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Background A standard of care for pretreated, advanced non–small‐cell lung cancers (NSCLCs), nivolumab has demonstrated long‐term benefit when administered for 2 years. We aimed to better discern an optimized administration duration by retrospectively analyzing real‐life long‐term efficacy in a prospective cohort. Methods All nivolumab‐treated adults with advanced NSCLCs (01/09/2015 to 30/09/2016) from nine French centers were eligible. On 31/12/2018, patients who are alive ≥ 2 years after starting nivolumab were defined as long‐term survivors (LTSs) and were divided into three nivolumab treatment groups: 2 years. Co‐primary endpoints were LTSs’ progression‐free survival (PFS) and overall survival (OS). Results The median follow‐up was 32 months (95% CI, 31.0 to 34.0). The 3‐year OS rate for the 259 cohort patients was 16.6%. Among them, 65 were LTSs: 47 treated 2 years. Their respective characteristics were: median age: 59, 52, and 58 years; smoking history: 92.9, 100, and 100%; adenocarcinomas: 66, 57.1, and 54.5%. LTSs’ median (m)PFS was 28.4 months; mOS was not reached. LTSs’ objective response rate was 61.6%. mOS was 32.7 months for those treated 2‐year group's 3‐year OS was longer. Twenty‐eight LTSs experienced no disease progression; 7 had durable complete responses. However, LTSs had more frequent and more severe adverse events. Conclusion In real‐life, prolonged nivolumab use provided long‐term benefit with 16.6% 3‐year OS and 25% LTSs. Survival tended to be prolonged with nivolumab continued beyond 2 years. Prospective randomized trials with adequate design are needed., Phase III trials didn't provide an optimal duration of immunotherapy for responder or stable patients in advanced non‐small‐cell lung cancer. A 2 years‐fixed duration or long‐term therapy are proposed to clinicians. The results of this observational study of 65 long‐term survivor pretreated patients showed a trends toward improvement of survival outcomes when continuing nivolumab after two years.

International audience; Background With the development of precision oncology, Molecular Tumor Boards (MTB) are developing in many institutions. However, the implementation of MTB in routine clinical practice has still not been thoroughly studied. Material and methods Since the first drugs approved for targeted therapies, patient tumor samples were centralized to genomic testing platforms. In our institution, all tumor samples have been analyzed since 2014 by Next Generation Sequencing (NGS). In 2015, we established a regional MTB to discuss patient cases with 1 or more alterations identified by NGS, in genes different from those related to drug approval. We conducted a retrospective comparative analysis to study whether our MTB increased the prescriptions of Molecular Targeted Therapies (MTT) and the inclusions of patients in clinical trials with MTT, in comparison with patients with available NGS data but no MTB discussion. Results In 2014, 86 patients had UGA, but the results were not available to clinicians and not discussed in MTB. During the years 2015 and 2016, 113 patients with an UGA (unreferenced genomic alteration) were discussed in MTB. No patients with an UGA were included in 2014 in a clinical trial, versus 2 (2%) in 2015-2016. 13 patients with an UGA (12%) were treated in 2015-2016 with a MTT whereas in 2014, no patient (p = 0.001). Conclusions In this retrospective analysis, we showed that the association of large-scale genomic testing and MTB was feasible, and could increase the prescription of MTT. However, in routine clinical practice, the majority of patients with UGA still do not have access to MTT.

Long-term changes in lung cancer (LC) patients are difficult to evaluate. We report results from the French KBP-2020 real-life cohort.KBP-2020 was a prospective cohort that included all patients diagnosed with LC in 2020, in nonacademic public hospital in France. Patient and tumour characteristics were described and compared with similarly designed cohorts in 2000 and 2010.In 2020, 82 centers included 8,999 patients diagnosed with LC. The proportion of women increased: 34·6% (3114/8999) compared to, 24·3% (1711/7051) and 16·0% (904/5667) in 2010 and 2000 (To our knowledge KBP cohorts have been the largest, prospective, real-world cohort studies involving LC patients conducted in worldwide. The trend found in our study shows an increase in LC in women and still a large proportion of patients diagnosed at metastatic or disseminated stage.The study was promoted by the French College of General Hospital Pulmonologists with financial support of industrials laboratories.

CERVOXY CLIN; International audience; Background - Anticancer immune responses are negatively regulated by programmed cell death 1 (PD-1) T-cell membrane protein interaction with its ligand, programmed death ligand 1 (PD-L1), on cancer cells. We sought to assess the prognostic role of PD-L1 expression in tumor samples from patients enrolled onto the IFCT-0701 MAPS randomized phase 3 trial (NCT00651456). Patients and methods - Tumor samples were analyzed by immunohistochemistry for percentages of PD-L1 membrane-stained tumor cells using the E1L3N clone, and data were correlated to survival by multivariate Cox models including stratification variables. Results - PD-L1 staining was assessed in 214 (47.75%) of 448 patients. Epithelioid subtype represented 83.7% (179/214). Absence of PD-L1 staining occurred in 137 (64.1%) of 214 malignant pleural mesothelioma (MPM) samples, while 77 (35.9%) of 214 were PD-L1 positive, with 50 (64.9%) of 77 showing < 50% PD-L1-expressing tumor cells. Sarcomatoid/biphasic subtypes were more commonly PD-L1 positive than epithelioid subtype (P < .001). In patients with 1% or more PD-L1-stained tumor cells, median overall survival (OS) was 12.3 months versus 22.2 months for other patients (hazard ratio [HR] = 1.25; 95% confidence interval [CI], 0.93-1.67; P = .14). OS did not differ according to PD-L1 positivity in multivariate analyses (adjusted HR = 1.10; 95% CI, 0.81-1.49; P = .55). With a 50% cutoff, PD-L1-positive patients displayed a 10.5 months median OS versus 19.3 months for patients with lower PD-L1 expression (HR = 1.93; 95% CI, 1.27-2.93; P = .002). OS did not significantly differ in adjusted Cox models (adjusted HR = 1.20; 95% CI, 0.74-1.94; P = .47). In the 179 epithelioid MPM patients, high PD-L1 staining (≥ 50% of tumor cells) negatively affected OS, although not significantly, showing a 12.3-month median OS (95% CI, 4.3-21.6) versus 23-month (95% CI, 18.5-25.2) for patients with tumor PD-L1 staining in < 50% cells (P = .071). The progression-free survival (PFS) differences were statistically significant, with a longer 9.9-month median PFS in patients with low PD-L1 staining (< 50% cells) compared to 6.7 months of median PFS in patients with high PD-L1 expression (≥ 50% cells) (P = .0047). Conclusion - Although high PD-L1 tumor cell expression was associated with poorer OS in MPM patients from the MAPS trial, its prognostic influence was lost in multivariate analyses in the whole cohort, while PD-L1 expression was strongly associated with the sarcomatoid/biphasic subtypes. In the epithelioid MPM subset of patients, high PD-L1 tumor expression (≥ 50%) negatively affected OS and PFS, with this prognostic influence remaining statistically significant for PFS after adjustment in multivariate Cox model.

The resistance mutation T790M is reported in 50–60% of patients pretreated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Osimertinib has been approved in these patients, but data in octogenarians remain rare. The objective of this retrospective analysis was to evaluate in real life the efficacy of osimertinib in a population of octogenarian patients. This retrospective multicentric study included pretreated octogenarian patients with EGFR T790M-mutated advanced non-small cell lung cancer (NSCLC) in the setting of the French early access program for osimertinib. The primary endpoints were progression-free survival (PFS) and overall survival (OS) from osimertinib initiation. In total, 43 patients were included (mean age 84.6 years; women 90.7%: adenocarcinoma 100%; never smokers 90.5%; at osimertinib initiation: performance status ≥ 2, 42.4%; stage 4, 93.0%; brain metastases 16.3%). Patients received a median of two lines of treatment before osimertinib initiation, and all received first- or second-generation EGFR TKIs before osimertinib (first line in 79.1%). Osimertinib was used as a second-line treatment in 41.9% of cases and third line or more in 58.1%. Median PFS was 17.5 (95% confidence interval [CI] 12.2–19.0) months for the entire population: 20.6 (95% CI 18.8–not reached) months in patients with brain metastases and 16.7 (95% CI 10.4–18.9) months in patients without (p = 0.1). There was no significant difference for osimertinib treatment as second or third line or more (17.1 vs. 18.6 months, respectively). OS was 22.8 (95% CI 15.7–not reached) months from osimertinib initiation. The efficacy of osimertinib as second-line treatment or more in octogenarian pretreated patients with EGFR T790M-mutated advanced NSCLC in a real-life setting was similar to that in randomized controlled trials.

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.

Background The KEYNOTE‐024 trial demonstrated that pembrolizumab, a PD‐1 inhibitor, significantly improves progression‐free survival (PFS) and overall survival (OS) in selected patients with previously untreated advanced non–small cell lung cancer (NSCLC) with a PD‐L1 tumor proportion score (TPS) ≥50% and without EGFR/ALK aberrations. The main aim of this study was to report the efficacy and safety profile of pembrolizumab in real‐life conditions. Method This was a French retrospective multicenter longitudinal study of 108 consecutive patients with advanced NSCLC, a PD‐L1 TPS ≥50% and without EGFR/ALK aberrations who were treated by pembrolizumab, in first line. Patient data were obtained from medical files. Results The main characteristics of the cohort were: median age [range] 66.7 [37‐87] years, 64.8% male, 23.1% with a performance status (PS) of 2, and 88.9% current or former smokers. Eighty‐seven percent had stage IV NSCLC at diagnosis, 9.2% untreated brain metastases at inclusion,. With a median follow‐up of 8.2 months, the median PFS was 10.1 months (95% CI, 8.8‐11.4). The objective response rate was 57.3% (complete response 2.7%, partial response 54.6%). Disease control rate was 71.1%. At 6 months, the OS rate estimated was 86.2%. Treatment‐related adverse events (AE) of grade 3 occurred in 8% of patients. There were no grade 4 or 5 AEs. Conclusion In a real‐life cohort of advanced NSCLC patients (including PS 2 and untreated brain metastases), with PD‐L1 TPS ≥50%, pembrolizumab demonstrates similar PFS to the pivotal clinical trial., This retrospective multicenter longitudinal study was intended to report the efficacy and safety profile of pembrolizumab in real‐life conditions for the first‐line treatment of advanced squamous none small‐cell lung cancer. The median progression free survival was 10.1 months (95% CI, 8.8‐11.4) and the treatment‐related adverse events of grade 3 occurred in 8% of patients. This study demonstrates similar progression‐free survival to KEYNOTE‐024.

International audience

// Romain Corre 1,12 , Radj Gervais 2 , Florian Guisier 3 , Louis Tassy 4 , Florent Vinas 5 , Regine Lamy 6 , Gislaine Fraboulet 7 , Laurent Greillier 8 , Helene Doubre 9 , Renaud Descourt 10 , Christos Chouaid 5 and Jean-Bernard Auliac 11 1 Department of Pneumology, CHU Pontchaillou, Rennes, France 2 Pneumo-Oncology Department, Centre Francois Baclesse, Caen, France 3 Pneumology Department, CHU Hopitaux de Rouen-Charles Nicolle, Rouen, France 4 Oncology Department, Institut Paoli-Calmette, Marseille, France 5 Pneumology Department, CH Intercommunal de Creteil, Creteil, France 6 Oncology Department, CH Sud-Bretagne, Lorient, France 7 Pneumology Department, Hopital Rene-Dubos, Pontoise, France 8 Pneumo-Oncology Department, Hopital Sainte-Marguerite, Assistance Publique-Hopitaux de Marseille, Marseille, France 9 Pneumology Department, Hopital Foch, Suresnes, France 10 Cancerology Institute, CHU Brest, Brest, France 11 Pneumology Department, CH Francois Quesnay, Mantes La Jolie, France 12 UMR INSERM U1242-COSS, Rennes University, Rennes, France Correspondence to: Romain Corre, email: // Keywords : targeted therapies; tyrosine-kinase inhibitors; non-small cell lung cancer; EGFR; elderly; Gerotarget Received : September 22, 2017 Accepted : November 13, 2017 Published : January 02, 2018 Abstract Objective. To assess efficacy and tolerance of EGFR tyrosine-kinase inhibitors (TKIs) for advanced EGFR-mutated non-small cell lung cancer (NSCLC) in octogenarians. Patients and methods. Patients aged 80 years or older with EGFR-mutated NSCLC treated by EGFR TKI between January 2011 and March 2015 whatever the line of treatment were retrospectively selected. Results. 20 centers retrospectively included 114 patients (women, 77.2%; Caucasians, 98.3%; mean age, 83.9 years). A performance status of 0–1 or 2–3 at diagnosis was reported for 71.6% and 28.4% of patients, respectively. Overall, 95.6% of patients had adenocarcinomas and histological stage at diagnosis was stage IV for 79.8% of patients. EGFR mutations were identified mainly on exon 19 (46.5%) and exon 21 (40.4%). A geriatric assessment was performed in 35.1% of patients. TKI treatment was administered to 97.3% of patients as first or second line of treatment. Overall response rate and disease control rate were 63.3% (69/109) and 78.9% (86/109), respectively. Median progression-free survival was 11.9 months (95% confidence interval [CI], 8.6–14.7) and median overall survival was 20.9 months (95% CI, 14.3–27.1). After progression, 36/95 (37.9%) patients received a new line of chemotherapy. Main toxicities were cutaneous for 66.7% of patients (grade 3–4, 10%), diarrhea for 56.0% (grade 3–4, 15%; grade 5, 2%) and others for 25.7% (grade 3–4, 41%). Conclusions. Octogenarians with EGFR-mutated NSCLC treated by EGFR TKI had clinical outcomes and toxicity profile comparable to younger patients. Geriatric assessment appeared to be underused in this population.

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.

There is no recommended therapy for malignant pleural mesothelioma that has progressed after first-line pemetrexed and platinum-based chemotherapy. Disease control has been less than 30% in all previous studies of second-line drugs. Preliminary results have suggested that anti-programmed cell death 1 (PD-1) monoclonal antibody could be efficacious in these patients. We thus aimed to prospectively assess the anti-PD-1 monoclonal antibody alone or in combination with anti-cytotoxic T-lymphocyte protein 4 (CTLA-4) antibody in patients with malignant pleural mesothelioma.This multicentre randomised, non-comparative, open-label, phase 2 trial was done at 21 hospitals in France. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, histologically proven malignant pleural mesothelioma progressing after first-line or second-line pemetrexed and platinum-based treatments, measurable disease by CT, and life expectancy greater than 12 weeks. Patients were randomly allocated (1:1) to receive intravenous nivolumab (3 mg/kg bodyweight) every 2 weeks, or intravenous nivolumab (3 mg/kg every 2 weeks) plus intravenous ipilimumab (1 mg/kg every 6 weeks), given until progression or unacceptable toxicity. Central randomisation was stratified by histology (epithelioid vs non-epithelioid), treatment line (second line vs third line), and chemosensitivity to previous treatment (progression ≥3 months vs3 months after pemetrexed treatment) and used a minimisation method with a 0·8 random factor. The primary outcome was the proportion of patients who achieved 12-week disease control, assessed by masked independent central review; the primary endpoint would be met if disease control was achieved in at least 40% of patients. The primary endpoint was assessed in the first 108 eligible patients. Efficacy analyses were also done in the intention-to-treat population and safety analyses were done in all patients who received at least one dose of their assigned treatment. This trial is registered at ClinicalTrials.gov, number NCT02716272.Between March 24 and August 25, 2016, 125 eligible patients were recruited and assigned to either nivolumab (n=63) or nivolumab plus ipilimumab (n=62). In the first 108 eligible patients, 12-week disease control was achieved by 24 (44%; 95% CI 31-58) of 54 patients in the nivolumab group and 27 (50%; 37-63) of 54 patients in the nivolumab plus ipilimumab group. In the intention-to-treat population, 12-week disease control was achieved by 25 (40%; 28-52) of 63 patients in the nivolumab group and 32 (52%; 39-64) of 62 patients in the combination group. Nine (14%) of 63 patients in the nivolumab group and 16 (26%) of 61 patients in the combination group had grade 3-4 toxicities. The most frequent grade 3 adverse events were asthenia (one [2%] in the nivolumab group vs three [5%] in the combination group), asymptomatic increase in aspartate aminotransferase or alanine aminotransferase (none vs four [7%] of each), and asymptomatic lipase increase (two [3%] vs one [2%]). No patients had toxicities leading to death in the nivolumab group, whereas three (5%) of 62 in the combination group did (one fulminant hepatitis, one encephalitis, and one acute kidney failure).Anti-PD-1 nivolumab monotherapy or nivolumab plus anti-CTLA-4 ipilimumab combination therapy both showed promising activity in relapsed patients with malignant pleural mesothelioma, without unexpected toxicity. These regimens require confirmation in larger clinical trials.French Cooperative Thoracic Intergroup.

Background: In the phase I I I CheckMate 227 s tudy, fi r s t - l ine nivolumab þ ipilimumab significantly prolonged progression-free survival (co-primary endpoint) versus chemotherapy in patients with advanced nonesmall-cell lung cancer (NSCLC) and high tumour mutational burden (TMB; 10 mutations/megabase). Aim: To evaluate patient-reported outcomes (PROs) in this population. Methods: Disease-related symptoms and general health status were assessed using the validated PRO questionnaires Lung Cancer Symptom Scale (LCSS) and EQ-5D, respectively. LCSS average symptom burden index (ASBI) and three-item global index (3-IGI) and EQ- 5D visual analogue scale (VAS) and utility index (UI) scores and changes from baseline were analysed descriptively. Longitudinal changes were assessed by mixed-effect model repeated measures (MMRMs) and time to first deterioration/improvement analyses. Results: In the high TMB population, PRO questionnaire completion rates were w90% at baseline and >80% for most on-treatment assessments. During treatment, mean changes from baseline with nivolumab þ ipilimumab showed early, clinically meaningful improvements in LCSS ASBI/3-IGI and EQ-5D VAS/UI; with chemotherapy, symptoms and health-related quality of life remained stable (LCSS ASBI/3-IGI, EQ-5D UI) or improved following induction (EQ-5D VAS). MMRM-assessed changes in symptom burden were improved with nivolumab þ ipilimumab versus chemotherapy. Symptom deterioration by week 12 was lower with nivolumab þ ipilimumab versus chemotherapy (22.3% versus 35.0%; absolute risk reduction: 12.7% [95% confidence interval 2.4e22.5]), irrespective of discontinuation. Time to first deterioration was delayed with nivolumab þ ipilimumab versus chemotherapy across LCSS and EQ-5D summary measures. Conclusion: First-line nivolumab þ ipilimumab demonstrated early, sustained improvements in PROs versus chemotherapy in patients with advanced NSCLC and high TMB, This work was supported by Bristol-Myers Squibb and Ono Pharmaceutical

Summary Background Malignant pleural mesothelioma is an aggressive cancer with poor prognosis, linked to occupational asbestos exposure. Vascular endothelial growth factor is a key mitogen for malignant pleural mesothelioma cells, therefore targeting of vascular endothelial growth factor might prove effective. We aimed to assess the effect on survival of bevacizumab when added to the present standard of care, cisplatin plus pemetrexed, as first-line treatment of advanced malignant pleural mesothelioma. Methods In this randomised, controlled, open-label, phase 3 trial, we recruited patients aged 18–75 years with unresectable malignant pleural mesothelioma who had not received previous chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0–2, had no substantial cardiovascular comorbidity, were not amenable to curative surgery, had at least one evaluable (pleural effusion) or measurable (pleural tumour solid thickening) lesion with CT, and a life expectancy of >12 weeks from 73 hospitals in France. Exclusion criteria were presence of central nervous system metastases, use of antiaggregant treatments (aspirin ≥325 mg per day, clopidogrel, ticlopidine, or dipyridamole), anti-vitamin K drugs at a curative dose, treatment with low-molecular-weight heparin at a curative dose, and treatment with non-steroidal anti-inflammatory drugs. We randomly allocated patients (1:1; minimisation method used [random factor of 0·8]; patients stratified by histology [epithelioid vs sarcomatoid or mixed histology subtypes], performance status score [0–1 vs 2], study centre, or smoking status [never smokers vs smokers]) to receive intravenously 500 mg/m 2 pemetrexed plus 75 mg/m 2 cisplatin with (PCB) or without (PC) 15 mg/kg bevacizumab in 21 day cycles for up to six cycles, until progression or toxic effects. The primary outcome was overall survival (OS) in the intention-to treat population. Treatment was open label. This IFCT-GFPC-0701 trial is registered with ClinicalTrials.gov, number NCT00651456. Findings From Feb 13, 2008, to Jan 5, 2014, we randomly assigned 448 patients to treatment (223 [50%] to PCB and 225 [50%] to PC). OS was significantly longer with PCB (median 18·8 months [95% CI 15·9–22·6]) than with PC (16·1 months [14·0–17·9]; hazard ratio 0·77 [0·62–0·95]; p=0·0167). Overall, 158 (71%) of 222 patients given PCB and 139 (62%) of 224 patients given PC had grade 3–4 adverse events. We noted more grade 3 or higher hypertension (51 [23%] of 222 vs 0) and thrombotic events (13 [6%] of 222 vs 2 [1%] of 224) with PCB than with PC. Interpretation Addition of bevacizumab to pemetrexed plus cisplatin significantly improved OS in malignant pleural mesothelioma at the cost of expected manageable toxic effects, therefore it should be considered as a suitable treatment for the disease. Funding Intergroupe Francophone de Cancerologie Thoracique (IFCT).

Background Anti-PD1 immunotherapy has emerged as a gold-standard treatment in stage IV non-small cell lung cancer (NSCLC). Despite long-term disease control in 5-20% of patients, secondary resistance often occurs. Local ablative treatment (LAT) and treatment beyond progression for oligo-progressive disease may improve long-term outcomes in stage IV non-small cell lung cancer after tumor response to anti-PD1 treatment. Methods In this retrospective multicentric cohort study, stage IV NSCLC patients treated with LAT for oligo-progression after initial tumor response to anti-PD1 were identified using electronic medical records from 3 centers. Here are reported clinical characteristics and outcomes of 27 patients. Quantitative data were summarized as median. Survival was estimated using Kaplan-Meier method. Results Twenty-seven patients received 31 LAT with surgery (n = 3, 10%), stereotactic radiotherapy (n = 18, 58%) or conformational radiotherapy (n = 10, 32%) after nivolumab (n = 19, 70%) or pembrolizumab (n = 8, 30%) treatment. Patients received anti-PD1 treatment in first (n = 3, 11%), second (n = 18, 67%) or third-line (n = 6,22 %) for stage IV NSCLC (adenocarcinoma/ squamous/not-otherwise specified: 18/8/1; PDL1 not evaluated/negative/1-49/>50: 10/8/1/6). Oligo-progression site was: brain (n = 19, 61%), lung (n = 5, 16%), adrenal gland (n = 2, 6%) and bone (n = 4, 13%). Anti-PD1 treatment was continued beyond progression after LAT in 22 (81%) patients. Oligo-progression occurred 6.9 months after anti-PD1 initiation. Progression Free Survival (PFS) after oligo-progression was 13.1 months (IC95: 7.0-not reached). Nine (33%) patients experienced ≥1 grade ≥2 immune adverse event before LAT. One patient had grade 3 toxicity after LAT (cerebral radionecrosis). Overall survival was not mature after a median follow-up of 9.1 months from LAT. Data will be updated before presentation and subgroup analysis will be presented. Conclusions LAT and treatment beyond progression for oligo-progression after initial tumor response to anti-PD1 treatment provide encouraging survival outcomes in selected stage IV NSCLC patients. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure F. Guisier: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (institution), Advisory / Consultancy: MSD / Merck US; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (institution): Boehringer Ingelheim. R. Gervais: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. M. Geier: Honoraria (self): BMS; Honoraria (self): MSD / Merck US. R. Corre: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: MSD / Merck US. R. Descourt: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Roche. C. Chouaid: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD / Merck US; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca. All other authors have declared no conflicts of interest.

Retrospective studies suggested a benefit of first-line tyrosine kinase inhibitor (TKI) treatment continuation after response evaluation in solid tumors (RECIST) progression in epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) patients. The aim of this multicenter observational retrospective study was to assess the frequency of this practice and its impact on overall survival (OS). The analysis included advanced EGFR-mutated NSCLC patients treated with first-line TKI who experienced RECIST progression between June 2010 and July 2012. Among the 123 patients included (67 ± 12.7 years, women: 69 %, non smokers: 68 %, PS 0-1: 87 %), 40.6 % continued TKI therapy after RECIST progression. There was no difference between the patients who did and did not continue TKI therapy with respect to progression-free survival (PFS1: 10.5 versus 9.5 months, p = 0.4). Overall survival (OS) showed a non-significant trend in favor of continuing TKI therapy (33.0 vs. 21.2 months, p = 0.054). Progressions were significantly less symptomatic in the TKI continuation group than in the discontinuation group (18 % vs. 37 %, p 0.01). Univariate analysis showed a higher risk of death among patients with PS1 (HR 4.33, 95 %CI: 2.21-8.47, p = 0.001),1 one metastatic site (HR 1.96, 95 %CI: 1.06-3.61, p = 0.02), brain metastasis (HR 1.75, 95 %CI: 1.08-2.84, p = 0.02) at diagnosis, and a trend towards a higher risk of death in cases of TKI discontinuation after progression (HR 1.62, 95 %CI: 0.98-2.67, p = 0.056 ). In multivariate analysis only PS1 (HR 6.27, 95 %CI: 2.97-13.25, p = 0.00001) and1 metastatic site (HR 2.54, 95 %CI: 1.24-5.21, p = 0.02) at diagnosis remained significant. This study suggests that under certain circumstances, first-line TKI treatment continuation after RECIST progression is an acceptable option in EGFR-mutated NSCLC patients.NCT02293733.

International audience; Letter to the Editor

Objectives: The aim of this study was to describe the demographic and clinico-pathological characteristics of lung cancer in patients younger than 40 years. Materials and Methods: This was a prospective study performed within the Groupe Français de Pneumo-Cancérologie. Consecutive patients diagnosed with lung cancer before the age of 40 years were eligible. Data on demographics, medical history, clinico-pathological characteristics, treatment and overall survival were analysed. Results: In total, 146 patients were included from January 2011 to December 2013. Median age was 38 years (IQR: 34–40). Women accounted for 41%. Main histological type was adenocarcinoma (77%). Only 3% had a prior history of cancer, but a family history (first- or second-degree relatives) of cancer was reported in 80 (55%) patients; 85 and 50% were current or past smokers of tobacco and cannabis, respectively; 82% had stage IIIB/IV at diagnosis. Median overall survival was 15.3 (95% CI: 8.1–24.0) months in the whole population, 10.3 (95% CI: 12.5–14.2) months in stage IV and 15 (95% CI: 8.7–35.2) months in stage III. One- and two-year overall survival rates were 57% (95 CI: 49–65) and 31.5% (95 CI: 27–43), respectively. Compared to smokers, non-smokers were significantly younger and more often females. Median overall survival was not statistically different between smokers and non-smokers.

Background: The prognostic role of a comprehensive geriatric assessment (CGA) on the management of elderly patients with advanced-stage non-small cell lung cancer (NSCLC) remains to be established. The objective of this analysis was to determine the prognostic role of each CGA domain on overall survival (OS) among elderly patients with advanced-stage NSCLC. Methods: We pooled individual data from two prospective, randomized phases II trials in patients over 65 years old with advanced-stage NSCLC, who were considered fit (0405 trial) or no-fit (0505 trial) based on a CGA. Both trials compared first-line chemotherapy followed by second-line erlotinib with the reverse strategy in terms of progression-free survival (PFS) and OS. Factors prognostic of OS were sought by using the Kaplan-Meier method and the log rank test for univariate analysis, and a Cox model for multivariate analysis. Results: Analysis performed on 194 patients (mean age: 77 years, male gender: 70%, never- or ex-smokers: 56%) showed, in univariate analysis that performance status (PS), smoking status, Charlson, simplified Charlson, nutritional scores, and a mobility score were prognostics of OS. In multivariate analysis, PS [HR: 1.4 (1.02–1.9), P=0.04] and the Charlson score [HR: 1.46 (1.07–1.99), P=0.02] were independently prognostic of OS, while the nutritional score [HR: 0.69 (0.46–1.04), P=0.07] and the mobility score [HR: 0.25 (0.06–1.01), P=0.06] were close to significance. Conclusions: PS and comorbidities appear to be the main predictors of OS in elderly advanced NSCLC patients selected on the basis of CGA.

LBA8507 Background: To date, no treatment is recommended in MPM pts progressing after 1st-line pemetrexed-platinum doublet. Disease control rate (DCR) is nd-line setting. Preliminary results suggested possible activity of anti-PD-1 mAb in 2nd/3rd-line, opposed to single agent anti-CTLA-4 mAb. Therefore anti-PD1 mAb efficacy deserves confirmation, and anti-PD-1 + anti-CTLA-4 combination value is currently unknown in MPM. Methods: In this multicenter randomized non comparative phase 2 trial, eligible pts had age>18, PS 0-1, histologically proven MPM relapsing after 1 or 2 prior lines including pemetrexed/platinum doublet, measurable disease. Randomized pts (1:1) received Nivo 3 mg/kg q2w, or Nivo 3 mg/kg q2w + Ipi 1 mg/kg q6w, until progression or unacceptable toxicity. Primary endpoint was DCR at 12 weeks with a blinded independent central review (BICR). 114 patients were to be randomized (with 108 eligible), with one-step Fleming procedure, H0 P40%, with 95% power, 5% one-sided a-risk: ≥17 failure-free pts had to be observed at 12 weeks in either arm, to conclude to the activity of the corresponding regimen. Results: From March to August 2016, 125 pts were enrolled in 21 centers. Males: 80%, median age: 71.8 years (range 32.5-88.1), PS 1: 62.4%, epithelioid 83.2%, 1 previous line: 69.6%; 70% of pts received ≥ 3 cycles of either treatment. Twelve weeks-DCR assessed by BICR in the first 108 eligible pts was 42.6% [IC95%: 29.4-55.8%] with Nivo (n=23/54), and 51.9% [38.5-65.2%] with Nivo+Ipi (n=28/54). ORR was 16.7% [6.7%-26.6%] with Nivo (n=9/54), and 25.9% [14.2-37.6%] with Nivo+Ipi (n=14/54). All grade/G3-4 toxicities were slightly increased in the combo arm (86.9%/16.4%) vs Nivo alone (77.8%/9.5%); 3 treatment-related deaths were observed in the combo arm (1 metabolic encephalopathy, 1 fulminant hepatitis, 1 acute renal failure). Full QoL, PFS and OS data will be presented at 2017 ASCO meeting. Conclusions: Both Nivo and Nivo+Ipi arms reached their endpoint in 2nd/3rd-line MPM pts, suggesting that immunotherapy may provide new options for these pts. Clinical trial information: NCT02716272.

Purpose Surgical resection plus adjuvant platinum-based chemotherapy is considered standard care for stage II to III non–small-cell lung cancer (NSCLC), but its efficacy is limited, and it involves toxic risks, justifying patient-tailored treatment. Excision repair cross-complementation group 1 (ERCC1) was shown to predict cisplatin-based chemotherapy response; EGFR mutations were predictive of epidermal growth factor receptor inhibition response. Patients and Methods This prospective randomized phase II trial enrolled 150 patients with completely resected non–squamous cell stage II or IIIA (non-N2) tumors. Patients in the control arm (n = 74) were treated with four standard-dose courses of cisplatin plus pemetrexed (CP). In the customized treatment arm (n = 76), patients with activated EGFR mutations received erlotinib 150 mg for 1 year; ERCC1-negative patients received four CP courses, whereas ERCC1-positive patients underwent follow-up. The trial sought to demonstrate the feasibility of customized adjuvant chemotherapy based on timely biomarker analysis within a 2-month postsurgery delay. Secondary objectives were tolerability, compliance with adjuvant therapy, and biomarker distribution. Results In arm A, all patients received CP; in arm B, seven received erlotinib, 53 were administered CP, and 16 underwent follow-up. Median erlotinib exposure was 344 days. Of the 127 patients allocated to CP, 82% received four cycles with good tolerability. The overall success rate of the trial (ie, percentage of patients with complete biomarker status able to start adjuvant treatment within 2 months of surgery) was 80%. Conclusion The primary end point of the trial was met, demonstrating the feasibility of a national biology-driven trial in the adjuvant NSCLC setting. Nevertheless, the phase III part was canceled because of the unreliability of the ERCC1 immunohistochemical readouts.

International audience; Introduction: Anaplastic lymphoma kinase (ALK) rearrangements occur in 1% to 7% of non-small-cell lung cancers (NSCLCs). Crizotinib, an ALK inhibitor, has been demonstrated to provide dramatic clinical benefits in ALK-positive advanced-stage NSCLC. Fluorescent in situ hybridization (FISH) has been established in clinical trials as the standard procedure method for detecting ALK rearrangements. Although the detection of ALK by immunohistochemistry (IHC) has been proposed for the screening of patients, large-scale studies are warranted to validate such a hierarchical approach. Methods: In this article, we report the largest series thus far of parallel FISH and IHC ALK testing in 3244 consecutive NSCLC cases analyzed at two independent French centers. Results: FISH-positive and/or IHC-positive results were demonstrated in 150 of 3244 cases (4.6%). An imbalanced sex ratio was detected, with women exhibiting a 2.2-fold relative risk for an alteration. Strikingly, only 80 of 150 specimens were classified as ALK positive by both techniques. The specimens with discordant FISH/IHC analyses were FISH-positive/IHC-negative (36), FISH-negative/IHC-positive (19), or FISH-noncontributive/IHC-positive (15). Thus, a single FISH or IHC analysis performed alone would have failed to detect approximately one-fourth of the ALK-positive cases with similar findings in our two centers. Conclusions: This study highlights the feasibility of systematic NSCLC testing by both FISH and IHC in routine practice. Many preanalytical factors may account for the apparent discrepancies between both methods, suggesting that hierarchical screening may underscore ALK-positive cases. This significant level of discrepancy supports the need of combined testing to optimize the detection of ALK-inhibitor-eligible patients given that some patients with discordant testing were found to respond to crizotinib.

Background Pembrolizumab significantly improves progression-free survival (PFS) (median 10.3 months) and overall survival (OS) (median 30.0 months) in selected patients with previously untreated advanced non–small-cell lung cancer (NSCLC) with a PD-L1 tumor proportion score (TPS) ≥ 50% and without EGFR/ALK aberrations. Data in real life conditions are missing. Methods This was a cross-sectional, retrospective study of untreated advanced NSCLC patients with TPS ≥ 50% and without EGFR/ALK aberrations, from 9 French hospitals in Brittany area. The study included 115 patients and analysis focused on 108 patients. At index, the main characteristics of our cohort were: median age [range] 66.7 [37 to 87] years, 71 % male, 23.1 % performans status (P.S) 2, 88.8 % current or former smokers. 87.1 % had Stage IV at diagnosis and 9.2 % had untreated brain metastasis. 23.4% had mutations (KRAS, MET, BRAF and ROS 1). We used Kaplan-Meier analysis for PFS and described tolerability. Results With a median follow-up of 7.1 months, median PFS was 10.1 months (95% confidence interval [CI], 8.8 to 11.4), (range, and 0.6 to 18.5 months). The objective response rate was 58,2% (complete response: 2.7 % and partial response: 55.5 %). Disease control rate was 72.1%. The estimated rate of OS at 6 months was 86.6 %. Treatment-related adverse events of grade 3 (AE) occurred in 7.4% of patients. There was no grade 4 or 5 AE and mean time between first administration of pembrolizumab and clinico-biological AE was 13.9 (± 9.7) weeks. Our data are immature to appreciate OS. Conclusions In a real life cohort of patients (PS 2, untreated brain metastasis), with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, pembrolizumab demonstrates similar PFS with KEYNOTE-024 phase III trial. Legal entity responsible for the study Renaud Descourt. Funding Association Bretonne de Cancerologie Thoracique (ABCT). Disclosure R. Corre: Travel / Accommodation / Expenses, Officer / Board of Directors: bms. G. Robinet: Advisory / Consultancy: MSD; Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): BMS; Research grant / Funding (institution): Roche. R. Descourt: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: takeda; Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy: Novartis; Advisory / Consultancy: BMS; Travel / Accommodation / Expenses: Pfizer. All other authors have declared no conflicts of interest. Linguistic correction

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.

Background The phase IIR trial IFCT-1501 (MAPS2) tested nivo or nivo+ipi in pts with relapsed MPM as second/third-line. This trial reached its primary endpoint with 40% or more of pts with disease control in both arms. We now focus on long-term survivals and specific patterns of progression. Methods 125 pts were randomized to receive Nivo 3 mg/kg q2w or Nivo 3 mg/kg q2w+Ipi 1mg/kg q6w, until progr or unacceptable toxicity. Median follow-up for OS is 32.5 months (Mar. 1st2019). HPD was defined by calculating the tumor growth rate before and during i.o. with determining the variation per month (ΔTGR) (Ferrara, JAMA Oncol 2018) or by measuring the tumor growth kinetics (TGK)on i.o. and on last treatment before, with TGK ratio (TGKr) calculation (Saâda-Bouzid, Ann. Oncol. 2017). HPD was defined as disease progression (assessed by BICR) with ΔTGR exceeding 50% or with a TGKr>2. Results Median OS was 11·9 mo. (6·7–17·4) in the nivo arm and 15·9 mo. (10·7–22.2) in the nivo+ipilimumab arm. 52 (82%) /63 pts in the nivo group and 49 (79%)/62 patients in the combo group had died by data cutoff. 1 & 2-year survivals were 49·2% (36·4–60·8) & 25·4% (15·5–36·6) in the nivo arm, and 58·1% (44·8–69·2) & 31·7% (20·5–43·4) in the Nivo +Ipi arm. With ΔTGR method, 4 and 2 patients in Nivo and combo group had HPD respectively, while 7 and 4 patients had HPD by using TGKr. HPD pts with TGKr had a poorer OS than pts with standard progression only in the nivolumab arm (median OS = 1.6 mo [0.8-7.7] vs. 4.4 mo [2.4-10.8], (p = 0.02 in Cox model), while no difference was seen with ΔTGR definition.When both arms were analyzed together, only HPD pts defined with the TGKr had significantly worse survival: HR (progressive pts vs HPD): 0.37 [0.19-0.75], p = 0.006, with HR (pts with DCR vs. HPD)= 0.12 [0.06-0.25], p Conclusions The durable efficacy of Nivo & Nivo+Ipi in MPM in confirmed, with 1/4 and 1/3 of pts alive at 2 yrs respectively. HPD pattern of progression did exist in both arms, associated with significantly worse survival when the TGKr definition of HPD is used. Clinical trial identification NCT02716272. Legal entity responsible for the study IFCT: French Cooperative Thoracic Intergroup. Funding BMS. Disclosure G. Zalcman: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (self): BMS; Honoraria (self), Honoraria (institution), Research grant / Funding (self), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Inventiva; Honoraria (self), Advisory / Consultancy: Merck (MSD); Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche-France; Travel / Accommodation / Expenses: AbbVie. J. Mazieres: Honoraria (institution), Research grant / Funding (self): Roche-France; Honoraria (institution): BMS; Honoraria (institution), Research grant / Funding (self): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. L. Greillier: Honoraria (self), Non-remunerated activity/ies: Roche; Honoraria (self), Non-remunerated activity/ies: Novartis; Honoraria (self), Non-remunerated activity/ies: Lilly; Honoraria (self), Non-remunerated activity/ies: Pfizer; Honoraria (self), Non-remunerated activity/ies: BMS; Honoraria (self), Non-remunerated activity/ies: Boerhinger-Ingelheim; Honoraria (self), Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Non-remunerated activity/ies: AbbVie; Honoraria (self), Non-remunerated activity/ies: MSD. S. Lantuejoul: Honoraria (self), Non-remunerated activity/ies: MSD; Honoraria (self), Non-remunerated activity/ies: Roche-Diagnostics; Honoraria (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Non-remunerated activity/ies: BMS. O. Bylicki: Honoraria (self), Non-remunerated activity/ies: MSD; Non-remunerated activity/ies: Roche. I. Monnet: Travel / Accommodation / Expenses: BMS. R. Corre: Advisory / Consultancy: Roche; Advisory / Consultancy: BMS. C. Audigier-Valette: Honoraria (self): Roche; Honoraria (self): Pfizer; Honoraria (self): Boerhinger-Ingelheim; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): Lilly; Honoraria (self): Amgen; Honoraria (self): BMS; Honoraria (self): Sysmex; Honoraria (self): MSD; Honoraria (self): Clovis Oncology; Honoraria (self): AbbVie. O. Molinier: Honoraria (self): BMS. F. Guisier: Honoraria (self), Non-remunerated activity/ies: 3MS; Honoraria (self): MSD US; Honoraria (self): AstraZeneca; Honoraria (self): Roche; Honoraria (self), Research grant / Funding (self): Boerhinger-Ingeheim; Non-remunerated activity/ies: Chugai. D. Planchard: Honoraria (self): AstraZeneca; Honoraria (self): Boerhinger Ingelheim; Honoraria (self): BMS; Honoraria (self): Celgene; Honoraria (self): Novartis; Honoraria (self): MSD; Honoraria (self): Pfizer; Honoraria (self): Roche. E. Amour: Full / Part-time employment: IFCT. F. Morin: Full / Part-time employment: IFCT. D. Moro-Sibilot: Honoraria (self), Non-remunerated activity/ies: BMS; Honoraria (self): Roche; Honoraria (self): MSD; Honoraria (self): Lilly; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): AstraZeneca; Honoraria (self): Boerhinger Ingelheim; Honoraria (self): Takeda; Honoraria (self): Leurquin Mediolanum. A. Scherpereel: Honoraria (self): BMS; Honoraria (self): Roche; Honoraria (self): MSD; Honoraria (self): Boerhinger Ingelheim. All other authors have declared no conflicts of interest.

Purpose Comprehensive geriatric assessment (CGA) is recommended to assess the vulnerability of elderly patients, but its integration in cancer treatment decision making has never been prospectively evaluated. Here, in elderly patients with advanced non-small-cell lung cancer (NSCLC), we compared a standard strategy of chemotherapy allocation on the basis of performance status (PS) and age with an experimental strategy on the basis of CGA. Patients and Methods In a multicenter, open-label, phase III trial, elderly patients >= 70 years old with a PS of 0 to 2 and stage IV NSCLC were randomly assigned between chemotherapy allocation on the basis of PS and age (standard arm: carboplatin-based doublet if PS

This randomized, open-label, parallel-group, phase II study evaluated the efficacy and safety of gefitinib and docetaxel in combination, as second-line therapy for advanced or metastatic non-small cell lung cancer (NSCLC). Eighty-nine patients who had failed first-line, platinum-based chemotherapy were randomly assigned to gefitinib (250 mg/day orally) in combination with docetaxel (75 mg/m2 every 3 weeks) or single-agent docetaxel (75 mg/m2 every 3 weeks). Objective response rates were 6.8% with gefitinib plus docetaxel and 9.1% with docetaxel alone. Disease control was experienced by a higher proportion of patients receiving gefitinib plus docetaxel (59.1%) versus docetaxel alone (34.1%). Median progression-free and overall survival appeared to be longer with gefitinib plus docetaxel (3.9 months [95% CI:2.3–5.4] and 7.6 months [95% CI:5.4–10.4], respectively) than with docetaxel alone (2.1 months [95% CI:2.1–3.7] and 6.2 months [95% CI:5.2–7.2], respectively). The most common non-hematological adverse events were diarrhea, alopecia, rash and dry skin in the combination arm, and vomiting and asthenia with docetaxel alone. Gefitinib and docetaxel combination therapy has antitumor activity and may be a feasible treatment option in patients with advanced NSCLC who have failed platinum-based chemotherapy.

Importance The EURTAC trial demonstrated the greater efficacy of erlotinib compared with chemotherapy for the first-line treatment of European patients with advanced non–small-cell lung cancer (NSCLC) harboring oncogenic epidermal growth factor receptor ( EGFR ) mutations (exon 19 deletion or L858R mutation in exon 21) in tumor tissue. Objective To assess the feasibility of using circulating free DNA (cfDNA) from blood samples as a surrogate for tumor biopsy for determining EGFR mutation status and to correlate EGFR mutations in cfDNA with outcome. Design, Setting, and Participants This prespecified analysis was a secondary objective of the EURTAC trial using patients included in the EURTAC trial from 2007 to 2011 with available baseline serum or plasma samples. Patients had advanced NSCLC, oncogenic EGFR mutations in the tumor, and no prior chemotherapy for metastatic disease and were treated with erlotinib or chemotherapy. EGFR mutations were examined in cfDNA isolated from 97 baseline blood samples by our novel peptide nucleic acid–mediated 5´ nuclease real-time polymerase chain reaction (TaqMan) assay. Main Outcomes and Measures Overall survival (OS), progression-free survival (PFS), and response to therapy were correlated with type of EGFR mutations in cfDNA. Results In samples from 76 of 97 (78%) patients with usable blood samples, EGFR mutations in cfDNA were detected. Median OS was shorter in patients with the L858R mutation in cfDNA than in those with the exon 19 deletion (13.7 [95% CI, 7.1-17.7] vs 30.0 [95% CI, 19.3-37.7] months; P EGFR mutations in cfDNA identified the L858R mutation in tumor tissue or in cfDNA as a marker of shorter OS (hazard ratio [HR], 2.70 [95% CI, 1.60-4.56]; P P = .008). For patients with the L858R mutation in tissue, median OS was 13.7 (95% CI, 7.1-17.7) months for patients with the L858R mutation in cfDNA and 27.7 (95% CI, 16.1-46.2) months for those in whom the mutation was not detected in cfDNA (HR, 2.22 [95% CI, 1.09-4.52]; P = .03). In the multivariate analysis of the 76 patients with EGFR mutations in cfDNA, only erlotinib treatment remained an independent predictor of longer PFS (HR, 0.41 [95% CI, 0.23-0.74]; P = .003). Conclusions and Relevance The peptide nucleic acid–mediated 5´ nuclease real-time polymerase chain reaction (TaqMan) assay used in this study can be used to efficiently assess EGFR mutations in cfDNA. The L858R mutation in cfDNA may be a novel surrogate prognostic marker. Trial Registration clinicaltrials.gov Identifier:NCT00446225

International audience; Hereditary hemorrhagic telangiectasia (HHT), a genetic vascular disorder associated with epistaxis and hepatic shunts, is responsible for high-output cardiac failure in rare cases. Bevacizumab, which targets vascular endothelial growth factor, was shown to decrease both cardiac index (CI) and epistaxis duration in HHT patients with severe liver involvement. The relationship between its serum concentration and change in both CI and epistaxis duration was investigated to design the bevacizumab maintenance dosing regimen of future therapeutic studies. Twenty-five HHT patients with dyspnea and high CI were included in a prospective non-comparative study. They received bevacizumab at a dose of 5 mg/kg per infusion every 14 days for a total of 6 injections. The relationships between bevacizumab serum concentration and both CI and epistaxis duration were described using transit compartments and direct inhibition pharmacokinetic-pharmacodynamic models. The performances of different maintenance regimens were evaluated using simulation. Infusions every 3, 2 and one months were predicted to maintain 41%, 45% and 50% of patients with CI

Context The only treatment available to restore normal cardiac output in patients with hereditary hemorrhagic telangiectasia (HHT) and cardiac failure is liver transplant. Anti–vascular endothelial growth factor treatments such as bevacizumab may be an effective treatment. Objectives To test the efficacy of bevacizumab in reducing high cardiac output in severe hepatic forms of HHT and to assess improvement in epistaxis duration and quality of life. Design, Setting, and Patients Single-center, phase 2 trial with national recruitment from the French HHT Network. Patients were 18 to 70 years old and had confirmed HHT, severe liver involvement, and a high cardiac index related to HHT. Intervention Bevacizumab, 5 mg per kg, every 14 days for a total of 6 injections. The total duration of the treatment was 2.5 months; patients were followed up for 6 months after the beginning of the treatment. Main Outcome Measure Decrease in cardiac output at 3 months after the first injection, evaluated by echocardiography. Results A total of 25 patients were included between March 2009 and November 2010. Of the 24 patients who had echocardiograms available for reread, there was a response in 20 of 24 patients with normalization of cardiac index (complete response [CR]) in 3 of 24, partial response (PR) in 17 of 24, and no response in 4 cases. Median cardiac index at beginning of the treatment was 5.05 L/min/m 2 (range, 4.1-6.2) and significantly decreased at 3 months after the beginning of the treatment with a median cardiac index of 4.2 L/min/m 2 (range, 2.9-5.2; P 2 ; range, 3.0-5.1). Among 23 patients with available data at 6 months, we observed CR in 5 cases, PR in 15 cases, and no response in 3 cases. Mean duration of epistaxis, which was 221 minutes per month (range, 0-947) at inclusion, had significantly decreased at 3 months (134 minutes; range, 0-656) and 6 months (43 minutes; range, 0-310) (P = .008). Quality of life had significantly improved. The most severe adverse events were 2 cases of grade 3 systemic hypertension, which were successfully treated. Conclusion In this preliminary study of patients with HHT associated with severe hepatic vascular malformations and high cardiac output, administration of bevacizumab was associated with a decrease in cardiac output and reduced duration and number of episodes of epistaxis. Trial Registration clinicaltrials.gov Identifier: NCT00843440

Background A large proportion of elderly patients (>70 years) with newly diagnosed NSCLC are shown to be frail by a comprehensive geriatric assessment. This population is more vulnerable to adverse effects of chemotherapy and might thus benefit more from targeted therapy. The objective of this study was to assess the cost-effectiveness of erlotinib followed by chemotherapy after progression, compared with the reverse strategy, in frail elderly patients with advanced NSCLC participating in a prospective randomized phase II trial (GFPC 0505). Materials and Methods Outcomes (progression-free survival and overall survival) and costs (limited to direct medical costs, from the third-party payer perspective) were collected prospectively until second progression. Costs after progression and health utilities (based on disease states and grade 3-4 toxicities) were derived from the literature. Results Median overall survival, QALYs, and total costs for the erlotinib-first strategy were 3.9 months, 0.33, and €15,233, respectively, compared with 4.4 months, 0.35, and €15,363 for the chemotherapy-first strategy. There was no significant difference between the 2 strategies in term of cost-effectiveness (respectively €47,381 and €44,350 per QALY). Conclusion No difference in cost-effectiveness was found between an erlotinib-first strategy and a chemotherapy-first strategy in frail elderly patients with NSCLC.

International audience; BACKGROUND: There is no consensus on the optimal treatment for patients with advanced non-small cell lung cancer and stable disease after cisplatin-based chemotherapy. The objective of the trial was to evaluate a switch to a different dual-agent chemotherapy. METHODS: Patients with stage IV non-small cell lung cancer and stable disease after two cycles of cisplatin (P) and gemcitabine (G) (P day1 (d(1)): 75 mg/m(2), G: 1250 mg/m(2) d(1) and d(8) every 3 weeks) were randomized to receive either two further cycles of PG (arm A) or paclitaxel (100 mg/m(2) d(1), d(8), d(15)) plus gemcitabine (1250 mg/m(2) d(1) and d(8), every 4 weeks) (arm B). RESULTS: Two-hundred-twenty-eight patients were enrolled between October 2003 and August 2006. After two cycles of PG, 98 patients (43%) had stable disease; 87 were randomized: 45 to arm A and 42 to arm B. The objective response rates were 15.6% (6.5-29.4) and 21.4% (10.3-36.8) in arms A and B. Overall survival after randomization was 9.6 months (7.0-13.8) in arm A and 9.3 months (7.4-13.3) in arm B. Adverse events were similar in the two arms for hematological and non hematological toxicities. CONCLUSIONS: Sequential first-line chemotherapy in these patients is feasible with no difference in response rates. These results do not warrant a phase III trial.

7500 Background: MPM median overall survival (OS) did not exceed 13 months with pemetrexed-platinum doublet, with virtually no surviving patients at 5 years. Vascular endothelial growth factor is a...

orrigendum to “Randomized open-label non-comparative ulticenter phase II trial of sequential erlotinib and docetaxel versus ocetaxel alone in patients with non-small-cell lung cancer after ailure of first-line chemotherapy: GFPC 10.02 study” Lung Cancer 85 (2014) 415–419] .B. Auliaca,∗, C. Chouaidb, L. Greillierc, I. Monnetd, H. Le Caere, L. Falcherof, R. Correg, . Descourth, S. Bota i, H. Berard j, R. Schottk, A. Bizieuxl, P. Fournelm, A. Labrunien, . Marinn, A. Vergnenegreo, the GFPC team

Aim: The use of a CGA is recommended to detect a patient's vulnerability but its integration in treatment decision making has never been prospectively evaluated. Our main objective was to test if the use of CGA in the allocation of treatment could improve the management of advanced NSCLC in first line. Methods: Randomized, multicentric, prospective phase III study in patients ≥70 y, PS 0-2 with stage IV NSCLC. Arm A standard algorithm of chemotherapy allocation: carboplatin based doublet in PS ≤ 1 and age ≤75y, docetaxel in PS =2 or age >75y. Arm B treatment allocation based on CGA: carboplatin based doublet for fit patients, mono-therapy for vulnerable patients and BSC for frail patients. Four cycles were given every three weeks. Main endpoint: time to failure free survival (TFFS) Secondary endpoints: overall Response Rate (ORR), overall survival (OS), toxicity, QoL and life expectancy adjusted on QoL. QoL was assessed during treatment by EQ-5D health questionnaire at baseline, weeks 6, 12, 20, 28, and 36. A mixed-effects model was used, to compare the utility score and therefore the QOL between arms A and B. Results: 493 patients were randomized from 01/2010 to 01/2013 by 45 centers. Respectively in arms A and B, 34.4% and 47% of patients received a carboplatin-based doublet, 65.6% and 31.4% received docetaxel and in arm B 21.5% received BSC. Median TFFS was 3.2 m, 95%CI:[2.9; 4.1] for standard arm and 3.1 m, 95%CI:[2.7; 4.4] for experimental arm, p = 0.71. Compliance with QoL was 87% at baseline and respectively 66%, 65%, 54%, 60% and 57% at week 6, 12, 20, 28 and 36. The utility score at each evaluation is superior in the experimental arm than in the standard arm, but this difference is significant only at week 36 (p = 0.02). Using a linear mixed generalized model, the utility score tends to decrease over time and is not significantly different between the two arms (p = 0.85). Life expectancy adjusted on QoL was 130.1 days in standard arm and 133.3 days in experimental arm, p = 0.51. Conclusions: ESOGIA did not show a superiority of a CGA-based treatment allocation. In the experimental arm, more patients received a carboplatin-based doublet and 21% of frail patients received an exclusive BSC management. Despite a trend in favor of CGA arm, there is no significant difference in terms of QoL score and life expectancy adjusted on QoL. Further sudies are needed for GA in NSCLC elderly patients. Disclosure: C. Chouaid: advisory board LILLY; H. Lena: advisory board Lilly. All other authors have declared no conflicts of interest.

Aim: Background: EGFR-TKI are a standard treatment for patients (pts) with NSCLC harboring activating EGFR mutations. All pts develop acquired resistance. At progression, the standard treatment is chemotherapy. Retrospective studies suggest that continuous use of EGFR-TKI beyond progressive disease (PD) may benefit some pts. Objective: The purpose of our retrospective multicentric study is to determine the frequency of continuation of EGFR-TKIs beyond RECIST-PD, and investigate the association of pts and disease characteristics with continuation of EGFR-TKIs at progression. Methods: Main inclusion criteria were: pts with NSCLC and activating EGFR mutations, EGFR-TKIs as their initial systemic therapy received between January 2010 and July 2012, Measurable lesion according to RECIST 1.1, acquired resistance to EGFR-TKI according to Jackman's criteria. Following data were collected: demographic and clinical data, Progression free survival (PFS), Overall Survival (OS), mutational status, mode of progression, therapeutic approach at PD. A comparison of clinical data and outcome of pts receiving EGFR-TKI beyond PD (group 1) versus discontinuing EGFR-TKI at PD (group 2) was made. Results: 133 pts were recruited in 29 centers: age 69 ± 12.7 years, female 67.6%, EGFR mutation exon 19/21/others: 65.4 %/ 30.8%/ 3.8%, adenocarcinoma 98%, never smokers 68.5%, PS 0/1: 80,5%. First line treatment: gefitinib 77.4%, erlotinib 21.8%. 40.6% pts continued EGFR-TKI beyond RECIST-PD (25,6% EGFR-TKI alone, 15% EGFR-TKI combined with local treatment). 59.3% pts changed treatment (39.8% chemotherapy, 7.5% combination chemotherapy +EGFR-TKI, 12% BSC). Median PFS was 9,4 (CI95% :8-10,9) months and median OS was 21,6 (CI95%18,7-25,8) months in the entire population. In group 1 and 2, m PFS was 10,1 (CI95% :7,7-12,3) and 8,7 (CI 95% :7,5-10,9) (p = 0,34) months and m OS was 23 and 20,4 months respectively (p = 0,08). All comparative data between groups 1 and 2, univariate and mutivariate analysis will be presented. Conclusions: This large retrospective study confirms that, in some circumstances, continuous use of EGFR-TKI beyond PD does not hamper OS and should be considered.Prospective studies will help to determine which patients benefit more this strategy. Clinical trial information: Supported by an academic grant from boehringer ingelheim, Hoffman Roche. Disclosure: J.B. Auliac: In the last five years, JB Auliac has received honoraria for attending scientific meetings, speaking, organizing research or consulting, from Boehringer Ingelheim, Hoffman-Roche, Lilly and Pfizer; C. Decroisette Phan van Ho: consultancy Hoffman roche; S. Bota Ouchlif: travel/accomodation meeting: Lilly; R. Corre: board membership: roche, lilly consultancy: roche, lilly travel/accommodations meeting: lilly, roche; P. Fournel: consultancy: roche, lilly, boehringer ingelheim; A. Vergnenegre: consultancy: roche grants/grants pending:roche, lilly, boehringer; L. Greillier: consultancy: roche, lilly grants/grants pending: roche travel/accommodation meeting: lilly, roche; R. Gervais: consultancy: Roche, Astra Zeneca et Boehringer ingelheim. All other authors have declared no conflicts of interest.