Search

Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) used in first line for the treatment of advanced EGFR-mutated non-small cell lung cancer (NSCLC).The identification of related histomolecular resistance mechanisms to first-line osimertinib is a critical step to define the optimal treatment strategy beyond progression.All consecutive patients treated in the first line with osimertinib for advanced EGFR-mutated NSCLC at 10 hospitals in the Greater Paris area between April 2015 and January 2021 were included. Histomolecular data from plasma and tissue samples taken at progression under osimertinib were collected, and all samples were analyzed using DNA next-generation sequencing. Data on objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and time to treatment discontinuation (TTD) were also collected.Overall, 104 patients were included. Most patients had adenocarcinoma (n = 102, 98%) with an exon 19 EGFR deletion (n = 54, 52%). Forty-two patients (50%) had central nervous system (CNS) metastasis at the time of osimertinib initiation. ORR was 76%, median PFS and OS were 12.6 months and 52 months, respectively, and TTD was 33 months. At the time of analysis, 44 patients (42%) had tumor progression, and among these patients, 27 (61%) contributive samples were available. The most frequent molecular alterations at progression were mesenchymal epithelial transition factor (MET) amplification (15%; n = 4) and EGFR C797S mutation (11%; n = 3). Histological transformation was found in one patient (4%). RNA next-generation sequencing was performed in eight patients and showed a CCDC6-RET fusion in one patient (12%).We confirmed the efficacy of osimertinib in patients with advanced EGFR mutation-positive NSCLC. At progression, the most frequent histomolecular alterations were MET amplification and EGFR C797S mutation.

Simple Summary EGFR exon 20 insertions are rare genetic alterations in non-small-cell lung cancers (NSCLCs) that are usually unresponsive to approved EGFR tyrosine kinase inhibitors (TKIs), but data is limited about this population. We aim to describe clinical features, survival, and response to chemotherapy and TKIs in this patient population. Abstract EGFR exon 20 insertions are rare genetic alterations in non-small-cell lung cancers (NSCLCs) that are usually unresponsive to approved EGFR tyrosine kinase inhibitors (TKIs). In this paper, we describe the clinical characteristics, efficacy of EFGR TKIs and chemotherapy, and resulting survival in this population. We retrospectively collected patients with EGFR exon 20 insertions (Exon20ins) from 11 French genetic platforms and paired them (1:2 ratio) with classic Exon 19/21 EGFR mutation patients (controls). Between 2012 and 2017, 35 Exon20ins patients were included. These patients were younger at diagnosis than the controls. All Exon20ins patients who were treated with first-line EGFR TKIs (n = 6) showed progressive disease as the best tumor response. There was no significant difference in the tumor response or the disease control rate with first-line platinum-based chemotherapy between the two groups. A trend towards shorter overall survival was observed in Exon20ins vs. controls (17 months (14—not reach(NR) 95% confidence interval(CI) vs. 29 months (17–NR 95%CI), p = 0.09), respectively. A significant heterogeneity in amino acid insertion in EGFR exon 20 was observed. EGFR exon 20 insertions are heterogeneous molecular alterations in NSCLC that are resistant to classic EGFR TKIs, which contraindicates their use as a first-line treatment.

International audience; Objectives: The understanding of histo-molecular mechanisms associated with resistance to osimertinib is a critical step to define the optimal treatment strategy in advanced EGFR-mutated Non-Small-Cell-Lung-Cancer (NSCLC).Materials and methods: We performed a multicentric retrospective analysis on a cohort of consecutive patients treated with osimertinib for an advanced EGFR-mutated NSCLC and collected histo-molecular data from plasma and tumor samples at the time of progression. Next-generation sequencing (NGS) was performed for all samples. Best Overall Response Rate (ORR), Progression Free Survival (PFS), Overall Survival (OS) and data on treatment post-progression efficacy were also collected.Results: Two-hundred and twenty-six patients were included from 9 Academic French Hospitals between April 2015-October 2018. Osimertinib was given in second-line or more in 219 patients (97%). Best ORR was 52% and best central nervous system ORR was 56%. Median PFS and OS were 9.5 months (IQR 4.0-17.2) and 24 months (IQR 12.4-NR) respectively. At the time of analysis, 150 patients (66%) had tumor progression. Among them, 73 contributive samples (56 tumor biopsies) were available. The most frequent molecular alterations were C797S mutation (n = 9 (13%)) and MET amplification (n = 8 (11%)). Histologic transformation occurred in 5 patients (9% of tumor biopsies). In T790M + NSCLC, loss of T790 M occurred in 68% of cases. Median PFS and OS with treatment beyond progression were 6.0 months (IQR 2.0-10.4) and 15.1 months (IQR 6.7-NR) respectively and longer in case of osimertinib continuation beyond progression.Conclusion: We confirmed the efficacy of osimertinib in patients with advanced EGFR mutation positive NSCLC. At progression, the most frequent molecular alterations were MET amplification and C797S mutation.

Aside from PD-L1 expression, biomarkers of response to immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer (NSCLC) are needed. In a previous retrospective analysis, we documented that fecal Akkermansia muciniphila (Akk) was associated with clinical benefit of ICI in patients with NSCLC or kidney cancer. In the current study, we performed shotgun-metagenomics-based microbiome profiling in a large cohort of patients with advanced NSCLC (n = 338) treated with first- or second-line ICIs to prospectively validate the predictive value of fecal Akk. Baseline stool Akk was associated with increased objective response rates and overall survival in multivariate analyses, independent of PD-L1 expression, antibiotics, and performance status. Intestinal Akk was accompanied by a richer commensalism, including Eubacterium hallii and Bifidobacterium adolescentis, and a more inflamed tumor microenvironment in a subset of patients. However, antibiotic use (20% of cases) coincided with a relative dominance of Akk above 4.8% accompanied with the genus Clostridium, both associated with resistance to ICI. Our study shows significant differences in relative abundance of Akk that may represent potential biomarkers to refine patient stratification in future studies.

After tobacco, cannabis is the most widely used drug worldwide, and the move to legalise it is growing in more and more countries. The literature about the involvement of cannabis smoking on the development of lung cancer is scarce and most often reassuring [1–3], even though the concentration of carcinogens in cannabis smoke is unquestionably greater than that in tobacco smoke [4]. Moreover, recent studies on cannabis tend to focus on possible therapeutic effects [5]. Studies of the carcinogenic impact of cannabis are indeed limited by its frequent association with tobacco smoking and by its illegal status in most countries [6]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Betser has nothing to disclose. Conflict of interest: Dr. Glorion has nothing to disclose. Conflict of interest: Dr. Mordan has nothing to disclose. Conflict of interest: Dr. Caramella has nothing to disclose. Conflict of interest: Dr. Ghigna has nothing to disclose. Conflict of interest: Dr. Besse has nothing to disclose. Conflict of interest: Dr. planchard has nothing to disclose. Conflict of interest: Dr. Le Pavec has nothing to disclose. Conflict of interest: Dr. Chapelier has nothing to disclose. Conflict of interest: Dr. Friard has nothing to disclose. Conflict of interest: Dr. Gounant has nothing to disclose. Conflict of interest: Dr. Castier has nothing to disclose. Conflict of interest: Dr. Levy has nothing to disclose. Conflict of interest: Dr. Mercier has nothing to disclose. Conflict of interest: Dr. Fabre has nothing to disclose. Conflict of interest: Dr. Fadel has nothing to disclose. Conflict of interest: Dr. pradere has nothing to disclose.

About 2-3% of non-small-cell lung cancers (NSCLCs) harbor MET exon-14-skipping (METex14) mutations. Efficacy of the MET-inhibitor crizotinib has been reported, but progression-free survival (PFS) was very short. Immune-checkpoint inhibitors (ICIs) have become a cornerstone of NSCLC treatment but appear to be less effective in non-smokers and against tumors exhibiting oncogenic addiction. We describe 6 remarkable (PFS exceeding 18 months) and durable responses to ICIs of NSCLCs harboring a METex14 mutation.Each patient's clinical and biological characteristics, and tumor responses after ICIs were examined. Complete tumor-DNA sequencing was available after starting second-line ICIs, which followed first-line chemotherapy. Tumor-cell programmed cell-death protein-1 ligand-1 (PD-L1) expression on tumor cells was evaluated using antibody clone E1L3N (Cell Signaling Technology).Among 25 patients with METex14-mutated NSCLCs, 13 of whom were ICI-treated, 6 had prolonged responses: 5 women, 1 man; 57-80 years old; 3 never-smokers, 1 ex-smoker and 2 smokers; 5 adenocarcinomas, 1 sarcomatoid carcinoma; 5 received nivolumab, 1 pembrolizumab. No EGFR, BRAF or KRAS mutations (only 1 minority KRAS mutation), or ALK or ROS translocations were detected. No concurrent MET amplification was observed. Tumor-mutation burden was low (10 mutations/Mb) in 3 tested tumors. Four partial and 2 complete responses were obtained during the first 3 months for 5 patients, while pseudoprogression was initially observed in 1. Tolerance was excellent, with only 1 grade-3 immune-related adverse event. Response was maintained for 18-49 months.ICIs could be considered to treat patients whose NSCLCs harbor a METex14 mutation. More biological marker data are needed to identify which patients are most likely to benefit from ICIs.

CERVOXY CLIN; International audience; IntroductionMET proto-oncogene (MET) exon 14 splice site (METex14) mutations were recently described in NSCLC and has been reported to correlate with efficacy of MET tyrosine kinase inhibitors. High diversity of these alterations makes them hard to detect by DNA sequencing in clinical practice. Because METex14 mutations induce increased stabilization of the MET receptor, it is anticipated that these mutations are associated with MET overexpression. We aim to determine whether NSCLC with high MET overexpression could define a subset of patients with a high rate of METex14 mutations.MethodsFrom The French Cooperative Thoracic Intergroup PREDICT.amm cohort of 843 consecutive patients with a treatment-naive advanced NSCLC who were eligible for a first-line therapy, 108 NSCLC samples with high MET overexpression defined by an immunochemistry score 3+ were tested for METex14 mutations using fragment length analysis combined with optimized targeted next-generation sequencing. MET copy number analysis was also derived from the sequencing data.ResultsMETex14 mutations were detected in two patients (2.2%) who also displayed a TP53 mutation and a PIK3CA mutation, respectively. An MET gene copy number increase was observed in seven additional patients (7.7%). Next-generation sequencing analysis revealed inactivating mutations in TP53 (52.7%) and PTEN (1.1%), and oncogenic mutations in KRAS (28.6%), EGFR (7.7%), PIK3CA (4.4%), BRAF (4.4%), NRAS (2.2%), GNAS (1.1%), and IDH1 (1.1%).ConclusionsThe rate of METex14 mutations in NSCLC with high MET overexpression was similar to that found in unselected NSCLC. Moreover, we observed a high frequency of driver alterations in other oncogenes. Consequently these findings do not support the use of MET immunohistochemistry as a surrogate marker for METex14 mutations.

9019 Background: The gut microbiome, most specifically centered on one of the most prevalent anaerobic bacterium Akkermansia muciniphila (Akk), has emerged as a potential hallmark of clinical benefit to ICI. The goal of this study was to validate the prognostic significance of Akk in advanced NSCLC patients amenable to ICI. Methods: The multicentric prospective observational study enrolled patients with advanced NSCLC amenable to single agent ICI in first and second line. Stool sample was collected at study entry. Primary end-point was investigator-assessed objective response rate (ORR). We considered that a meaningful clinical difference would correlate to a 10% ORR increase in the Akk-Pos group compared to the Akk-Neg group. At least 292 patients equally divided each in each group would be required for a power at 80% and a two-sided alpha level of 5%. Results: From Dec 2015 to Nov 2019, a total of 409 patients were screened and 311 patients enrolled across 12 academic centers in France and Canada. Median age was 64yr, 32% were female, 77% had non-squamous NSCLC and PD-L1 was ≥1% in 70% of the 213 assessable samples. Akk was detectable in 158 (51%) and absent in 153 (49%) patients. Baseline characteristics were well balanced between the two groups. When considering Akk-Pos vs Akk-Neg groups the primary endpoint ORR was 27% and 17% respectively ( p = 0.04). Rates of partial response, stable disease and progressive disease (PD) were 62%, 50% and 46% respectively in the Akk-Pos group compared to 38%, 50% and 54% in the Akk-Neg group ( p = 0.04). Moreover, 57% of patients were still alive after 12 months in the Akk-Pos group vs 43% in the Akk-Neg group ( p = 0.04). Microbiome profiling demonstrated that Akk-Pos group was associated with increase bacterial diversity and enrichment of Ruminococcus, Alistipes and Eubacterium. When considering the variations of the relative abundance of Akk within the Akk-Pos group, we obtained a large interval ranging from 0.0022% up to 64.78% with a 75th percentile at 4.42%. The relative abundance of Akk within > 0% to < 4.42% range in stools at diagnosis was associated with increased ORR, overall survival (OS) in multivariate analysis, independent of PD-L1 expression and ECOG. This sub-group was associated with more inflamed tumors with upregulation of CD3e, IfngTH1 and Vcam-1. Conversely, patients with overrepresentation of Akk > 4.42% experienced more PD and shorter OS. Antibiotic use was associated with a shift in favor of Gammaproteobacteria, enrichment of Akk ( > 4.42%) and shorter OS. Conclusions: We validated the prognostic role of Akk in patients with NSCLC. Stratification based on Akk relative abundance represents a more accurate independent predictor than the binary modality. Our study provides the rationale to develop microbiome-based approach to study gut dysbiosis in routine clinical oncology care. Clinical trial information: NCT04567446.

Introduction L’osimertinib est un inhibiteur de tyrosine kinase (ITK) qui a montre sa superiorite par rapport aux autres ITK dans le cancer bronchique non a petites cellules (CBNPC) mute EGFR de stade avance. La comprehension des mecanismes de resistance a l’osimertinib est necessaire afin d’optimiser la prise en charge de ces patients lors de la progression. Methodes Nous avons recueilli les donnees histo-moleculaires de tous les patients traites par osimertinib de 9 hopitaux universitaires en Ile-de-France entre 2015 et 2018, a partir des prelevements plasmatiques et tumoraux realises lors de la progression. Tous les echantillons avaient ete analyses par Next Generation Sequencing. Le taux de reponse objective (TRO), la survie globale (SG), la survie sans progression (SSP) et la duree sous traitement jusqu’a arret (TTD) ont aussi ete recueillis. Resultats Deux cent vingt-six patients ont ete inclus (2e ligne et plus : 219 [97 %]). Il s’agissait dans la plupart des cas d’un adenocarcinome (n = 218, 95 %) avec une deletion de l’exon 19 du gene EGFR (n = 134, 59 %). Cent vingt et un patients (53 %) avaient une atteinte secondaire du systeme nerveux central (SNC) a l’introduction de l’osimertinib. La duree mediane de suivi etait de 11,6 mois (IQR : 4,6–18,2). Le TRO etait de 52 % et le TRO pour le SNC etait de 56 %. La SSP et la SG mediane etaient de 9,5 mois (IQR : 4,0–17,2) et de 24 mois (IQR [12,4–Non Atteinte (NA)]). Le TTD etait de 12,7 mois (IQR : 5,1–24). A la date de recueil, 150 patients (66 %) avaient progresse dont 73 prelevements contributifs (56 biopsies) ont ete analyses. Les alterations histo-moleculaires les plus frequentes etaient la mutation C797S (n = 9 [13 %]) et l’amplification de MET (n = 8 [11 %]). Une transformation histologique etait retrouvee chez 5 patients (9 % des biopsies). La perte de la T790 M etait retrouvee dans 68 % des cas. La SSP et la SG apres progression etaient de 6,0 mois (IQR : 2,0–10,4) et 15,1 mois (IQR : 6,7–NA) respectivement, et plus longues en cas de poursuite de l’osimertinib apres progression par rapport a l’introduction d’un nouveau traitement systemique : 10,4 mois (IQR : 8,7–20,6) et 22,6 mois (IQR : 9,9–NR) versus 3,2 mois (IQR : 1,3–5,4) et 10,2 mois (IQR : 3,8–18,1) (p Conclusion Ce travail « en vie reelle » confirme l’efficacite de l’osimertinib dans le CBNPC mute EGFR de stade avance. Les alterations les plus frequentes retrouvees a la progression etaient l’amplification de MET et la mutation C797S.

International audience; Introduction: Immune checkpoint inhibitors (ICIs) have revolutionised cancer care especially in lung cancer. New response patterns have been described under ICIs such as pseudo-progression or hyper-progressive disease (HPD). The definition of HPD is yet to be consensual. The aim of this study was to suggest a clinical definition of nivolumab-refractory patients and find factors associated with this entity.Methods: We performed a multi centric retrospective study including all patients who received nivolumab for the treatment of advanced non-small cell lung cancer (NSCLC) during the French authorisation for temporary use in 2015.Results: 303 patients were included in the cohort and 292 had details on the number of nivolumab injections received. 57 patients (20%) were nivolumab-refractory. These patients had worse PS at nivolumab initiation (p

Background: Nivo is the gold standard for second line treatment of advanced NSCLC. Hyper-progression (HP) is a form of early progression observed during treatment by immune checkpoint inhibitors and usually fatal which has been poorly evaluated. Aim: To determine factors associated with HP in patients with advanced NSCLC treated with nivo. Methods: Our multi-center retrospective study included all patients with advanced NSCLC receiving nivo during the French authorisation for temporary use between January and December 2015. HP was defined as progression or death occurring before any tumour evaluation or before 3 injections of nivo. Results: 263 patients were included with 14.6-months median follow-up. Median overall survival (OS) at the date of cut-off was 10.1 months [95% CI (7.7 – 13.0)]. Baseline characteristics were as follows: 65 years, 68% male, 92% smokers, 62% with adenocarcinoma histology, 28% with squamous cell carcinoma and 10% with other, 66% with PS 0-1 at nivo initiation. Fifty-one patients (19%) had progressed before receiving 3 injections of nivo and a further 51 (19%) before receiving 5. Patients who presented with more rapid progression had worse PS at nivo initiation (p=0.042), worse PS at first nivo evaluation (p Conclusion: Nearly 20% of our patients experienced HP before 3 injections of nivo resulting in worsening OS. HP needs to be further studied in order to better select patients who will truly benefit from immune checkpoint inhibitors.

We report here the first cases, to our knowledge, of pulmonary arterial hypertension induced by lorlatinib. It s the first time that a tyrosine kinase inhibitor for lung cancer is associated with pulmonary arteriel hypertension.

Here we report our experience of ceritinib in crizotinib-pretreated patients with anaplastic lymphoma kinase (ALK) positive (ALK+) non-small cell lung cancer (NSCLC) in a French temporary authorisation for use (TAU) study. The French TAU study included crizotinib-pretreated patients with advanced ALK+ or ROS proto-oncogene 1 positive (ROS1+) tumours. Patients received oral ceritinib (750 mg·day−1 as a starting dose) and best tumour response (as evaluated by the investigator) and safety were reported every 3 months. A total of 242 TAUs were granted from March 12, 2013 to August 05, 2015. Of the 242 patients, 228 had ALK+ NSCLC and 13 had ROS1+ NSCLC. The median age of ALK+ patients (n=214) was 58.5 years, 51.9% were female, 70.8% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1 and 50.0% had brain metastases. Of the 149 efficacy evaluable ALK+ NSCLC patients, 5.4% had a complete response (CR), 47.0% had a partial response (PR) and 22.8% had stable disease (SD). At September 05, 2015, the median duration of ceritinib treatment (n=182) was 3.9 months but 5.5 months for patients (n=71) with a follow-up of ≥12 months. Higher objective response rate (ORR) was observed for patients with ECOG PS 0 to 1 (55.0% versus 42.4%) and those receiving prior crizotinib for >5 months (51.6% versus 36.1%). Treatment-related adverse events (AEs) were reported in 118 of 208 patients (56.7%), the most common being diarrhoea (22.1%) and hepatic toxicity (19.7%). Ceritinib (750 mg·day−1) demonstrated efficacy similar efficacy to ASCEND-1, ASCEND-2 and phase 3 ASCEND-5 trials with manageable safety in crizotinib-pretreated patients with ALK+ NSCLC., Ceritinib (750 mg per day) showed similar efficacy as in clinical trials in crizotinib-pretreated ALK+ NSCLC patients http://ow.ly/8oXe30h27D0

Nivolumab for the treatment of advanced nonsmall cell lung cancer (NSCLC) evaluated in phase III trials showed 50% progression at first evaluation, but better overall survival (OS), suggesting regained efficacy of treatments given thereafter. We aimed to evaluate the efficacy of nivolumab and of next treatment received after nivolumab progression in patients with advanced NSCLC. Our multicentre retrospective study included all patients receiving nivolumab between January and December 2015. The primary end-point was progression-free survival (PFS) of treatment given after nivolumab. The 303 patients had the following characteristics: median age 63 years, 69% males, 92% smokers, 67% performance status 0–1 and 61% adenocarcinoma. Nivolumab was given as second-line treatment in 40% of patients. With 13.7 months of median follow-up, nivolumab PFS and OS were 2.6 and 11.3 months, respectively. At the cut-off analysis 18% were controlled under nivolumab, 14% were deceased and 5% were lost to follow-up under nivolumab. Among the 191 (63%) patients eligible for post-nivolumab (PN) treatment, 115 (38%) received further treatment and were characterised by better performance status (p=0.028) and by receiving more injections of nivolumab (p=0.001). Global PN-OS and PN-PFS were 5.2 and 2.8 months, respectively. Drugs most frequently used after nivolumab were gemcitabine (23%), docetaxel (22%) and erlotinib (16%), with median PFS of 2.8, 2.7 and 2.0 months, respectively. Nivolumab produced similar efficacy as in phase III trials, although patients received nivolumab later and had worse performance status. 38% received treatment after nivolumab progression with efficacy comparable to historical second-line trials., Efficacy of nivolumab in nonsmall cell lung cancer http://ow.ly/k2uX30iGZbY

Background: Nivo is authorised for 2nd line treatment of advanced NSCLC. Although 50% of pts progressed at 1st Nivo evaluation in phase III trials overall survival (OS) favoured Nivo suggesting better efficacy of treatments given post Nivo. Aim: To evaluate the efficacy of the next treatment received after Nivo progression in advanced NSCLC patients receiving Nivo. Methods: Our multi-center retrospective study included all pts receiving Nivo during the French authorisation for temporary use (ATU) between Jan and Dec 2015. Primary end point was progression free survival (PFS) on the next treatment given post Nivo. Results: Characteristics of the 297 pts included at Nivo initiation: 65 years, 69% males, 90% smokers; 61% adenocarcinoma, 29% squamous and 10% others; 68% PS 0-1. Nivo was given in 40%, 29% and 31% in 2nd, 3rd or ≥4th line treatment respectively. With a 22 months (mos) median follow-up, PFS on Nivo was 2,6 mos (95%CI [2.1-3.5]) and OS 10,9 mos [8,5 -NR]. 32% of pts died before further treatment, 4% were lost of follow-up, 24% were controlled, 5% were progressive but did not receive post Nivo treatment and 34% (n=101) received post Nivo treatment. Characteristics of these pts did not differ from that of the overall population. Most frequent drugs used were: 24% gemcitabine (G), 21% docetaxel (D) and 15% Erlotinib (E). The PFS after Nivo was 2.7 mos [2.1-3.4]; 2.7 mos for G, 2.7 mos for D and 1.8 mos for E. Treatment duration was >5 mos for G and >4 mos for D in 25% of pts. Conclusion: Nivo produced similar efficacy as in phase III trials. Although only 34% of pts received post Nivo treatment, 25% had longer treatment duration on G or D.

Introduction Solid organ transplant patients are at heightened risk of several cancers compared to the general population. Secondary to a higher number of procedures and better survival after transplantation, cancer is a rising health concern in this situation. Limited data exist for lung cancer (LC) after renal transplantation. We report here the most important series of renal transplant recipients with lung cancer. Methods Retrospective study of all cases of LC diagnosed in three French Renal Transplant Units from 2003 to 2012. A control group consisted of non-transplant patients with LC matched with the cases for age ( 65 years), gender and diagnosis date. We recruited two controls for each case. Results Thirty patients (median age 60 years; range 29–85; male/female ratio 80/20%) with LC were analysed. LC incidence was 1.89/1000 person-years over the period 2008–2012. All patients were former or active smokers (median 30 pack-years). Transplanted patients had significantly more comorbidities, mainly cardiovascular disease. The median interval of time from kidney transplantation (KT) to diagnosis of LC was 7 years (range 0.5–47 years). LC was incidentally diagnosed in 40%. Most patients (70%) had advanced LC (stage III or IV) disease. Stage of LC at diagnosis was similar in cases and controls. Surgery and chemotherapy were proposed to the same proportion of patients. In cases, mortality was cancer related in 87% and median survival time after diagnosis was 24 months. Survival was not significantly different between the 2 groups. Conclusion Despite frequent medical and radiological examinations, diagnosis of LC is usually made at an advanced stage and the overall prognosis remains poor.

Introduction Les immunotherapies (IO) sont devenues un traitement incontournable du CBNPC. Cependant, certaines toxicites peuvent etre severes. Les complications pulmonaires des IO sont surtout d’origine immunologique. Le diagnostic doit etre fait rapidement car le pronostic peut etre defavorable. Methodes Etude retrospective descriptive menee au sein de l’unite d’oncologie thoracique du service de pneumologie de l’hopital Foch de 9 patients atteints d’un CBNPC et ayant recu une IO compliquee d’une toxicite pulmonaire. Resultats Nous rapportons les cas de 9 patients representant des types variables de toxicite pulmonaire secondaire a une immunotherapie pour un CBNPC. Il s’agit de 6 hommes et 3 femmes dont l’âge moyen etait de 66,1 ans. L’anatomopathologie est cancer epidermoide dans 5 cas et adenocarcinome dans 4 cas. Toutes les tumeurs sont PDL1 negatif ou inconnu et l’immunotherapie etait utilisee en 2e ligne (4 cas), ou 3e ligne ou plus (5 cas). Les molecules incriminees sont le nivolumab (8 cas) et le durvalumab (1 cas). Cinq patients avaient recu une radiotherapie thoracique avant l’immunotherapie. Le delai moyen d’apparition des symptomes etait de 14,5 semaines. L’imagerie thoracique montrait des images variees, allant de condensations alveolaires, verre depoli, epaississements peri bronchovasculaires et septaux, ou alveolite. Certains patterns pouvaient etre associes entre eux. Chez les patients ayant ete irradie au prealable, et ayant presente une pneumopathie radique, les images de pneumopathie aux anti-PDL1 etaient localisees dans le meme site que la pneumopathie radique ou des champs d’irradiation. Le lavage broncho-alveolaire quand il a pu etre realise montrait une predominance lymphocytaire ou une formule panachee. Tous les patients ont ete traites par corticotherapie. L’evolution a ete la regression complete des images (3 cas), la regression partielle des images (5 cas), la rechute apres arret de la corticotherapie (1 cas). Conclusion La toxicite pulmonaire de l’IO n’est pas exceptionnelle. Elle survient habituellement au cours des premiers mois. Les symptomes cliniques sont non specifiques mais les signes radiologiques sont suggestifs. Le LBA peut affiner un diagnostic en excluant l’infection pulmonaire et montrant la predominance lymphocytaire. La sensibilisation des cliniciens aux manifestations radiographiques et cliniques est essentielle pour obtenir le diagnostic et gerer cet evenement indesirable potentiellement grave.

Introduction Le traitement des cancers bronchiques depend d’un diagnostic anatomopathologique et moleculaire precis. Les adenocarcinomes sont le type histologique le plus frequent et le plus accessible a des traitements cibles (en cas de mutations EGFR ou translocations ALK et ROS1). Les tumeurs neuroendocrines (NE) regroupent les tumeurs de bas grade ou de grade intermediaire (carcinoides typiques et atypiques) et celles de haut grade (CNEGC et cancers a petites cellules). Elles sont reputees n’avoir aucune cible moleculaire accessible a des traitements cibles. Methodes Nous realisons une analyse retrospective de 3 cas de CNEGC, mais pouvant evoquer des tumeurs carcinoides (apres relecture, dans la limite de l’exiguite des prelevements), chez des patientes non fumeuses. Resultats Les caracteristiques morphologiques et immunohistochimiques sont presentes dans le tableau : les contingents NE presentaient un marquage net de la chromogranine et de la synaptophysine. L’immunohistochimie etait positive pour ALK sur les contingents NE et ces rearrangements etaient confirmes par FISH. Cas no 1 : patiente de 58 ans presentant un CNEGC cT2N2M0 diagnostique en octobre 2018. Maladie stable apres chimiotherapie (platine VP16) - radiotherapie concomitante. Apparition de 3 metastases cerebrales en mars 2019, traitees par stereotaxie. Maladie controlee 6 mois puis nouvelle progression cerebrale qui va etre traitee par alectinib. Cas no 2 : patiente de 74 ans presentant un CNEGC stade IV (os), diagnostique en mai 2015. Progression osseuse apres 6 cures de carboplatine VP16. Mise sous crizotinib en juin 2016 : reponse thoracique, stabilite osseuse. En mai 2017 apparition de metastases cerebrales. Mise sous ceritinib : stabilite jusqu’en mai 2018 puis progression cerebrale. Reponse cerebrale sous brigatinib (en ATU) maintenue jusqu’a septembre 2019. Cas no 3 : patiente de 34 ans presentant un CNEGC stade IV (os, cerveau). Mise sous alectinib qui est arrete suite a une toxidermie et hepatite grade 3. Reponse partielle apres 2 mois de crizotinib au niveau thoracique et cerebral mais une progression cerebrale a 4 mois de traitement. Malgre la mise sous ceritinib en fevrier 2019, elle decede des suites d’une progression cerebrale en mai 2019 ( Tableau 1 ). Conclusion La recherche d’une translocation ALK en cas de tumeurs NE doit etre discutee chez les non-fumeurs du fait des implications therapeutiques et pronostiques.

Introduction Les effets antitumoraux/anti-metastasiant des heparines sont documentes in vitro et dans des etudes animales. Les rares essais cliniques dedies rapportent des resultats contradictoires, mais dans des populations heterogenes (divers primitifs) et chez des patients en majorite metastatiques ou porteurs de tumeurs localement avancees. Des analyses de sous-groupes suggerent que l’effet antitumoral des heparines pourrait etre limite aux stades precoces, mais aucun essai specifique n’a ete realise. L’essai de phase III Tinzaparine In Lung Tumors (TILT) a ete construit pour evaluer l’effet de la tinzaparine sur la survie des cancers bronchiques non a petites cellules (CBNPC) localises. Methodes Apres resection complete d’un CBNPC de stade I, II ou IIIA, et moins de 8 semaines apres la chirurgie, les patients inclus recevaient, apres tirage au sort, le traitement de reference seul ou avec tinzaparine 100 UI/kg/j pendant 12 semaines. Le critere principal d’evaluation etait la survie globale. Tous les evenements cliniques etaient adjudiques par un comite independant en aveugle du bras de traitement. Resultats Entre aout 2007 et juin 2013, 549 patients inclus dans 35 centres francais ont ete randomises dans le bras tinzaparine ( n = 269) ou controle ( n = 280) ; 359 patients (65,4 %) avaient un stade I, et 220 (40,1 %) ont recu une chimiotherapie adjuvante. Le suivi median etait de 5,7 ans. La survie globale n’etait pas significativement differente entre les deux bras (hazard ratio [HR] = 1,24 ; IC95 % : 0,92–1,68 ; p = 0,17), de meme que l’incidence cumulee des recidives (SHR = 0,94 ; IC :0,68–1,30 ; p = 0,70) ( Figure 1 ). Dans une analyse de sous-groupe planifiee, la survie globale des patients ayant recu une chimiotherapie adjuvante etait inferieure dans le bras tinzaparine (HR = 1,78 ; IC : 1,13–2,81 ; p = 0,013), mais il n’y avait pas de difference significative de l’incidence cumulee des recidives (SHR = 1,12 ; IC : 0,70–1,79 ; p = 0,24). Deux patients du groupe tinzaparine ont presente un saignement majeur pendant le traitement ( Figure 1 ). Conclusion En situation adjuvante apres resection complete d’un CBNPC localise, la tinzaparine a la dose de 100 UI/kg/j pendant 12 semaines n’a eu aucun impact detectable sur la survie globale et la survie sans recidive. Ces resultats pourraient mettre un terme a l’exploration clinique des effets antitumoraux des heparines (financements : PHRC nationaux AOM05185 et AOM12612 ; Leo Pharma France a fourni la tinzaparine et un soutien logistique complementaire. ClinicalTrials.gov identifier : NCT00475098 ).

Introduction Les inhibiteurs de points de controle immunologiques, dont le nivolumab, sont un traitement cle pour les CBNPC mais sont reputes peu efficaces chez les non-fumeurs et en cas d’addiction oncogenique (patients mutes pour EGFR ou transloques pour ALK). Les mutations induisant un epissage de l’exon 14 du gene MET, recemment decrites, sont retrouvees chez 3 % des adenocarcinomes (adk) et la reponse a l’immunotherapie dans cette situation n’a pas ete rapportee. Methodes Nous presentons 4 cas de CBNPC mutes pour MET (induisant un epissage de l’exon 14), survenus chez des patientes (A, B, C, D) traitees par nivolumab en deuxieme ligne ( Tableau 1 ). Elles etaient non fumeuses, sans antecedent particulier sauf un cancer du sein traite il y a 20 ans pour B et 15 ans pour D. Cette mutation de MET a ete recherchee au cours de ce traitement, les mutations EGFR, KRAS et BRAF et la translocation ALK etant negatives. Resultats Pour A, le nivolumab est debute apres une progression surrenalienne et permet apres 4 cures une excellente reponse partielle thoracique et surrenalienne. Le traitement est arrete apres la cinquieme cure pour diarrhee grade 3 et acidocetose diabetique attribuees au traitement. Apres un controle tumoral pendant 6 mois sans traitement, une radiotherapie (RT) thoracique est proposee sur la masse residuelle, uniquement thoracique, fixant au TEP scanner. Le nivolumab est repris 5 mois plus tard pour une recidive surrenalienne bilaterale et permet une reponse complete sans aucune toxicite. La patiente B subit d’abord l’exerese d’une metastase cerebrale, puis une RT stereotaxique postoperatoire, recoit une chimiotherapie puis une RT thoracique de cloture. Elle recidive au niveau thoracique (nodules bilateraux et pleuresie) et cerebrale. La patiente recoit 4 cures de nivolumab qui entrainent une reponse thoracique maintenue a 8 cures (en cours actuellement). La patiente C est en reponse complete apres 25 cures de nivolumab en deuxieme ligne. D a progresse apres 2 cures de carboplatine pemetrexed. Elle presente une aggravation clinique et radiologique majeure apres 4 cures de nivolumab. Elle est alors incluse dans l’essai ACSE et presente une excellente reponse sous crizotinib maintenue plus de 6 mois (en cours). Nous n’avons le niveau d’expression de PDL1 au niveau des cellules tumorales que pour A (70 %) et B (20 %). Conclusion Pour 3 des 4 patientes mutees pour MET, le nivolumab a permis une excellente reponse. Il peut donc etre une alternative therapeutique dans cette addiction oncogenique.

Introduction Les insertions de l’exon 20 (EGFR ins20) representent entre 1 et 4 % des alterations moleculaires du gene de l’EGFR dans le cancer bronchique non a petites cellules (CBNPC). Les donnees precliniques suggerent l’absence d’efficacite des inhibiteurs de tyrosines kinases ciblant l’EGFR (TKI). Le but de notre etude etait de comparer les pts ayant un CBNPC EGFR ins20, metastatique, a une cohorte controle de pts ayant un CBNPC EGFR exon 19/21. Methodes Tous les pts ayant un CBNPC EGFR ins20 metastatique, diagnostiques entre 2012 et 2017 dans 11 centres d’Ile-de-France etaient inclus et apparies sur la date diagnostique et le centre a des pts ayant un CBNPC EGFR exon19/21 metastatique (cohorte controle) afin de comparer les caracteristiques cliniques, la reponse au traitement et la survie. Resultats Trente-six pts EGFR ins20 et 78 pts EGFR exon19/21 etaient inclus. Les pts EGFR ins20 etaient significativement plus jeunes (63,9 ± 12,8 vs 69,6 ± 11,7 ans, p = 0,03) que les pts « controles ». Il n’y avait pas d’autre difference demographique. Les pts EGFR ins20 etaient traites plus frequemment par chimiotherapie (CT) a base de platine en premiere ligne que les pts EGFR exon19/21 (91 % vs 36 %, respectivement, p Conclusion Les pts EGFR ins20 etaient plus jeunes, refractaires aux TKI et avaient un pronostic plus sombre que les pts EGFR exon19/21.

ALK rearrangement and EGFR/KRAS mutations constitute the primary biomarkers tested to provide targeted or nontargeted therapies in advanced nonsmall cell lung cancer (NSCLC) patients. Our objective was to assess the cost-effectiveness of biomarker testing for NSCLC.Between 2013 and 2014, 843 treatment-naive patients were prospectively recruited at 19 French hospitals into a longitudinal observational cohort study. Two testing strategies were compared, i.e. with “at least one biomarker status known” and “at least KRAS status known”, in addition to “no biomarker testing” as the reference strategy. The Kaplan–Meier approach was employed to assess restricted mean survival time. Direct medical costs incurred by hospitals were estimated with regard to treatment, inpatient care and biomarker testing.Compared with “no biomarker testing”, the “at least one biomarker status known” strategy yielded an incremental cost-effectiveness ratio of EUR13 230 per life-year saved, which decreased to EUR7444 per life-year saved with the “at least KRAS status known” testing strategy. In sensitivity analyses, biomarker testing strategies were less costly and more effective in 41% of iterations.In summary, molecular testing prior to treatment initiation proves to be cost-effective in advanced NSCLC management and may assist decision makers in defining conditions for further implementation of these innovations in general practice.

The improved survival of patients since the use of highly active antiretroviral treatments has lead to the reporting of non-AIDS defining tumors, such as lung cancer.Analysis of the records of 22 HIV-infected patients with lung cancer (LC) diagnosed in three hospitals located in the Paris area (France).Twenty-one patients were smokers. The patients (86% male, 14% female) had a median age of 45 yr (range, 33-64 yr). Risk factors for HIV infection were intravenous drug use in 5 patients, homosexual transmission in 10 patients, and heterosexual transmission in 7 patients. At diagnosis of LC, seven patients had previously developed a CDC-defined AIDS manifestation, the median CD4 cell count was 364/mm3 (range 20-854/mm3) and median HIV1 RNA viral load was 3000 copies/mL. The most frequent histological subtype was squamous cell carcinoma (11 cases). A stage III-IV disease was observed in 75% of the patients. Only one patient had a small-cell lung carcinoma. Twenty-one patients received combined specific therapy, of which six patients underwent surgery for the LC. The median overall survival was 7 mo. No opportunistic infections occurred during LC therapy.LC occurs at a young age in HIV-infected smokers. LC is not associated with severe immunodeficiency. The prognosis is poor because of their initial extensive disease and a poor response to therapy. However, surgery appears to improve outcome in much the same way as in the general population.

Introduction Le Nivo (Ac anti-PD-1) est actuellement autorise pour le traitement de deuxieme ligne du CBNPC de stade avance. Malgre des taux de progression proches de 50 % lors de la premiere evaluation tumorale dans les etudes de phase III, les analyses de survie globale (SG) favorisent le Nivo par rapport a la chimiotherapie (CT) suggerant une meilleure efficacite des traitements recus apres le Nivo. Le but de cette etude etait d’evaluer l’efficacite des traitements recus apres progression sous Nivo chez les patients atteints de CBNPC de stade avance traites par Nivo. Methodes Une etude multicentrique (neuf centres), retrospective a ete realisee incluant les patients consecutifs recevant le Nivo dans le cadre de l’autorisation temporaire d’utilisation (ATU) entre janvier et decembre 2015. Les dossiers des patients etaient revus de maniere retrospective et les donnees collectees. Resultats Les caracteristiques des 303 patients inclus sont les suivantes : 63 ans, 69 % de sexe masculin, 92 % de fumeurs ou anciens fumeurs, 90 % de stade avance au diagnostic. L’histologie principale etait l’adenocarcinome (61 %) suivie du carcinome epidermoide (28 %). Lors de l’initiation du Nivo, 67 % des patients etaient de PS 0–1 et 20 % de PS 2. Les principaux sites metastatiques etaient pulmonaire (40 %), pleural (29 %) et cerebral (20 %). Le Nivo etait donne en deuxieme ligne dans 40 % des cas, en troisieme ligne dans 29 % des cas et en quatrieme ligne ou plus dans 31 % des cas. Le suivi median etait de 14,6 mois (m) avec sous Nivo 18 % de patients controles, 14 % decedes et 5 % perdus de vue. 191 patients (63 %) ont progresse et etaient eligibles a un traitement ulterieur dont 115 (38 %) en ont recu un. La SSP et SG sous Nivo etaient respectivement 2,6 m (IC95 % [2,1–3,5]) et 11,3 m (IC95 % [8,5–13,8]). Les patients recevant un traitement apres Nivo avaient un meilleur PS (p = 0,028) et etaient plus jeunes (âge median 63 vs 65,5, p = 0,11). Les traitements les plus utilises apres progression etaient : gemcitabine (23 %), docetaxel (22 %) et erlotinib (16 %) avec respectivement des PFS de 2,8 m, 2,7 m et 2,0 m. Conclusion Le Nivo semble aussi efficace dans la vraie vie que dans les essais cliniques malgre un PS plus eleve et une ligne de traitement plus avancee. 38 % des patients ont recu un traitement apres progression sous Nivo avec des survies proches des etudes historiques malgre la ligne plus avancee de traitement. Apres progression sous Nivo, la CT demeure le traitement standard. Un effet post traitement du Nivo reste a demontrer.

Introduction Le nivolumab (N) est un traitement de reference du cancer bronchique non a petites cellules (CBNPC) des la 2 e ligne. En 2015, un programme d’autorisation temporaire d’utilisation du N a inclus de janvier a aout 2015 les CBNPC epidermoides (EPI) et de juin a aout 2015 les CBNPC non epidermoides (NON-EPI), des la 2 e ligne therapeutique. Cette cohorte offre l’opportunite d’evaluer l’efficacite et la tolerance du N et du traitement post-nivolumab (TPN) en condition de vie reelle. Methodes Au total, 902 patients presentant un CBNPC de stade IIIB/IV, ayant recu au moins une dose de nivolumab 3 mg/kg/2 semaines ont ete inclus dans l’etude. Les variables recueillies etaient : objectif principal : survie globale (SG), objectifs secondaires : survie sans progression (SSP) sous N et TPN, facteurs predictifs de survie, de reponse (RO) au N et TPN, toxicites maximales severes sous N (TMS). Resultats Les caracteristiques des patients etaient identiques selon les histologies (EPI et non EPI), a l’exception des non-fumeurs (6,9 vs 16,2 %) et des localisations cerebrales (12,6 vs 26,8 %). Le taux de TMS de grades ≥ 3 etait de 10,9 %. L’efficacite sous N etait : RO 19,0 % [16,2 ; 21,7], taux de controle 54,5 % [50,9 ; 58,0], SG 9,9 mois [9,1–11,3], SSP 2,0 mois [1,9–2,2]. On notait 2 facteurs pronostiques defavorables sous N : presence de metastases cerebrales : HR = 1,38 (IC95 % 1,15–1,67 ; p = 0,0007) et PS ≥ 2 : HR = 2,21 (IC95 % : 1,82–2,69 ; p Conclusion Les resultats d’efficacite et de tolerance du N dans ces indications sont comparables a ceux des essais cliniques. Le pronostic sous TPN est correle a la RO sous N.

Study objective In patients with proven acute pulmonary embolism (PE), a systematic search for “residual” deep vein thrombosis (DVT) using venography or compression duplex ultrasonography (CDUS) of the lower limbs is negative in 20 to 50% of patients. We hypothesized that undetectable pelvic vein thrombosis (from the external iliac vein to the inferior vena cava) could account for a substantial proportion of patients with negative CDUS findings. Using a noninvasive test, magnetic resonance angiography (MRA), the objective of the study was to assess the prevalence of pelvic DVT in patients with acute PEs and normal findings on lower limb CDUS. Design Prospective study. Setting: A 35-bed respiratory unit in a 680-bed Parisian teaching hospital. Patients From June 1995 to October 1996, 24 patients (mean age, 49 years; age range, 18 to 83 years) with acute PEs and normal findings on lower limb CDUS underwent pelvic MRA. Measurements and results MRA disclosed pelvic DVT in seven patients (29%). The common iliac vein was involved in five patients. Internal iliac vein (hypogastric) thrombosis was imaged in two patients, but no patients had DVT limited to this vein. Three patients underwent subsequent venography studies that confirmed the MRA findings. In three other patients, a new MRA at the end of anticoagulant therapy showed the resolution of the DVT. Conclusions Our data support the view that, among patients with negative findings on CDUS, a substantial proportion of the DVTs that are responsible for PE originates in the pelvic veins. This study provides additional arguments to suggest that MRA might become the reference test for the exploration of pelvic DVT.

e20543 Background: Nivolumab (NIV) is now widely used in ≥ 2ndline of advanced non-small cell lung cancer (NSCLC). The aims of this real-life study were (1) to evaluate its efficacy, (2) to identify predictive factors of worsening under NIV. Methods: This retrospective multicentric study (8 Thoracic Oncology regional centers) included all patients treated by NIV in 2015 (follow-up until 2016, June 30th). Demographics and tumor characteristics were extracted. Objective tumor response was assessed by computerized tomography (RECIST v1.1). Median NIV treatment duration and overall survival (OS) were calculated. Clinical and biological factors evaluated as predictive markers of earlyprogression (discontinuation before 1stevaluation) were: NSCLC histology, PS, smoking-history, number of previous chemotherapy received and initial albumine (alb), C-reactive protein (CRP) and lactate dehydrogenase (LDH) serum levels. For these factors, patients quickly worsened and responders were compared (Student’s t-test, Chi-2 test). Results: Our cohort included 297 patients (non-squamous NSCLC n = 181 [61%]; PS > 1 n = 66 [22%]). At first evaluation, partial response was observed in 16% (n = 47), stable disease in 18% (n = 54) and progression in 49% (n = 144). A total of 45 patients (15%) were early progressors and no evaluation could be performed. Median NIV duration of treatment was 2.8 months [0-15], OS 6.9 months [0-16] (n = 146 still alive on June 30th, 2016). Early progressor patients were PS > 1 in 42% versus (vs) 21% for responders (mean PS 1.7 vs 1.0 for responders (p < 0.001)) and an alb level of 29.9 g/L vs 33.6 (p = 0.03). Mean CRP (p = 0.06) and LDH (p = 0.08) serum levels, NSCLC histology (p = 0.64), smoking-history (p = 0.08), number of previous chemotherapy (p = 0.90) were non-significant. Conclusions: This study confirms that NIV may be effective in NSCLC, with a 16% objective response rate. However early progression observed in 15% of patients was associated with a lower initial alb level and a higher PS. Missing data for LDH and CRP levels may have influenced their non-significance. Further studies must be realized to determine the interest of these factors as predictive markers.

Introduction En 2013, il etait recommande dans les CBNPC etendus d’administrer un doublet de chimiotherapie a base de platine (PCT), avec du bevacizumab (BEV-PCT), un ITK-EGFR ou une CT sans P (nonPCT) en fonction des caracteristiques cliniques, histologiques et moleculaires du CBNPC. En France, ces tests moleculaires sont accessibles pour tous les CBNPC etendus. Cependant, leur impact pronostique pour la 1 re ligne est mal connu. Methodes KRAS, EGFR et ALK ont ete evalues chez 843 CBNPC etendus consecutifs non pre-traites. Le statut a ete classe en 5 groupes : EGFR+ ou ALK+, KRAS+, sauvage (S), indetermine (I), non fait (NF) et les traitements en 4 groupes : PCT, BEVA-PCT, ITK, nonPCT. La survie globale (SG) et sans progression (SSP) ont ete renseignees pour chaque ligne. Une analyse pronostique a ete realisee incluant les classes moleculaires (ref. sauvage) et therapeutiques (ref. P-CT) comme variables d’interet. Resultats Les traitements ont ete classes chez 767 (91,0 %) des 843 CBNPC inclus entre 01/2013 et 02/2014. Les patients etaient des caucasiens a 93,1 %, des hommes a 66,2 %, âges de 62,4 ans (28–92). Au total, 13,4 % etaient non-fumeurs ; 21,4 % de PS ≥ 2 et 90,3 % de stade IV et 76,5 % avaient un adenocarcinome ; 14,5 % un epidermoide et 9 % d’autres histologies. Les statuts moleculaires etaient : S = 40,4 %, KRAS+ = 23,1 %, EGFR+/ALK+ = 10,2 %, I = 5,1 % et NF = 21,2 %. La 1 re ligne etait PCT = 75,9 %, BEVA-PCT = 14,2 %, ITK = 7,8 % et nonPCT = 2,1 %. Avec un recul median de 30,3 mois, la SG mediane etait de 10,7 mois et la SSP de 5,3 mois. Les facteurs independants associes a la SG etaient un PS ≥ 2 (HR = 2,08, p p = ,002 ; 1,53, p = ,02 ; 1,29, p = 0,02) et un traitement par nonPCT en 1 re ligne (HR = 1,92, p = 0,01). Un statut EGFR+/ALK+ (HR = 0,38, p p re ligne. Un traitement par BEVA-PCT etait associe a une meilleure SG dans les CBNPC KRAS+ ou S ( p re ligne n’affectait pas la SG chez les CBNPC EGFR+/ALK+. Conclusion L’etude IFCT-PREDICT.amm montre que le pronostic des CBNPC avances pourrait etre optimise en 1 re ligne par la connaissance du statut EGFR/ALK, mais aussi par un traitement par BEVA-PCT, en particulier dans les CBNPC KRAS+ ou S.

Introduction La valeur pronostique des mutations de KRAS n’est pas clairement connue dans les CBNPC etendus, bien qu’analysees en routine en France. L’objectif de ce STIC etait d’evaluer l’impact pronostique de KRAS , dans une cohorte prospective de 843 CBNPC etendus non prealablement traites. Un des objectifs secondaires etait d’evaluer l’impact d’ EGFR et ALK . Methodes KRAS , EGFR et ALK ont ete evalues selon les pratiques locales ; ALK par immunohistochimie (IHC) et par hybridation in situ (HIS). Donnees cliniques et traitements ont ete recueillis et les patients (pts) suivis jusqu’au deces. Une analyse de survie sans progression (SSP) et de survie globale (SG) a ete faite selon un modele de Cox. Resultats Au total, 788 (93,5 %) tumeurs des 843 pts inclus entre 01/2013 et 02/2014 ont ete analysees. 93,1 % des pts etaient caucasiens, 66,2 % des hommes, 14,2 % non-fumeurs, 57,4 % ex- et 28,4 % actifs. L’âge median etait de 63 ans (28–92). Le PS de 0 a 4 etait 22,8/57/16,6/3,6/0 %. Les histologies etaient : 74,6 % adenocarcinomes, 14,4 % epidermoides, 11,0 % autres. 89,6 % etaient de stade IV. KRAS et EGFR ont ete determines dans 92,3 et 92,7 % des cas ; 26,5 % et 9,3 % etaient mutes pour KRAS et EGFR . ALK a ete evalue par IHC et HIS dans 75,1 % et 46,1 % des cas ; 4,1 % et 3,0 % etaient positifs par IHC et HIS. Un doublet de platine a ete donne a 84,2 % des pts dont 14 % en association avec le bevacizumab. Un ITK-EGFR etait donne en 1 re ligne a 80 % des pts ayant une mutation connue d’EGFR. La SSP etait de 5,4 mois et la SG de 12,4 mois. Les facteurs associes au risque de deces etaient : PS ≥ 2 (HR = 2,44, p p = 0,02) et mutation de KRAS (HR = 1,34, p = 0,03). Une alteration d’ EGFR ou de ALK etaient de bon pronostic (HR = 0,38, p = 0,0005). Conclusion Les caracteristiques des pts de IFCT-PREDICT.amm sont comparables a celles d’une population Europeenne de CBNPC etendus. Ce travail montre la valeur pronostique des mutations KRAS . L’impact des codons (12 vs 13), des transitions et transversions de KRAS sera presente au congres.

Introduction Le Crizotinib, inhibiteur de tyrosine kinase oral ciblant ALK, a permis une augmentation de la survie sans progression des patients presentant un cancer bronchique non a petites cellules (CBNPC) rearrange pour ALK. Ce traitement est habituellement bien tolere, toutefois un des effets indesirables graves rapporte dans la litterature est la survenue de pneumopathie interstitielle diffuse (PID) severe. Patients et methodes En septembre 2011, nous avons observe un cas de PID associe a la prise de Crizotinib (PID-Crizo), nous conduisant a reprendre toutes les caracteristiques cliniques et l’imagerie des patients presentant un CBNPC rearrange pour ALK traites par Crizotinib a l’hopital Tenon entre octobre 2010 et juillet 2013. Resultats Vingt-neuf patients ont ete traites par Crizotinib. Cinq d’entre eux en plus du cas index ont developpe une PID (20,7 %). Il semble exister deux formes de PID-Crizo. La premiere forme est severe, habituellement fatale, et survenant lors du premier mois de traitement (n = 1). La seconde est moins severe, survenant plus tardivement (n = 5). Elle est habituellement peu symptomatique, se presente sous forme de verre depoli pure sur le scanner avec une alveolite lymphocytaire sur le lavage broncho-alveolaire. Ces patients ont une longue reponse au Crizotinib avec une mediane de survie sans progression de 19,9 mois (17,9–23,5). Conclusion Deux types de PID semblent etre observes chez les patients traites par Crizotinib. La survenue d’opacites en verre depoli ne doit pas etre d’emblee consideree comme une progression tumorale. Elle ne necessite pas obligatoirement l’interruption du Crizotinib et semble plutot etre associee a un bon controle de la maladie sous Crizotinib.

7511^ Background: Cisplatin-based chemotherapy and concurrent radiotherapy, the standard treatments for locally advanced unresectable NSCLC have reach a plateau. New therapeutic combinations of molecular targeted drugs are needed. IFCT-0803 phase II trial aimed to evaluate the benefit of adding cetuximab to a combination of radio and concomitant chemotherapy with cisplatin and pemetrexed in patients with stage III, non-squamous NSCLC. Methods: Based on a 2-stage Simon approach, a total of 106 patients were to accrue. An interim analysis of the first 34 patients authorized the continuation of the study. Eligible patients receive thoracic radiation (66 Gy) along with cisplatin (75 mg/m²) and pemetrexed (500 mg/m²) on D1 administered every 21 days for four cycles; weekly cetuximab (400 mg/m²) for the first week, then 250 mg/m²) is added from the first week of therapy for a total of 12 doses. The primary objective is to assess the disease control rate at the 16th week (16W-DCR), one month after the treatment ...

Auteur(s) : Etienne GIROUX Leprieur, Sylvie Friard, Louis-Jean Couderc Service de Pneumologie, Hopital Foch, 40 rue Worth, 92150 Suresnes, France We report here the case of a 58-year-old man diagnosed with lung adenocarcinoma and hepatic metastasis. After six cycles of chemotherapy with cisplatyl and docetaxel the patient remained stable for two years before a relapse. Treatment with a tyrosine-kinase inhibitor of epidermal growth factor receptor (EGFR), erlotinib, was instituted. The daily [...]

BACKGROUND: Nebulized cyclosporine (CsA) has been shown to limit lung allograft rejection as well as intramuscular (IM) CsA, with limited blood diffusion. The present study determined the pharmacokinetic parameters of nebulized CsA, by the assessment of regional lung deposition and extrapulmonary diffusion of CsA. METHODS: CsA was given either by IM injection (10 mg/kg) or by aerosol (at 10 and 25 mg/kg doses); 70 rats were killed at 25 and 50 min, and at 2, 4, 6, 8, 12, 24, or 48 hr after CsA administration. CsA levels were measured in the whole lung, in central and peripheral parts of the lung, in whole blood, kidney, and heart. The areas under the concentration time curves (AUCs) were determined. RESULTS: In blood, kidney, and heart, CsA levels were significantly higher for IM than for aerosol administrations at 10 and 25 mg/kg doses. In the whole lung, the AUC was greater for the aerosol route at 25 mg/kg doses (588 ng x hr/mg) than for the low-dose (200 ng x hr/mg) or IM administration (200 ng x hr/mg). The central to peripheral index of CsA (ratio of AUC central/peripheral part of the lung) was not significantly different for both aerosol administrations (0.63 and 0.69, respectively) and for the IM route (0.81). CONCLUSIONS: Nebulized CsA allows better pulmonary concentration than IM administration, with equivalent central and peripheral deposition whatever the mode of administration, and results in lower levels in blood, kidney, and heart.

TPS7112 Background: MPM median OS does not exceed 13 months with pem/CDDP doublet. U.S. Intergroup phase II trial of gemcitabine/CDDP, with or without bevacizumab, gave an appealing 15.6 months median OS in the bevacizumab arm. French Intergroup aimed to test pem/CDDP with bevacizumab (PCB), in a randomized phase III trial. Methods: Eligible patients had unresectable histologically proved MPM, no prior chemo, PS 0-2, no thrombosis, nor bleeding. Primary endpoint: The primary outcome will be survival. The secondary endpoint will be Progression-Free Survival. Patients received pem 500 mg/m2, CDDP 75 mg/m2 (PC),at D1, and vitamin B12 +B9 substitution, with (arm B) or without bevacizumab (arm A), 15 mg/kg Q21D, for 6 cycles. Arm B nonprogressive patients received bevacizumab maintenance therapy until progression or toxicity. 445 patients to be recruited during a period 48 months, with at least 24 months of follow-up, and 385 events (deaths), will be needed to assure a power of 80% and detect at least a 4.3 months of median survival increase. This hypothesis leads to a Hazard Ratio (HR) of 1.33 and a 3-years survival of 14.7% in control arm and 23.6 % in experimental arm, with an absolute difference of 8.9% in survival rates. Accrual status: The first patient was included in February 2008. On January 31, 2012, 257 patients from 85 French centers had been enrolled. The end of accrual can be expected for September 2013. Ancillary studies: For molecular biomarker analyses, thoracoscopic tissue specimens (TS, ERCC1, MSH2, TUBB3, NF2, p16, RASSF1A methylation,15 microRNAs ) and blood samples (micro-RNAS, VEGF, osteopontin, SRMP) at diagnosis are centrally collected. Finally, a prospective study comparing PET-CT to standard CT with central blinded analysis, is currently on-going for evaluation of response, and accuracy of modified RECIST criteria for mesothelioma.

7521 Background: First-line EGFR-TKI in advanced BAC yielded a 2.9 to 4-month PFS in Phase II trials. We have suggested that EGFR-TKI had a reduced activity in M-BAC but that C/P and pemetrexed cou...

Background: Crizotinib, an oral tyrosine kinase inhibitor that targets anaplastic lymphoma kinase, has proven to offer sustained progression-free survival in anaplastic lymphoma kinase–rearranged non–small-cell lung cancers. Occurrence of severe interstitial lung disease (ILD) was one of the crucial adverse events reported in randomized clinical trials and case reports. Methods: In September 2011, we observed a crizotinib-associated ILD case. Following this index case, we reviewed the clinical and computed tomographic scan features of all patients treated with crizotinib in our department, between October 2010 and July 2013, comparing patients with and without ILD. A systematic literature review was performed. Results: During this period, 29 patients were treated with crizotinib, five of whom developed ILD, in addition to the index case. Two types of adverse lung reactions may be observed in patients undergoing crizotinib therapy. The first is a severe, usually fatal, ILD that occurs during the first month of treatment ( n = 1). The second is a less severe ILD, occurring later in time ( n = 5). It occurs gradually with only few clinical symptoms, but predominant ground-glass opacities on computed tomography, along with an intensive lymphocytic alveolitis in bronchoalveolar lavage fluid. These cases had a longer response with a median progression-free survival duration at 19.9 months (17.9–23.5) compared with 6.2 months (1.2–13.6) for controls ( p = 0.04). Conclusion: Forty-nine cases of crizotinib-associated ILD have been identified by the systematic review of the literature, including our six cases. Two types of adverse lung reactions may be observed with different presentation, prognosis, and treatment. Their potential mechanisms should be clarified. Nine patients with the less severe form of ILD were safely retreated.