la prescription reguliere de bilans biologiques thyroidiens. L’objectif de notre etude etait de caracteriser ces dysthyroidies, leur evolution et d’evaluer la proportion de dosages hormonaux finalement utiles aux patients. Notre etude observationnelle, monocentrique, retrospective, inclue tous les patients consecutifs traites par ICPI de juillet 2011 a mai 2017 au CHU de Bordeaux dans les services d’oncologie, dermatologie et pneumologie. Des bilans biologiques thyroidiens etaient realises avant chaque cure d’immunotherapie. Parmi les 565 patients traites, 43 patients (8 %) dont 26 hommes (61 %) presentaient une dysthyroidie avec un âge moyen de 61 ans ± 15. La prevalence des dysthyroidies quel que soit le cancer traite, etait de 8 % en monotherapie et de 20 % en cas de double immunotherapie. Des hypothyroidies isolees (35 %), des thyroidites biphasiques (thyrotoxicose transitoire suivie d’hypothyroidie) (32,5 %) et des thyrotoxicoses isolees (32,5 %) etaient observees, toutes de grade 1 ou 2. Les thyrotoxicoses etaient toutes transitoires (duree mediane de 1 mois). Au total, 70 % etaient asymptomatiques, decouvertes sur un bilan systematique et ne necessitaient pas de traitement. En cas d’hypothyroidie, la levothyroxine etait debutee 3 mois ± 2 apres le debut de l’immunotherapie. Qunize mois apres le diagnostic d’hypothyroidie, 84 % des patients etaient toujours traites par levothyroxine (≥ 50 μg). Parmi ces patients, 67 % avaient arrete l’immunotherapie. Parmi les 266 bilans thyroidiens prescrits, 29 (10 %) ont justifie un traitement hormonal. La surveillance systematique du bilan thyroidien apparait utile pour les patients 3 mois apres le debut de l’immunotherapie.

A cold plasma ionization device has been designed to monitor freeze-drying processes in situ by monitoring lyophilization chamber moisture content. This plasma device, which consists of a probe that can be mounted directly on the lyophilization chamber, depends upon the ionization of nitrogen and water molecules using a radiofrequency generator and spectrometric signal collection. The study performed on this probe shows that it is steam sterilizable, simple to integrate, reproducible, and sensitive. The limitations include suitable positioning in the lyophilization chamber, calibration, and signal integration. Sensitivity was evaluated in relation to the quantity of vials and the probe positioning, and correlation with existing methods, such as microbalance, was established. These tests verified signal reproducibility through three freeze-drying cycles. Scaling-up studies demonstrated a similar product signature for the same product using pilot-scale and larger-scale equipment. On an industrial scale, the method efficiently monitored the freeze-drying cycle, but in a larger industrial freeze-dryer the signal was slightly modified. This was mainly due to the positioning of the plasma device, in relation to the vapor flow pathway, which is not necessarily homogeneous within the freeze-drying chamber. The plasma tool is a relevant method for monitoring freeze-drying processes and may in the future allow the verification of current thermodynamic freeze-drying models. This plasma technique may ultimately represent a process analytical technology (PAT) approach for the freeze-drying process.

An ex-vivo test was used to evaluate the activity of antimicrobials against three microorganisms, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. The ex-vivo test is a carrier test using freshly excised animal skin samples maintained in viable conditions for a short period of time. Skin samples came from a veterinary practice and were excised from either dogs or cats. The antimicrobial activity of povidone iodine, chlorhexidine diacetate, cetrimide and benzalkonium chloride was also evaluated with suspension and glass-carrier tests. Generally, the activity of the antimicrobials tested was reduced when applied to the skin surface. Apart from povidone iodine (2%) against S. aureus, the biocides investigated failed to achieve a 5 log10 reduction in bacterial titre when tested with the ex-vivo method. There was no significant difference in reduction of bacterial titres after treatment with antimicrobials between the glass-carrier and the suspension tests. Furthermore, the drying process of bacterial inoculum was less detrimental on skin than on glass surfaces. This study confirmed that the activity of a biocide tested in suspension or on an inanimate surface did not reflect its activity when tested on skin. Further development of the ex-vivo test may be useful, especially for testing the antimicrobial activity of formulations with antiseptic properties.