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In advanced cancers, healthcare resource utilization (HCRU) and costs usually increase until death. However, few studies have measured HCRU over time in patients treated with immunotherapies. The objective was to describe the evolution of HCRU and costs over four years for patients with advanced non-small cell lung cancer (aNSCLC) initiating nivolumab. Based on the French hospital reimbursement database, all aNSCLC patients initiating nivolumab in the 2nd line or later in 2015 or 2016 were followed until 2019. HCRU (including hospitalizations and hospital visits) and costs (payer perspective) were described annually after nivolumab initiation. Trends in HCRU were analyzed with the Mann-Kendall test. As most patients did not reach the four-year follow-up, cost-analysis was performed without adjustment throughout, without adjustment in uncensored cases only or with adjustment using for all patients using the Bang&Tsiatis method. 10,452 patients initiating nivolumab were evaluated. The percentage of patients hospitalized or with hospital visits decreased (p p p per capita costs also decreased. The method without adjustment provided the lowest cost over time (€44,404 (Y1), €32,206 (Y2); €28,552 (Y3); €18,841(Y4)) while the Bang&Tsiatis method presented the highest cost (€45,002 (Y1), €36,330 (Y2); €35,080 (Y3); €28,931 (Y4)). HCRU and costs for NSCLC patients treated with nivolumab decreased over time. Cost estimates are dependent on the statistical method used to take into account uncertainty, but costs decreased over time whatever the method used.

BackgroundSurvivors of severe-to-critical coronavirus disease 2019 (COVID-19) may have functional impairment, radiological sequelae and persistent symptoms requiring prolonged follow-up. This pragmatic study aimed to describe their clinical follow-up and determine their respiratory recovery trajectories, and the factors that could influence them and their health-related quality of life.MethodsAdults hospitalised for severe-to-critical COVID-19 were evaluated at 3 months and up to 12 months post-hospital discharge in this prospective, multicentre, cohort study.ResultsAmong 485 enrolled participants, 293 (60%) were reassessed at 6 months and 163 (35%) at 12 months; 89 (51%) and 47 (27%) of the 173 participants initially managed with standard oxygen were reassessed at 6 and 12 months, respectively. At 3 months, 34%, 70% and 56% of the participants had a restrictive lung defect, impaired diffusing capacity of the lung for carbon monoxide (DLCO) and significant radiological sequelae, respectively. During extended follow-up, bothDLCOand forced vital capacity percentage predicted increased by means of +4 points at 6 months and +6 points at 12 months. Sex, body mass index, chronic respiratory disease, immunosuppression, pneumonia extent or corticosteroid use during acute COVID-19 and prolonged invasive mechanical ventilation (IMV) were associated withDLCOat 3 months, but not its trajectory thereafter. Among 475 (98%) patients with at least one chest computed tomography scan during follow-up, 196 (41%) had significant sequelae on their last images.ConclusionsAlthough pulmonary function and radiological abnormalities improved up to 1 year post-acute COVID-19, high percentages of severe-to-critical disease survivors, including a notable proportion of those managed with standard oxygen, had significant lung sequelae and residual symptoms justifying prolonged follow-up.

The most frequent mutation in advanced non-small–cell lung cancer (NSCLC), Kirsten rat-sarcoma viral oncogene (KRAS) is found in 20–25% of these patients’ tumors. While phase III trials on therapies targeting KRAS, especially KRASG12C, are ongoing, the clinical efficacy of anti-programmed death protein-1 (PD-1) or its ligand (PD-L1) against KRAS-mutant NSCLCs remains a topic of debate. This meta-analysis examined randomized-trial data comparing first- or second-line anti-PD-(L)1 with or without chemotherapy vs. chemotherapy alone for advanced KRAS-mutant NSCLCs. Outcome measures included overall survival (OS) and progression-free survival (PFS). Analyses were computed using the Cochrane method of collaboration for meta-analyses, with Review Manager software (RevMan version 5.3; Oxford, UK). We analyzed 3 first-line trials (IMpower-150, Keynote-189 and Keynote-042) and 3 second-line trials (Oak, Poplar and CheckMate-057) that included 1313 NSCLCs (386 KRAS-mutant and 927 KRAS wild-type tumors). For KRAS-mutant NSCLCs, anti-PD-(L)1 with or without chemotherapy was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS (0.59 [0.49–0.72]; p

Results of previous studies demonstrated that high-intensity end-of-life (EOL) care improves neither cancer patients' survival nor quality of life. Our objective was to assess the incidence of and factors associated with aggressiveness of care during the last 30 days of life (DOL) of lung cancer (LC) patients and the impacts of aggressiveness of care in EOL-care costs.Using French national hospital database, all patients with LC who died between January 1, 2010, and December 31, 2011, or between January 1, 2015, and January 31, 2016, were included. EOL-care aggressiveness was assessed using the following criteria: chemotherapy administered within the last 14 DOL; more than one hospitalization within the last 30 DOL; admission to the intensive care unit within the last 30 DOL; and palliative care initiated 3 days before death. Expenditures were limited to direct costs, from a health care payer's perspective.Among 79,746 adult LC patients identified; 57% had at least one indicator of EOL-care aggressiveness (49% repeated hospitalizations, 12% intensive care unit admissions, 9% chemotherapy, 5% palliative care). It increased significantly between the 2 periods (56% vs. 58%, P .001). Young age, male sex, shorter time since diagnosis, comorbidities, no malnutrition, type of care facility other than general hospital, social deprivation, and low-density population were independently associated with having one or more indicator of aggressive EOL care. The mean EOL cost was €8152 ± 5117 per patient, but the cost was significantly higher for patients with at least one EOL-care aggressiveness criterion (€9480 vs. €6376, P .001).In France, a majority of LC patients had at least one criterion of aggressive EOL care that had a major economic impact on the health care system.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options. In this study, we evaluated the impact of CDK4/6 inhibition by palbociclib in a panel of 28 MPM cell lines, including 19 patient-derived cell lines, using a variety of approaches including RNA-sequencing. Palbociclib used alone sufficed to strongly and durably inhibit the proliferation of 23 MPM cell lines, indicating a unique sensitivity of MPM to CDK4/6 inhibition. Importantly, insensitivity to palbociclib was mostly explained by the lack of active T172-phosphorylated CDK4. This was associated with the high p16INK4A (CDKN2A) levels that accompany RB1 defects or inactivation, and also (unexpectedly) cyclin E1 over-expression in the presence of wild-type RB1. Prolonged treatment with palbociclib irreversibly inhibited proliferation despite re-induction of cell cycle genes upon drug washout. A senescence-associated secretory phenotype including various potentially immunogenic components was also irreversibly induced. Phosphorylated CDK4 was detected in 80% of 47 MPM tumors indicating their intrinsic sensitivity to CDK4/6 inhibitors. The absence of this phosphorylation in some highly proliferative MPM tumors was linked to partial deletions of RB1, leading to very high p16 (CDKN2A) expression. Our study strongly supports the clinical evaluation of CDK4/6 inhibitory drugs for MPM treatment, in monotherapy or combination therapy.

To determine FDG-PET biomarkers associated with long-term benefit (LTB) and survival in advanced non-small cell lung cancer (NSCLC) patients receiving first-line immunotherapy. In this multicenter study, we retrospectively analyzed advanced NSCLC patients with a PD-L1 tumor proportion score (TPS) ≥ 50%, who underwent FDG-PET/CT before first-line pembrolizumab, received from August 2017 to September 2019. Parameters extracted were SUVmax, SUVmean, TMTV (total metabolic tumor volume) and TLG (total lesion glycolysis). LTB was defined as objective (complete or partial) response or stable disease as best overall response, maintained for ≥ 12 months. A multivariate prediction model was developed using logistic regression for LTB and Cox models for progression-free survival (PFS) and overall survival (OS). On the 63 eligible patients, with a median follow-up of 13.4 (range, 1.5–29.1) months, 17 (27%) had LTB. Median PFS and OS were 7.7 months (95%CI 5.0–10.5) and 12.1 months (95%CI 8.6–15.6). In multivariate analyses, high TMTV (> 84cm3) and high tumor SUVmean (> 10.1) remained independent factors for predicting LTB (OR 0.2; p = 0.03 and OR 3.7; p = 0.04) and PFS (HR 2.2; p = 0.02 and HR 0.5; p = 0.045). High TMTV was significantly associated with poor OS (HR 3.1; p = 0.03). No association was observed between tumor SUVmax or TLG and clinical outcomes. In patients with advanced NSCLC and PD-L1 TPS ≥ 50%, baseline low TMTV and high tumor SUVmean correlate with survival and LTB from upfront pembrolizumab. Beyond the initial staging, FDG-PET/CT scan could provide relevant biomarkers associated with clinical outcomes that should be taken into account when considering first-line treatment options.

PURPOSE Immune checkpoint inhibitors substantially changed advanced non–small-cell lung cancer (aNSCLC) management and can lead to long-term survival. The aims of this study were (1) to use a machine learning method to establish a typology of treatment sequences on patients with aNSCLC who were alive 2 years after initiating a treatment with anti–programmed death-ligand 1 monoclonal antibody nivolumab and (2) to describe the patients' characteristics according to the typology of treatment sequences. MATERIALS AND METHODS This retrospective observational study was based on data from the comprehensive French hospital discharge database for all patients with lung cancer with at least one line of platinum-based chemotherapy, starting nivolumab between January 1, 2015, and December 31, 2016, and alive 2 years after nivolumab treatment initiation. Patients were followed until December 31, 2018. A typology of most common treatment sequences was established using hierarchical clustering with time sequence analysis. RESULTS Two thousand two hundred twelve study patients were, on average, 63.0 years old, 69.9% of them were men, and 61.9% had a nonsquamous cell carcinoma. During the 2 years after nivolumab treatment initiation, clusters of patients with four basic types of treatment sequences were identified: (1) almost continuous nivolumab treatment (44% of patients); (2) nivolumab most of the time followed by a treatment-free interval or a chemotherapy (15% of patients); and a short or medium nivolumab treatment, followed by (3) a long systemic treatment-free interval (17% of patients) or (4) a long chemotherapy (23% of patients). CONCLUSION This machine learning approach enabled the identification of a typology of four representative treatment sequences observed in long-term survival. It was noted that most long-term survivors were treated with nivolumab for well over 1 year.

International audience; Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options. We evaluated the impact of CDK4/6 inhibition by palbociclib in 28 MPM cell lines including 19 patient-derived ones, using various approaches including RNA-sequencing. Palbociclib strongly and durably inhibited the proliferation of 23 cell lines, indicating a unique sensitivity of MPM to CDK4/6 inhibition. When observed, insensitivity to palbociclib was mostly explained by the lack of active T172-phosphorylated CDK4. This was associated with high p16(INK4A) (CDKN2A) levels that accompany RB1 defects or inactivation, or (unexpectedly) CCNE1 overexpression in the presence of wild-type RB1. Prolonged palbociclib treatment irreversibly inhibited proliferation despite re-induction of cell cycle genes upon drug washout. A senescence-associated secretory phenotype including various potentially immunogenic components was irreversibly induced. Phosphorylated CDK4 was detected in 80% of 47 MPMs indicating their sensitivity to CDK4/6 inhibitors. Its absence in some highly proliferative MPMs was linked to very high p16 (CDKN2A) expression, which was also observed in public datasets in tumors from short survival patients. Our study supports the evaluation of CDK4/6 inhibitors for MPM treatment, in monotherapy or combination therapy.

Erlotinib is indicated as first-line treatment for patients with non-small-cell lung cancer (NSCLC) harboring an epidermal growth-factor–receptor (EGFR) mutation. Addition of a vascular endothelial growth factor (VEGF) inhibitor (anti-VEGF) in combination with the tyrosine-kinase inhibitor erlotinib in this setting is controversial. We conducted a meta-analysis of randomized trials comparing anti-VEGF plus erlotinib vs erlotinib alone as first-line therapy for advanced NSCLC harboring an EGFR mutation. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and median duration of response (DOR). A fixed-effect model was used. Four studies evaluated bevacizumab + erlotinib (ARTEMIS, NEJ026, J025667, Stinchcombe et al.), and another evaluated ramucirumab + erlotinib (RELAY). These five eligible studies included 1230 non-squamous NSCLC patients, 654 (53.2%) with exon 19 deletion (ex19del) and 568 (46.8%) with EGFRL858R. Patients were predominantly women (63%), Asians (85%) and non-smokers (60%); the median age was 64 years. The combination (anti-VEGF + erlotinib) was significantly associated with prolonged PFS (hazards ratio [HR] 0.59 [95% confidence interval (CI) 0.51–0.69]; p

The c-MET proto-oncogene (MET) plays an important role in lung oncogenesis, affecting cancer-cell survival, growth and invasiveness. The MET receptor in non-small-cell lung cancer (NSCLC) is a potential therapeutic target. The development of high-output next-generation sequencing techniques has enabled better identification of anomalies in the MET pathway, like the MET exon-14 (METex14) mutation. Moreover, analyses of epidermal growth factor-receptor (EGFR) and mechanisms of resistance to tyrosine-kinase inhibitors (TKIs) demonstrated the importance of MET amplification as an escape mechanism in patients with TKI-treated EGFR-mutated NSCLCs. This review summarizes the laboratory findings on MET and its anomalies, trial results on METex14 alterations and MET amplification in non-EGFR mutated NSCLCs, and acquired resistance to TKI in EGFR-mutated NSCLCs. The outcomes of the first trials with anti-MET agents on non-selected NSCLC patients or those selected for MET overexpression were disappointing. Two situations seem the most promising today for the use of anti-MET agents to treat these patients: tumors harboring METex14 and those EGFR-sensitive mutation mutated under TKI-EGFR with a MET-amplification mechanism of resistance or EGFR-resistance mutation.

Development of precision medicine for malignant pleural mesothelioma (MPM) requires a deep knowledge of tumor heterogeneity. Histologic and molecular classifications and histo‐molecular gradients have been proposed to describe heterogeneity, but a deeper understanding of gene mutations in the context of MPM heterogeneity is required and the associations between mutations and clinical data need to be refined. We characterized genetic alterations on one of the largest MPM series (266 tumor samples), well annotated with histologic, molecular and clinical data of patients. Targeted next‐generation sequencing was performed focusing on the major MPM mutated genes and the TERT promoter. Molecular heterogeneity was characterized using predictors allowing classification of each tumor into the previously described molecular subtypes and the determination of the proportion of epithelioid‐like and sarcomatoid‐like components (E/S.scores). The mutation frequencies are consistent with literature data, but this study emphasized that TERT promoter, not considered by previous large sequencing studies, was the third locus most affected by mutations in MPM. Mutations in TERT promoter, NF2, and LATS2 were more frequent in nonepithelioid MPM and positively associated with the S.score. BAP1, NF2, TERT promoter, TP53, and SETD2 mutations were enriched in some molecular subtypes. NF2 mutation rate was higher in asbestos unexposed patient. TERT promoter, NF2, and TP53 mutations were associated with a poorer overall survival. Our findings lead to a better characterization of MPM heterogeneity by identifying new significant associations between mutational status and histologic and molecular heterogeneity. Strikingly, we highlight the strong association between new mutations and overall survival., Our comprehensive genetic characterization of key‐altered genes including TERT promoter in malignant pleural mesothelioma led to the identification of new significant associations between the mutational status and the histological and molecular classifications. Our findings allow a better understanding of the genetic landscape in the context of tumor heterogeneity and highlight the high prognostic value of gene mutations in mesothelioma.

Introduction: Despite recent therapeutic advances, lung cancer remains the primary cause of cancer deaths worldwide, and early lung mortality was poorly studied.Area covered: Early lung-cancer mort...

Objectives We aimed to compare the prognostic value of inflammatory biomarkers extracted from pretreatment peripheral blood and [18F]-FDG PET for estimating outcomes in non-small cell lung cancer (NSCLC) patients treated with first-line immunotherapy (IT) or chemotherapy (CT). Materials and methods In this retrospective multicenter study, we evaluated 111 patients with advanced NSCLC who underwent baseline [18F]-FDG PET/CT before IT or CT between 2016 and 2019. Several blood inflammatory indices were evaluated: derived neutrophil-to-lymphocyte ratio (dNLR), platelet-to-lymphocyte ratio (PLR), C-reactive protein (CRP) and systemic immune-inflammation index (SII). FDG-PET inflammatory parameters were extracted from lymphoid tissues (BLR and SLR: bone marrow or spleen-to-Liver SUVmax ratios). Association with survival and relationships between parameters were evaluated using Cox prediction models and Spearman's correlation respectively. Results Overall, 90 patients were included (IT:CT) (51:39pts). Median PFS was 8.6:6.6 months and median OS was not reached:21.2 months. In the IT cohort, high dNLR (>3), high SII (≥1,270) and high SLR (0.77) were independent statistically significant prognostic factors for one-year progression-free survival (1y-PFS) and two-year overall survival (2y-OS) on multivariable analysis. In the CT cohort, high BLR (≥0.80) and high dNLR (>3) were associated with shorter 1y-PFS (HR 2.2, 95% CI 1.0–4.9) and 2y-OS (HR 3.4, 95CI 1.1–10.3) respectively, on multivariable analysis. Finally, BLR significantly but moderately correlated with most blood-based inflammatory indices (CRP, PLR and SII) while SLR was only associated with CRP (p Conclusion In advanced NSCLC patients undergoing first-line IT or CT, pretreatment blood and inflammatory factors evaluating the spleen or bone marrow on [18F]-FDG PET/CT provided prognostic information for 1y-PFS and 2y-OS. These biomarkers should be further evaluated for potential clinical application.

Introduction: Platin-based chemotherapy (CT) has long been the first-line standard-of-care for patients with extensive-stage small-cell lung cancer (ES–SCLC). Adding immune-checkpoint inhibitor(s) to CT (ICI+CT) in this setting is an option of interest, although its benefit is apparently modest. Methods: This meta-analysis was conducted on randomized trials comparing first-line ICI+CT versus CT alone for ES–SCLC. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), response at 12 months and adverse events (AEs). Subgroup analyses were computed according to the immunotherapy used, performance status (PS), age, platinum salt, liver metastases and brain metastases at diagnosis. Results: The literature search identified one randomized phase II (ECOG-ACRIN-5161) and four phase III trials (CASPIAN, IMPOWER-133, KEYNOTE-604 and Reck et al. 2016) that included 2775 patients (66% males, 95% smokers, median age: 64 years, PS = 0 or 1). ICI+CT was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS [0.82 (0.75–0.89); p Conclusions: First-line ICI+CT appears to be superior to CT alone for ES–SCLC except for patients with brain metastases at diagnosis.

Objective: To describe long-term outcomes of patients treated with nivolumab for advanced non-small cell lung cancer (aNSCLC) in everyday clinical practice in France, with a focus on patients aged ⩾80 years, patients with renal impairment and patients with brain metastases. Methods: The study included all patients with aNSCLC recorded in the French national hospital database, starting nivolumab in 2015–2016 and followed until December 2018. Patients were stratified by age, the presence of renal impairment and brain metastasis, as documented in the hospital discharge summaries. Information was retrieved on demographics, comorbidities and treatment history at baseline. Time to discontinuation of nivolumab treatment and overall survival were estimated using Kaplan–Meier survival analysis. Results: Overall, 10,452 patients were included, of whom 514 were octogenarians, 479 had renal impairment and 1800 had brain metastases at baseline. Median duration of nivolumab treatment was 2.8 months in the overall population and in both the octogenarian and renally impaired subgroups, and 2.3 months in patients with brain metastases. Median overall survival in these patient groups was 11.7 months (95% confidence interval: 11.3–12.2), 11.7 months (11.3–12.1), 11.7 months (11.3–12.2) and 9.9 months (9.0–10.9) respectively. Three-year overall survival rates were 19.1% (18.1–20.2) in the overall population, 16.5% (11.6–23.4) in octogenarians, 15.9% (11.8–21.4) in patients with renal impairment and 21.7% (19.4–24.2) in those with brain metastases. Conclusion: This large nationwide retrospective real-life cohort provided narrow estimates of long-term overall survival, which reached 19% at 3 years, consistent with data from phase III trials of nivolumab. Survival rates were comparable in the three special populations of interest and the overall population.

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.

Background Immune checkpoint inhibitor (ICPi) rechallenge could represent an attractive option in non–small-cell lung cancer (NSCLC), yet no sufficient data supporting this strategy are available. This retrospective observational multicenter national study explored the efficacy of anti–programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) rechallenge in advanced NSCLC patients, looking for potential clinical features associated with greater outcomes. Patients and Methods We retrospectively collected data from 144 advanced NSCLC patients whose disease was rechallenged with ICPis after ≥ 12 weeks of discontinuation. The progression-free survival (PFS) and overall survival (OS) were calculated from first or second ICPi initiation to disease progression (PFS1 and PFSR, respectively), death, or last follow-up (OS1, OSR), respectively. Results The median (interquartile range) age was 63 (58-70) years. Most patients were male (67%) and smokers (87%). Most had adenocarcinomas (62%) and/or stage IV disease at diagnosis (66%). The best response at rechallenge was not associated with that under the first ICPi (P = 1.10−1). The median (95% confidence interval) PFS1 and PFSR were 13 (10-16.5) and 4.4 (3-6.5) months, respectively. The median (95% confidence interval) OS1 and OSR were 3.3 (2.9-3.9) and 1.5 (1.0-2.1) years, respectively. Longer PFSR and OSR were found in patients discontinuing first ICPi because of toxicity or clinical decision, those not receiving systemic treatment between the two ICPis, and those with good Eastern Cooperative Oncology Group performance status at rechallenge. Only performance status proved to affect outcomes at multivariate analysis. Conclusion Patients discontinuing first ICPi because of toxicity or clinical decision, those able to maintain a treatment-free period, and those with good performance status may be potential candidates for rechallenge.

Supplemental material, sj-pdf-1-tam-10.1177_1758835920977137 for First-line immune-checkpoint inhibitor plus chemotherapy versus chemotherapy alone for extensive-stage small-cell lung cancer: a meta-analysis by Thierry Landre, Kader Chouahnia, Gaëtan Des Guetz, Boris Duchemann, Jean-Baptiste Assié and Christos Chouaïd in Therapeutic Advances in Medical Oncology

Objectives Nivolumab is now a reference treatment for patients with advanced non-small cell lung cancer (NSCLC) after failure of prior platinum-based chemotherapy. Little data are available on treatment approaches following discontinuation of nivolumab and on the interest of a second course of immunotherapy after nivolumab discontinuation. The aims of this study were to describe treatment pathways following nivolumab discontinuation and to describe survival following retreatment with immunotherapy. Materials and methods The analysis includes all patients with NSCLC recorded in a national hospital database, starting nivolumab in 2015-2016. Nivolumab treatment was considered discontinued if ≥3 infusions were missed. Patients starting a second course of PD-1 inhibitor following nivolumab discontinuation were analysed according to the duration of their initial nivolumab treatment course. Results 10,452 patients were included (71 % men; mean age: 63.8 ± 9.6 years; squamous histology: 44 %). Median nivolumab treatment duration was 2.8 months [IQR :1.4–6.9]. Median OS was 11.5 months [95 %CI: 11.1–11.9]; 5118 (53.4 %) patients received post nivolumab therapy lines: 1517 (29.6 %) of these received a second course of PD-1 inhibitor, either after a treatment-free interval (resumption: n = 1127) or after intervening chemotherapy (rechallenge: n = 390). Median OS after nivolumab discontinuation was 15.0 months [13.9–16.7] in the resumption group and 18.4 months [14.8–21.9] in the rechallenge group. Median OS was significantly longer in patients with an initial nivolumab treatment duration ≥3 months. Conclusion In this real-world setting, outcome after retreatment with a PD-1 inhibitor following a first course of nivolumab was significantly better in patients with a longer duration of initial nivolumab treatment.

International audience; This study was undertaken to determine the healthcare burden of malignant pleural mesothelioma (MPM) in France and to analyze its associations with socioeconomic deprivation, population density, and management outcomes. A national hospital database was used to extract incident MPM patients in years 2011 and 2012. Cox models were used to analyze 1- and 2-year survival according to sex, age, co-morbidities, management, population-density index, and social deprivation index. The analysis included 1,890 patients (76% men; age: 73.6 ± 10.0 years; 84% with significant co-morbidities; 57% living in urban zones; 53% in highly underprivileged areas). Only 1% underwent curative surgical procedure; 65% received at least one chemotherapy cycle, 72% of them with at least one pemetrexed and/or bevacizumab administration. One- and 2-year survival rates were 64% and 48%, respectively. Median survival was 14.9 (95% CI: 13.7-15.7) months. The mean cost per patient was 27,624 ± 17,263 euros (31% representing pemetrexed and bevacizumab costs). Multivariate analyses retained men, age >70 years, chronic renal failure, chronic respiratory failure, and never receiving pemetrexed as factors of poor prognosis. After adjusting the analysis to age, sex, and co-morbidities, living in rural/semi-rural area was associated with better 2-year survival (HR: 0.83 [95% CI: 0.73-0.94]; P < 0.01); social deprivation index was not significantly associated with survival. With approximately 1,000 new cases per year in France, MPMs represents a significant national health care burden. Co-morbidities, sex, age, and living place appear to be significant factors of prognosis.

Introduction L’immunotherapie (IO) par les inhibiteurs des points de controle est une nouvelle option therapeutique dans le mesotheliome pleural malin (MPM). En deuxieme ou troisieme ligne, l’etude prospective MAPS 2 a montre une mediane de survie sans progression (PFS) et de survie globale (OS) de 4 [2,8–5,7] et 11,9 [6,7–17,7] mois dans le groupe nivolumab et de 5,6 [3,1–8,3] et 15,9 [10,7–NR] mois dans le groupe nivolumab + ipilimumab, respectivement. L’objectif de cette etude est d’evaluer l’efficacite et la securite de l’IO en 2e ligne ou plus dans un contexte reel. Methodes Etude francaise retrospective multicentrique incluant des patients atteints de MPM traites par IO (anti-PD-1) en vraie vie, entre novembre 2017 et avril 2020, evaluant l’efficacite (taux de reponse, PFS et OS) et la tolerance. Cette etude a recu l’accord d’un comite national d’ethique (SPLF). Resultats Trente-trois patients inclus (homme 79%, âge median 70 ans, PS 0 (27%) ou 1 (73%), epithelioide 81%, perte de BAP1 24%, albumine 36 [33–40] g/L, LDH sang 224 [213; 290] U/L, PNN 5 [4,1–6,1] G/L, Hb 12,3 [11,4–13,7] g/dL); avant IO, les patients recevaient en mediane de 2 lignes de traitement (IO administree en 1re, 2e, 3e ou 4e ligne dans 1, 14, 16 et 2 cas, respectivement). Soixante-dix-huit pour cent recevaient un sel de platine + pemetrexed ± bevacizumab dans 16% des cas supplementaires. La duree mediane du nivolumab etait de 3 [1–5] mois. Avec un suivi median de 12 mois, la SSP et la SG etaient respectivement de 4 [1–6] et 6 [4–11,5] mois; le taux de controle de la maladie etait de 57% (5 reponses partielles et 14 stables); 42% ont eu des effets indesirables (EI) de tout grade : cutane (43%), pulmonaire (21%) et digestif (21%), principalement de grade 2 (71%). Deux EI de grade 3 (cutanes et rhumatologiques) ont fait stopper nivolumab. 15/27 (56%) patients ont eu une chimiotherapie post-IO (principalement gemcitabine). Conclusion L’anti-PD-1 (nivolumab) semble etre une option cliniquement pertinente pour certains patients en routine au-dela du traitement de premiere ligne, malgre une survie globale mediane plus courte dans cette petite serie par rapport a la litterature. Ce resultat peut s’expliquer par le fait que les patients ont ete moins selectionnes et ont recu majoritairement du nivolumab en 3e ligne ou plus. Par consequent, cette etude ainsi que l’essai PROMISE-Meso soulignent la necessite de disposer de biomarqueurs pour mieux selectionner les meilleurs candidats a l’IO. Des etudes complementaires sont en cours dans ce but.

Introduction: Malignant pleural mesothelioma (MPM) is a heterogeneous cancer characterized by a diffuse locoregional growth within the thoracic cavity. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. Methods: Intra-tumor heterogeneity was investigated in 16 patients biopsied at distinct anatomic sites (apex, side wall, costo-diaphragmatic and highly metabolic site detected by PET scan when present). Paired biopsies and five derived primary cell lines were screened by targeted sequencing. Part of the cohort was also deeply characterized by whole exome sequencing, RNA-seq and DNA methylation profiling. Molecular classification and recently defined histo-molecular gradients were assessed, as were the cell populations infiltration of the tumor microenvironment. Results: Sequencing analysis showed that most of the protein-altering somatic variants were common between paired samples from a given patient. However, we identified heterogeneous variants notably in NF2, the well-known mesothelioma driver tumor suppressor gene. Furthermore, we highlighted subclonal tumor populations shared among paired biopsies, suggesting a polyclonal dissemination of the tumor. Chromosomal abnormalities profiles were similar between different regions within the same tumor suggesting that the main chromosomal alterations occurring in MPM are early events of mesothelial carcinogenesis. Transcriptomic analysis showed major differential gene expression between anatomic sites, leading to the dysregulation of specific pathways notably linked to cell adhesion and extracellular matrix. Accordingly, histo-molecular gradient determining the proportions of epithelioid-like and sarcomatoid-like cellular entities varied between these samples. These changes were linked to epigenetic mechanisms in two patients. Finally, we found consequent spatial intra-tumor heterogeneity of the immune microenvironment with differential expression of immune mediators and immune checkpoints, and differential infiltration of immune populations. These changes led to a switch from a hot to a cold immune profile in three patients. Conclusions: This study is the first to report on the multi-omics profiling of a substantial series of multi-site MPM tumor samples. Spatial intra-tumor heterogeneity is complex in MPM and varies among patients. We highlighted multiple types of heterogeneity, i.e. (i) genetic, (ii) transcriptomic, (iii) epigenetic and (iv) in the immune landscape of the tumor microenvironment. These results support the need for multi-sampling for the implementation of molecular-based precision medicine in MPM. Citation Format: Clément Meiller, François Montagne, Théo Z. Hirsch, Stefano Caruso, Julien de Wolf, Quentin Bayard, Jean-Baptiste Assié, Léa Meunier, Yuna Blum, Lisa Quetel, Laure Gibault, Ecaterina Pintilie, Cécile Badoual, Marie-Christine Copin, Eric Letouzé, Arnaud Scherpereel, Jessica Zucman-Rossi, Françoise Le Pimpec-Barthes, Marie-Claude Jaurand, Didier Jean. Spatial intra-tumor molecular heterogeneity in malignant pleural mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3128.

9025 Background: KRAS comprise the most frequently found oncogene driver mutation in non-small cell lung cancer (NSCLC), accounting for 20-25% of these patients. Single-agent Anti PD-(L)1 clinical efficacy against KRAS mutant NSCLC is a topic of debate. Methods: This meta-analysis examined randomized-trial data comparing first-or second line Anti PD-(L)1 +/- chemotherapy (CT) vs CT alone for KRAS mutant advanced NSCLCs. Outcome measures included overall survival (OS) and progression-free survival (PFS). Analyses were computed using the Cochrane method of collaboration for meta-analyses, with Review Manager software (RevMan version 5.3; Oxford, UK). Results: We analyzed 3 trials in first line (IMPOWER-150, KEYNOTE-189 and KEYNOTE-042), as well as 3 trials in second line (OAK, POPLAR and CHECKMATE-057) including 1313 NSCLCs (386 KRAS mutant and 927 KRAS wild-type tumor). Anti PD-(L)1 +/- CT was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS (0.59 [0.49-0.72]; p < 0.00001) and PFS (0.58 [0.43-0.78]; p = 0.0003) compared to CT alone in KRAS mutant NSCLCs. Survival benefits occured in both first and second line. Survival benefits observed in KRAS wild-type NSCLCs were (0.87 [0.76-0.99]; p = 0.03) and (0.79 [0.56-1.11]; p = 0.17) respectively. OS benefit in KRAS mutant was significantly superior compared to OS benefit in KRAS wild-type (p = 0,001). Conclusions: Anti PD-(L)1 (+/- CT) appears superior to CT alone both for mutant and wild-type KRAS in advanced NSCLCs for OS and PFS with higher magnitude of benefit in KRAS mutated group for OS.

Introduction Les donnees en vie reelle peuvent completer celles des essais cliniques afin d’optimiser la prise en charge courante du CBNPC. Apres l’arret du nivolumab, peu de donnees existent concernant les pratiques, les options therapeutiques et leurs resultats. Methodes A partir des donnees du PMSI, une cohorte retrospective regroupant tous les patients atteints de CBNOC ayant initie nivolumab en 2015–2016 apres une chimiotherapie a ete suivie jusqu’au 31 decembre 2017 (suivi minimum de 12 mois). Les caracteristiques des patients (donnees demographiques, comorbidites, antecedents de traitement) ont ete recherchees. L’arret du nivolumab etait defini comme l’absence d’au moins 3 perfusions consecutives. Le temps avant arret du traitement (TTD) et la survie globale (SG) ont ete estimes par la methode de Kaplan–Meier. La SG des patients en re-challenge d’immunotherapie a ete analysee en fonction de la duree de leur traitement initial par nivolumab avec les intervalles suivants : Resultats Nous avons identifie 10 452 patients atteints de CBNPC initiant le nivolumab au cours de la periode d’inclusion (homme : 71 % ; âge moyen : 63,8 ± 9,6 ans ; histologie epidermoide : 44 % ; metastases cerebrales : 17,4 % ; anciennete mediane du CBNPC : 12,5 mois ; chirurgie curative anterieure : 15,6 % ; temps median depuis la premiere chimiotherapie : 10,5 mois ; dose moyenne du nivolumab : 213 ± 54 mg). Les medianes de TTD et de SG etaient de 2,8 mois et 11,6 mois. Les taux de SG a 1 an et 2 ans etaient de 48,8 % et 27,4 %. Au total, 5118 (53,4 %) patients ont recu un traitement systemique apres l’arret du nivolumab. Parmi eux, 1517 patients (29,6 %) ont ete traites a nouveau avec un anti-PD1 (nivolumab : 98,8 %) soit apres une pause therapeutique (groupe « reprise » : n = 1127 ; mTTD2 : 4,1 mois ; mSG2 : 14,9 mois a partir de la 2e sequence d’immunotherapie), soit apres une progression traitee par chimiotherapie (« groupe re-challenge » : n = 390 ; mTTD2 : 3,0 mois ; mSG2 : 18,2 mois a partir de la 2e sequence d’immunotherapie). La Fig. 1 presente les courbes de SG2 de l’immunotherapie du « groupe re-challenge » en fonction de la duree du traitement initial par nivolumab. Conclusion Parmi les patients recevant un traitement systemique apres l’arret du nivolumab, environ 30 % ont a nouveau recu une immunotherapie en reprise apres une pause ou en re-challenge apres une chimiotherapie. L’influence de la duree du traitement initial par nivolumab sur la survie en re-challenge doit etre etudiee davantage.

Introduction En France, environ 10 % des patients diagnostiques avec un cancer bronchique non a petites cellules (CBNPC) sont octogenaires. L’efficacite du nivolumab dans cette population specifique est peu connue et les donnees de vie reelle representent une source d’information pertinente. Le but de cette etude etait de decrire l’utilisation et l’efficacite du nivolumab chez les patients âges de 80 ans et plus. Methodes A partir des donnees hospitalieres du PMSI, une cohorte retrospective, regroupant tous les patients atteints de cancer bronchique (code CIM10 : C34*) et ayant initie nivolumab en 2015–2016 apres une chimiotherapie, a ete suivie jusqu’au 31 decembre 2017 (suivi minimum de 12 mois). Les caracteristiques des patients (donnees demographiques, comorbidites, antecedents de traitement) ont ete recherchees selon deux populations distinctes : ≥ 80 ans et Resultats Parmi les 10 452 patients atteints de CPNPC initiant nivolumab pendant la periode d’inclusion, 514 (4,9 %) etaient âges de 80 ans ou plus. L’âge moyen a l’initiation du groupe octogenaire etait de 82,5 ans (± 2,4) vs 62,8 ans (± 8,8) pour le reste de la cohorte. Les patients octogenaires etaient plus frequemment des hommes (p Tableau 1 . Conclusion Parmi les patients initiant nivolumab au cours de la periode d’etude, seul un faible pourcentage etaient âges de 80 ans ou plus (

Treatment of advanced-stage or metastatic non-small-cell lung cancers (NSCLCs) without EGFR mutations or ALK rearrangements, which can now be treated with molecularly targeted therapies, had been based on cytotoxic chemotherapy for a long time. Immune checkpoint inhibitors (ICIs), notably antibodies directed against programmed cell-death protein-1 (PD-1) and its ligand (PD-L1) have transformed therapeutic standards in thoracic oncology. These ICIs are now the reference second-line treatment and numerous phase III trials have examined their efficacy in treatment-naive patients. First-line pembrolizumab monotherapy was validated for patients with ≥ 50% of tumor cells expressing PD-L1; pembrolizumab, atezolizumab, and nivolumab have obtained good outcomes in combination with chemotherapy or another immunotherapy. However, in this context, other phase III trials yielded negative findings for nivolumab alone (CheckMate-026) or in combination (MYSTIC trial). Biomarkers, such as PD-L1 and the tumor mutation burden (TMB), enable better selection of patients who should benefit the most from first-line ICI use.

Introduction Le crizotinib et d’autres inhibiteurs de tyrosine kinase ciblant MET ont demontre une efficacite sur des CBNPC exprimant une mutation du gene MET (METexon14) associe a un saut d’exon 14. Il existe de nombreux variants de cette mutation. Certains n’affectent pas les sites d’epissage et donc n’entraineraient pas ce saut d’exon. Pour cette derniere categorie de variants, les tests in silico ne peuvent predire de maniere fiable un saut d’exon. Il pourrait etre important de s’appuyer sur d’autres techniques comme les analyses fonctionnelles. Methodes AFonMET est une etude retrospective multicentrique francaise de vraie vie portant sur l’analyse fonctionnelle des mutations identifiees au voisinage de l’exon 14 et l’efficacite du crizotinib chez des patients porteurs d’un CBNPC de stade IV mute METexon14. Resultats Cent dix neuf patients ont ete inclus entre le 1er decembre 2015 et le 1er juin 2019, dans 13 centres : âge median de 73 ans, 62 % de femmes, non-fumeurs : 47 %, adenocarcinome : 83 %, carcinomes sarcomatoides : 5 %, stade IV : 92 %, metastases cerebrales : 22 %, plus de 3 sites metastatiques : 26 %. Quinze co-amplifications de MET et 22 co-mutations ont ete retrouvees. Les 63 variants differents etaient composes de 69 % de deletions et de 28 % de mutations ponctuelles. 28 % des variants ne touchaient pas les sites d’epissage. 79 (66 %) patients ont beneficie d’au moins un TKI anti MET : crizotinib : 55 (69 %), tepotinib : 18 (22 %), capmatinib : 11 (14 %) et cabozantinib : 2 (3 %). Sept (8,8 %) patients ont beneficie de deux TKI anti MET dans leurs sequences therapeutiques. A la date de point du 1er juin 2020, avec une mediane de suivi de 16 mois, la mediane de survie globale (SG) de la population etait de 22.3 mois (CI95 %, 13.4–28.8). Les medianes de SG des cohortes « traite par crizotinib » et « non-traite par crizotinib » etaient de 21,6 mois (CI95 %, 14.5–29.7) et 27.1 mois (CI95 %, 15.7–42.5) respectivement. Cette difference n’etait pas significative (p= 0.77). Les medianes de SG des cohortes de patients ayant ete expose ou non a un TKI anti MET etaient de 26 mois (CI95 %, 18–28.8) et de 15.3 mois (CI95 %, 5.4-non atteinte) respectivement. Conclusion Dans cette etude de vrai vie, les TKI anti MET augmentent la survie globale des patients porteurs d’un CBNPC de stade IV mute MET exon 14. Les resultats de l’efficacite des anti MET en fonction des analyses fonctionnelles seront presentes au congres.

Introduction Le cancer pulmonaire est la premiere cause de deces par cancer dans le monde. Malgre les avancees therapeutiques, le pronostic reste sombre. L’objectif principal est d’identifier des facteurs de risque de mortalite a 90 jours de la premiere hospitalisation pour cancer pulmonaire (mortalite precoce). Methodes Il s’agit d’une analyse des donnees du Systeme National des Donnees de Sante incluant les patients avec une premiere hospitalisation pour cancer pulmonaire entre le 1er janvier 2016 et le 31 decembre 2018 (code C34* de la CIM-10). L’analyse inclue des caracteristiques cliniques, les modes d’entree et de sortie, et des indicateurs socio-economiques (a partir du lieu de domicile). Un modele predictif de mortalite precoce est developpe a partir des variables disponibles lors du premier sejour. Resultats L’etude inclut 144 087 patients, majoritairement des hommes (67 %), avec un âge median de 68 ans [60–76]. Parmi eux 47 % sont diagnostiques a un stade metastatique, 34 % et 23 % beneficient respectivement d’une chimiotherapie et d’une chirurgie; 27 % souffrent de BPCO. La duree de la premiere hospitalisation est de 6 jours [95 %IC: 1–13]; les patients sont pris en charge a 40 % dans des CH et a 26 % dans des CHU; 26 % sont hospitalises apres un passage aux urgences; la majorite (58 %) habite en zones urbaines. La mortalite precoce est de 19 %. Elle augmente avec l’âge (OR 1.33 [1.22–1.45] pour les plus de 70 ans), le sexe masculin (OR 1.50 [1.44–1.55), le stade metastatique (OR 3.30 [3.18–3.43]), une entree via les urgences (OR 1.65 [1.59–1.71]), et la duree du premier sejour (OR 1.58 [1.49–1.68] pour plus de 30 jours). Les facteurs socio-economiques (densite de population, territoires ruraux, indicateur d’accessibilite potentielle localisee et indice de privation sociale) n’influencent pas la mortalite precoce. Le modele predictif le plus performant est celui obtenu par regression logistique (score F1 0.44, specificite 0.88 et AUC ROC 0.65). Les variables avec le plus gros poids dans ce modele sont le statut metastatique, l’hospitalisation via les urgences et une duree de sejour initial de plus de 7 jours. Conclusion En France, 19 % des patients decedent dans les 90 jours suivants la premiere hospitalisation pour cancer pulmonaire. Ce sont majoritairement des hommes, âges, diagnostiques a un stade metastatique apres un passage aux urgences. Un diagnostic plus precoce pourrait reduire la mortalite precoce. Le developpement d’un modele predictif pourrait aider la prise en charge des patients.

Objectif La prise en charge au long cours des patients avec cancer bronchique non a petites cellules metastatique traite par nivolumab (immunotherapie anti-PD1) est peu documentee. L’heterogeneite des pratiques rend l’analyse des sequences de traitement complexe et propice a une approche par « Machine learning ». L’objectif de cette analyse est d’identifier des typologies de prise en charge des patients long-survivants apres l’initiation de nivolumab. Methode A partir des bases de donnees hospitalieres francaises (PMSI), les patients ayant initie nivolumab en 2015–2016 et en vie deux ans apres ont ete identifies. Un algorithme de « Machine learning » a permis de classer et regrouper automatiquement les patients en cluster presentant des sequences de traitement similaires en termes de duree et de succession des differentes options therapeutiques (nivolumab, chimiotherapies ou pause therapeutique). Resultats Parmi 10 452 patients ayant initie nivolumab sur la periode d’inclusion, 2212 (21,2 %) presentaient une survie d’au moins 24 mois. Quatre clusters ont ete identifies (Tableau 1): Cluster 1) Nivolumab est le traitement principal utilise presque en continu sur la periode avec une duree mediane cumulee (DMC) de 21,0 mois; Cluster 2) Nivolumab est le traitement majoritaire sur la periode (DMC: 16,5 mois), suivi d’une courte chimiotherapie (DMC: 2,5 mois) et/ou d’une pause therapeutique (DMC: 5,3 mois); Cluster 3) Le traitement par nivolumab est court (DMC: 6,4 mois), suivi d’une longue pause therapeutique (DMC: 14,4 mois); Cluster 4) Le traitement par nivolumab et court (DMC: 5,5 mois) suivi d’une ou plusieurs lignes de chimiotherapie (DMC: 9,5 mois). Les patients des clusters presentaient egalement des caracteristiques differentes en termes d’âge, de comorbidites et de prise en charge anterieure. Conclusion A partir d’un large echantillon de patients survivants deux ans apres l’initiation de nivolumab en deuxieme ligne ou plus, l’approche par « Machine learning » a permis de classer les patients ayant des sequences homogenes de traitement et d’identifier quatre groupes de patients a la prise en charge differente. Une etude approfondie de leur profil clinique pourrait permettre de mieux comprendre leur prise en charge.

Background: We aimed to assess the clinical utility of a previously published score combining the total metabolic tumor volume (TMTV) on baseline FDG-PET/CT and pretreatment derived from the neutrophils to lymphocytes ratio (dNLR) for prognostication in NSCLC patients undergoing first-line immunotherapy (IT). Methods: In this multicenter retrospective study, 63 advanced NSCLC patients with a PD-L1 tumor proportion score (TPS) &ge, 50%, who underwent FDG-PET/CT before first-line IT, treated from January 2017 to September 2019, were enrolled. Associations between this score and the progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and overall response rate (ORR) were evaluated. Results: The median (m) PFS and mOS were 7.7 (95% CI 4.9&ndash, 10.6) and 12.1 (8.6&ndash, 15.6) months, respectively, and DCR and ORR were 65% and 58%, respectively. mOS was 17.9 months (14.6 not reached) for the good group versus 13.8 (95%CI 8.4&ndash, 18.9) and 6.6 (CI 2.0&ndash, 11.2) months for the intermediate and poor groups, respectively. mPFS was 15.1 (95%CI 12.1&ndash, 20.0) months for the good group versus 5.2 (1.9&ndash, 8.5) and 1.9 (95%CI 1.3&ndash, 2.5) months for the intermediate and poor groups, respectively. The poor prognosis group was associated with DCR and ORR (p &lt, 0.05). Conclusions: The metabolic score combining TMTV on the baseline FDG-PET/CT scan and pretreatment dNLR was associated with the survival and response in a cohort of advanced NSCLC patients with &ge, 50% PD-L1 receiving frontline IT.

We have recently reported the development of YAP-TEAD interaction inhibitors that disrupt the YAP-TEAD complex and block proliferation of tumor cells. These compounds represent promising new treatment modalities for mesothelioma where the Hippo pathway is highly deregulated, with around 45% of MPM cases displaying a mutation of NF2 or LATS and predominantly nuclear YAP localization. MPM is an extremely aggressive disease with limited treatment options and no cure and is inherently chemoresistant, with only 50% of patients responding to the standard-of-care treatment; consequently, it has a very poor prognosis. The aim of this study was to support a multipronged approach to treat MPM. We have first established the in vitro proof of concept using siRNA experiments. Then, we have evaluated the effect of several Inventiva compounds (YAP-TEAD inhibitors) on the proliferation of a well-characterized YAP-dependent mesothelioma cell line (H2052) and on a large panel of MPM cells. We have further demonstrated the mechanism of action (MOA) of our compounds investigating the nuclear localization of YAP, the YAP-TEAD interactions, and the YAP protein expression levels in H2052 cancer cell line. To demonstrate the MOA, we have used immunofluorescence, proximity ligation assay, as well as Co-IP and Western blot experiments. Furthermore, we have examined the effect of IVA compounds in combination with the standard-of-care agent pemetrexed in a 3D spheroid model, and demonstrated the target engagement by looking at YAP-TEAD target gene expression. The effect of IVA compounds has been compared to this obtained with siRNA transfection. To assess the efficacy of pemetrexed +/- Inventiva compounds, we exposed H2052 cells to either each of the single agents or to their combination for 4 or 15 days in 2D or in 3D cultures. We used EdU incorporation assay or the measure of the spheroid area to access cell proliferation. We found a synergistic effect between YAP-TEAD inhibitors and pemetrexed, leading to a drastic inhibition of cancer cell proliferation and an increase of cytotoxicity. This suggests that YAP-TEAD inhibitors used in combination with existing chemotherapeutics could be used to attenuate multidrug resistance and resensitize chemoresistant cancer cells. We are currently exploring the effect of Inventiva compounds in H2052 mouse xenograft model. This study will be expanded to other indications and combination strategies where standard-of-care agents are ineffective and YAP is activated. Citation Format: Anne Soudé, Martine Barth, Jean-Michel Luccarini, Séverine Delaporte, Florence Chirade, Christelle Valaire, Aude Boulay, Geneviève Cheret, Marie Dorchie, Céline Estivalet, Pascale Tuya-Boustugue, Robin Tranchand, Didier Jean, Lisa Quetel, Jean-Baptiste Assié, Irena Konstantinova, Jean-Louis Junien, Pierre Broqua. Discovery of YAP-TEAD protein-protein interaction inhibitors (PPI) for treating malignant pleural mesothelioma (MPM) [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B14.

Introduction Les ICPis ont profondement modifie l’algorithme therapeutique du CBNPC au cours des dernieres annees. Malheureusement, la majorite des patients connaissent une progression de la maladie. Le rechallenge avec ICPi pourrait etre une option attrayante, mais aucune donnee a l’appui de cette strategie n’est disponible. Nous presentons les Resultats d’une cohorte de patients ayant recu un rechallenge par ICPi. Methodes Nous avons recueilli retrospectivement les donnees de 144 patients atteints de CBNPC avance (diagnostic entre 2010–2018) parmi 26 centres francais. Les patients ont recu le rechallenge avec ICPi apres au moins 12 semaines d’arret en raison d’une toxicite, progression ou decision clinique. La survie sans progression (SSP) et la survie globale (SG) ont ete calculees a partir du debut du premier ou de la deuxieme ICPi jusqu’a la progression de la maladie (SSP1 ; SSP2) et le deces ou le dernier suivi (SG1 ; SG2) respectivement. Resultats L’âge median etait de 63 ans, la plupart etaient des hommes (67 %), fumeurs (87 %), adenocarcinomes (62 %), au stade IV au moment du diagnostic (66 %). La plupart des patients ont recu le premier ICPi en premiere/deuxieme ligne (66 %) et le deuxieme ICPi en troisieme ligne ou plus tard (79 %). La meilleure reponse au cours du deuxieme ICPi n’etait pas correlee a celle obtenue lors du premier (p = 0,149). Les SSP1 et SSP2 medianes etaient de 13 et de 4,4 mois respectivement. La SSP2 etait plus longue chez les patients ayant abandonne le premier ICPi pour une decision clinique (6,5 mois) ou toxicite (5,8 mois), comparativement a ceux qui ont arrete pour une progression de la maladie (2,9 mois) (p = 0,021), et chez ceux qui n’ont pas recu une chimiotherapie entre les deux ICPis (5,8 mois) comparativement a ceux qui l’ont recue (3,0 mois) (p = 0,002). La SG1 mediane etait de 3,3 ans sans difference selon la raison d’arret du premier ICP (p = 0,266). La SG2 mediane etait de 1,5 ans et etait plus longue chez les patients ayant abandonne le premier ICPi pour toxicite (2,1 ans) comparativement a ceux qui ont arrete pour progression de la maladie (1 an) ou pour decision clinique (1,5 ans) (p = 0,031). Ni la SG1 ni la SG2 n’ont ete affectes par les traitements recus entre les deux ICPis (p = 0,345 et p = 0,117 respectivement). Conclusion La reprise de l’ICPi pourrait etre une option utile, principalement chez les patients qui arretent le premier ICPi pour toxicite ou sur decision clinique et chez ceux qui ont eu un intervalle libre entre les deux ICPi.

Introduction L’anti-PD-1 nivolumab a demontre une superiorite en survie globale (SG) dans deux essais de phase III par rapport au docetaxel chez des patients pretraites atteints de CBNPC de type squameux (Sq) et non squameux (NSq) au stade avance. L’objectif etait de decrire, en vie reelle et selon l’histologie du CBNPC, les caracteristiques et la SG des patients francais traites par nivolumab. Methodes A partir des donnees hospitalieres du PMSI, une cohorte retrospective regroupant tous les patients atteints de CBNPC (CIM10 : C34*) pretraites par chimiotherapie ayant initie nivolumab en 2015–2016 a ete suivie jusqu’au 31 decembre 2017 (suivi minimum de 12 mois). Les caracteristiques des patients (demographiques, comorbidites, antecedents de traitement) ont ete recuperees selon le groupe histologique. Le temps avant arret du traitement (TTD) et la SG ont ete estimes par la methode de Kaplan–Meier. Resultats La cohorte globale comprenait 10 452 patients. Parmi eux, une majorite (n = 5805 ; 56 %) presentait une histologie NSq. Compares aux patients Sq (n = 4647), les patients NSq etaient plus jeunes (61,9 vs 66,1 ans ; p Conclusion Cette etude sur une large cohorte retrospective nationale a permis d’evaluer les caracteristiques des patients et la survie associee au nivolumab en pratique clinique. Pour les deux histologies, les resultats suggerent une similarite entre les SG en vie reelle et celles observees dans les essais.

Background Nivolumab demonstrated superior overall survival (OS) in clinical trials compared to docetaxel in patients previously treated for squamous (Sq) and non-squamous (NSq) aNSCLC. The objective was to describe in French real-world setting the characteristics and outcomes of patients treated with nivolumab for aNSCLC according to histology. Methods Based on the National hospitals database (PMSI), we performed a retrospective cohort of all NSCLC patients (ICD code: C34*) initiating nivolumab in 2015-2016 and followed until Dec 2017. Information on patients’ baseline characteristics (demographics, comorbidities, treatment history) was retrieved for Sq and NSq patients, and time to treatment discontinuation (TTD) with nivolumab and OS were estimated with Kaplan-Meier methodology. Results The overall cohort included 10,452 patients. Among them, a majority (N = 5805; 56%) presented NSq histology. Compared to Sq patients (N = 4647), NSq patients were younger (61.9 vs. 66.1 years; p Conclusions This analysis of a large nationwide retrospective cohort assessed patients’ characteristics and outcomes associated with nivolumab treatment in clinical practice in France. In both histologies, results suggest similar TTD and OS in real life setting as those observed in phase III trials. Legal entity responsible for the study Bristol-Myers Squibb France. Funding Bristol-Myers Squibb. Disclosure C. Chouaid: Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb. C. Calvet: Full / Part-time employment: Bristol-Myers Squibb. A. Gaudin: Full / Part-time employment: Bristol-Myers Squibb. V. Grumberg: Full / Part-time employment: Bristol-Myers Squibb. R. Jolivel: Honoraria (institution): Bristol-Myers Squibb. B. Jouaneton: Honoraria (institution): Bristol-Myers Squibb. F. Cotte: Full / Part-time employment: Bristol-Myers Squibb. All other authors have declared no conflicts of interest.