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Background: BRAF mutations occurring in 1%-5% of patients with non-small-cell lung cancer (NSCLC) are therapeutic targets for these cancers but the impact of the exact mutation on clinical activity is unclear. The French National Cancer Institute (INCA) launched the AcSé vemurafenib trial to assess the efficacy and safety of vemurafenib in cancers with various BRAF mutations. We herein report the results of the NSCLC cohort., Patients and Methods: Tumour samples were screened for BRAF mutations in INCA-certified molecular genetic centres. Patients with BRAF-mutated tumours progressing after ≥1 line of treatment were proposed vemurafenib 960 mg twice daily. Between October 2014 and July 2018, 118 patients were enrolled in the NSCLC cohort. The primary outcome was the objective response rate (ORR) assessed every 8 weeks (RECIST v1.1). A sequential Bayesian approach was planned with an inefficacy bound of 10% for ORR. If no early stopping occurred, the treatment was of interest if the estimated ORR was ≥30% with a 90% probability. Secondary outcomes were tolerance, response duration, progression-free survival (PFS), and overall survival (OS)., Results: Of the 118 patients enrolled, 101 presented with a BRAF V600 mutation and 17 with BRAF nonV600 mutations; the median follow-up was 23.9 months. In the BRAF nonV600 cohort, no objective response was observed and this cohort was stopped. In the BRAF V600 cohort, 43/96 patients had objective responses. The mean Bayesian estimated success rate was 44.9% [95% confidence intervals (CI) 35.2%-54.8%]. The ORR had a 99.9% probability of being ≥30%. Median response duration was 6.4 months, median PFS was 5.2 months (95% CI 3.8-6.8), and OS was 10 months (95% CI 6.8-15.7). The vemurafenib safety profile was consistent with previous publications., Conclusion: Routine biomarker screening of NSCLC should include BRAF V600 mutations. Vemurafenib monotherapy is effective for treating patients with BRAF V600 -mutated NSCLC but not those with BRAF nonV600 mutations., Trial Registration: ClinicalTrials.gov identifier: NCT02304809., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In 2013, the French National Cancer Institute initiated the AcSé program to provide patients with secure access to targeted therapies outside of their marketed approvals. Efficacy and safety was then assessed using a two-stage Simon phase II trial design. When the study design was designed, crizotinib was approved only as monotherapy for adults with anaplastic lymphoma kinase plus non-small-cell lung cancers (NSCLC)., Patients and Methods: Advanced NSCLC patients with c-MET ≥6 copies, c-MET-mutated, or ROS-1-translocated tumours were enrolled in one of the three cohorts. Patients were treated with crizotinib 250 mg twice daily. Efficacy was assessed using the objective response rate (ORR) after two cycles of crizotinib as primary outcome. Secondary outcomes included disease control rate at four cycles, best ORR, progression-free survival, overall survival, and drug tolerance., Results: From August 2013 to March 2018, 5606 patients had their tumour tested for crizotinib targeted molecular alterations: 252 patients had c-MET ≥6 copies, 74 c-MET-mutation, and 78 ROS-1-translocated tumour. Finally, 25 patients in the c-MET ≥6 copies cohort, 28 in the c-MET-mutation cohort, and 37 in the ROS-1-translocation cohort were treated in the phase II trial. The ORR was 16% in the c-MET ≥6 copies cohort, 10.7% in the mutated, and 47.2% in the ROS-1 cohort. The best ORR during treatment was 32% in the c-MET-≥6 copies cohort, 36% in the c-MET-mutated, and 69.4% in the ROS-1-translocation cohort. Safety data were consistent with that previously reported., Conclusions: Crizotinib activity in patients with ROS1-translocated tumours was confirmed. In the c-MET-mutation and c-MET ≥6 copies cohorts, despite insufficient ORR after two cycles of crizotinib, there are signs of late response not sufficient to justify the development of crizotinib in this indication. The continued targeting of c-MET with innovative therapies appears justified., Clinical Trial Number: NCT02034981., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Adjuvant treatment in resected stage I non-small-cell lung cancer (NSCLC) is generally not recommended. Pazopanib is an oral tyrosine kinase inhibitor of VEGFR-1/2/3 and PDGFR-α/β. We explored the feasibility and efficacy of adjuvant pazopanib in this population., Patients and Methods: In this double-blind phase II/III trial, patients with resected stage I NSCLC were randomized to placebo or pazopanib 800 mg/day (P800) for 6 months with a two-step Fleming design. The primary endpoint was compliance (percentage of patients receiving ≥3 months pazopanib). From the interim analysis after 64 patients were included, the IDMC recommended reducing to pazopanib 400 mg/day (P400) due to insufficient compliance, with a one-step Fleming. Although unplanned, survival data were analyzed., Results: A total of 71 patients were enrolled in each arm; 61% were male, 91% were smokers, median age was 60 years, 80% had pathological stage IA, and 16% had squamous cell carcinoma. Pazopanib compliance was 38% [95% confidence interval (CI) 23-55] with P800, increasing to 69% (95% CI 50-84; P = 0.027) with P400. Two patients had grade 4 toxicities with P800. The most common grade 3 toxicities were increased transaminases (16%), hypertension (13%), and diarrhea (9%) with P800, and gastrointestinal disorders (16%; 6% diarrhea) and hypertension (6%) with P400. Median follow-up was 47 months. Three-year recurrence-free survival was 76% (95% CI 65%-86%) with pazopanib and 83% (95% CI 74%-92%) with placebo [hazard ratio = 1.3 (95% CI 0.6-2.7), P = 0.53]. Five-year overall survival was 83% (95% CI 72-94) with pazopanib and 94% [95% CI 88-100] with placebo [hazard ratio = 1.8 (95% CI 0.6-5.5), P = 0.26]., Conclusions: In resected stage I NSCLC patients adjuvant 400 mg/day pazopanib but not 800 mg/day was feasible, although possibly infra-therapeutic and failed to improve relapse-free survival., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: This randomized phase II-III trial sought to evaluate the efficacy and safety of adding bevacizumab (Bev) following induction chemotherapy (CT) in extensive small-cell lung cancer (SCLC)., Patients and Methods: Enrolled SCLC patients received two induction cycles of CT. Responders were randomly assigned 1:1 to receive four additional cycles of CT alone or CT plus Bev (7.5 mg/kg), followed by single-agent Bev until progression or unacceptable toxicity. The primary end point was the percentage of patients for whom disease remained controlled (still in response) at the fourth cycle., Results: In total, 147 patients were enrolled. Partial response was observed in 103 patients, 74 of whom were eligible for Bev and randomly assigned to the CT alone group (n = 37) or the CT plus Bev group (n = 37). Response assessment at the end of the fourth cycle showed that disease control did not differ between the two groups (89.2% versus 91.9% of patients remaining responders in CT alone versus CT plus Bev, respectively; Fisher's exact test: P = 1.00). Progression-free survival (PFS) since randomization did not significantly differ, with a median PFS of 5.5 months [95% confidence interval (CI) 4.9% to 6.0%] versus 5.3 months (95% CI 4.8% to 5.8%) in the CT alone and CT plus Bev groups, respectively [hazard ratio (HR) for CT alone: 1.1; 95% CI 0.7% to 1.7%; unadjusted P = 0.82]. Grade ≥2 hypertension and grade ≥3 thrombotic events were observed in 40% and 11% of patients, respectively, in the CT plus Bev group. Serum vascular endothelial growth factor (VEGF) and soluble VEGF receptor titrations failed to identify predictive biomarkers., Conclusion: Administering 7.5 mg/kg Bev after induction did not improve outcome in extensive SCLC patients., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The optimal treatment of large-cell neuroendocrine carcinoma (LCNEC) of the lung remains unclear. Here, our primary objective was to assess the efficacy of cisplatin-etoposide doublet chemotherapy in advanced LCNEC. Accuracy of the pathological diagnosis and treatment toxicity were assessed as secondary objectives., Patients and Methods: Prospective, multicentre, single-arm, phase II study with a centralised review of treatment-response and pathological data. Patients had untreated performance status (PS) 0/1 stage IV/IIIB LCNEC and received cisplatin (80 mg/m22 d1) and etoposide (100 mg/m22 d1-3) every 21 days., Results: Eighteen centres included 42 patients (mean age, 59 ± 9 years; 69% men; median of four cycles/patient). At least one grade-3/4 toxicity occurred in 59% of patients (neutropaenia, thrombocytopaenia, and anaemia in 32%, 17%, and 12%, respectively). The median progression-free survival (PFS) and overall survival (OS) were 5.2 months (95% confidence interval, CI, 3.1-6.6) and 7.7 months (95% CI, 6.0-9.6), respectively. The centralised pathologist review reclassified 11 of 40 (27.5%) patients: 9 as small-cell lung cancer, 1 as undifferentiated non-small-cell lung cancer, and 1 as atypical carcinoid. Survival data were not significantly changed by excluding the reclassified patients., Conclusions: The pathological diagnosis of LCNEC is difficult. The outcomes of advanced LCNEC treated with cisplatin-etoposide doublets are poor, similar to those of patients with advanced small-cell lung carcinoma (SCLC).

Background: Despite advances in cancer therapy, mortality is still high except in early-stage tumors, and screening remains a challenge. The randomized National Lung Screening Trial (NLST), comparing annual low-dose computed tomography (LDCT) and chest X-rays, revealed a 20% decrease in lung-cancer-specific mortality. These results raised numerous questions. The French intergroup for thoracic oncology and the French-speaking oncology group convened an expert group to provide a coherent outlook on screening modalities in France., Methods: A literature review was carried out and transmitted to the expert group, which was divided into three workshops to tackle specific questions, with responses presented in a plenary session. A writing committee drafted this article., Results: The multidisciplinary group favored individual screening in France, when carried out as outlined in this article and after informing subjects of the benefits and risks. The target population involves subjects aged 55-74 years, who are smokers or have a 30 pack-year smoking history. Subjects should be informed about the benefits of quitting. Screening should involve LDCT scanning with specific modalities. Criteria for CT positivity and management algorithms for positive examinations are given., Conclusions: Individual screening requires rigorous assessment and precise research in order to potentially develop a lung-cancer screening policy.

Background: Brain metastases (BM) considerably worsen the prognosis of non-small-cell lung cancer (NSCLC) patients. The usefulness and choice of chemotherapy remain uncertain in this indication since these patients are excluded from most clinical trials. We conducted a phase II study to determine the efficacy and tolerability of up-front chemotherapy with association of temozolomide and cisplatin in NSCLC patients with BM., Patients and Methods: Fifty NSCLC patients with BM received temozolomide (200 mg/m(2)/day for 5 days every 28 days) and cisplatin (75 mg/m(2) at day 1 of each cycle), up to six cycles, followed by whole brain radiotherapy (WBRT). An evaluation was carried out every two cycles and after WBRT. WBRT was performed earlier in case of progressive disease at any time or stable disease after cycle 4., Results: Eight objective responses were achieved (16%). Overall median survival was 5 months. Median time to progression was 2.3 months. Ten patients (20%) presented a grade 3/4 neutropenia and 11 patients (22%) presented a grade 3/4 thrombopenia., Conclusion: This study demonstrates a lack of efficacy of up-front chemotherapy with association of temozolomide and cisplatin in these patients. Nevertheless, it supports the feasibility of chemotherapy before brain radiotherapy in NSCLC patients with BM.

Background: We conducted an economic analysis of a phase III clinical trial comparing sequential radiochemotherapy (RT-CT) with concurrent RT-CT in patients with locally advanced non-small-cell lung cancer., Patients and Methods: The trial was a randomized multicenter study comparing three cycles of chemotherapy (arm A) followed by radiotherapy against an RT-CT combination (two cycles of platinum etoposide) followed by two cycles of platinum-vinorelbine (arm B). The economic analysis adopted the payer's perspective and only included direct costs. Costs (euro, 1996-2003) were recorded until the cut-off date. A cost minimization analysis and a sensitivity analysis were carried out., Results: Data from 173 patients were used in the economic study. Protocol costs tended to be higher in arm B, while relapse costs were significantly higher in arm A. The total number of hospital days was higher in arm B. The average total cost per patient was euro16,074 in arm A and euro15,245 in arm B (P=0.15). The cost minimization analysis favored arm B. This advantage persisted in the sensitivity analysis., Conclusions: Concurrent RT-CT was not the more costly strategy in this phase III trial, despite lengthier hospitalization for toxicity. Other studies of similar design are needed to confirm these results in future randomized trials.

Background: This multicenter, randomized, phase III study compared the efficacy, including progression-free survival (PFS), and safety of gemcitabine-docetaxel (GD) combination versus cisplatin-vinorelbine (CV) in the treatment of advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: Chemonaive patients with stage IIIB or IV NSCLC were treated with GD (gemcitabine 1000 mg/m(2) days 1 and 8 plus docetaxel 85 mg/m(2) day 8, every 3 weeks for eight cycles) or CV (cisplatin 100 mg/m(2) day 1 plus vinorelbine 30 mg/m(2), days 1, 8, 15 and 22, every 4 weeks for six cycles)., Results: A total of 311 patients were enrolled (155 GD and 156 CV). Neither PFS nor overall survival differed significantly between the two arms (median PFS 4.2 and 4 months; median survival 11.1 and 9.6 months; 1-year survival 46% and 42%, for GD and CV, respectively). For the GD arm compared with the CV arm, the hazard ratio for PFS was 1.04 [95% confidence interval (CI) 0.83-1.32], and for overall survival, it was 0.90 (95% CI 0.70-1.16). Objective response rates did not differ significantly (31% for GD, 35.9% for CV). Myelosupression, emesis and frequency of febrile neutropenia were less pronounced on the GD arm, whereas fluid retention and pulmonary events were more pronounced. The CV arm experienced a higher number of serious adverse events and a lower compliance with the protocol. There was no quality of life (QoL) difference between arms. Median time to definite impairment of health-related QoL was 153 and 168 days in GD and CV arms, respectively., Conclusions: There was no advantage in PFS with GD compared with CV; however, the CV regimen had higher rate of toxic events, mainly myelosuppression. The herein, non-platinum-containing regimen could be considered as a rational alternative to the cisplatin-based doublet.

Background: The standard doublet, vinorelbine-cisplatin, was compared with a triplet of vinorelbine-ifosfamide-cisplatin, in terms of survival, in patients with advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: From February 1998 to June 1999, 259 chemonaïve patients entered the study and were randomised to receive either vinorelbine-cisplatin (NP; vinorelbine 30 mg/m(2) on days 1, 8 and 15 with cisplatin 80 mg/m(2) on day 1) or vinorelbine-ifosfamide-cisplatin (NIP; vinorelbine 25 mg/m(2) on days 1 and 8, ifosfamide 3 g/m(2) on day 1 and cisplatin 75 mg/m(2) on day 1), with both regimens being repeated every 3 weeks. All patients had stage IV or relapsed disease and a performance score of 0 or 1., Results: The overall response rate was 34.6% for NP and 35.7% for NIP. Median and 1-year survival rates were 10.0 months and 38.4% for NP, and 8.2 months and 33.7% for NIP, respectively. A median of four cycles was administered in each arm. The major World Health Organization grade 3-4 toxicities for NP and NIP, respectively, were: neutropenia (20.3% compared with 9% of cycles), anaemia (4.1% compared with 5% of cycles), nausea and vomiting (22.2% compared with 19.4% of patients) and alopecia (5.6% compared with 29.8% of patients). Four toxic deaths occurred in the NP arm and eight in the NIP arm., Conclusions: The different schedules of vinorelbine in the two arms led to a greater survival in the NP arm without impairing the tolerance profile, although this is not statistically significant. This confirms that the two-drug combination NP is a reference treatment for metastatic NSCLC. The role of three-drug combinations remains questionable in this subset of patients.

We report a case of rhabdomyosarcoma which occurred in a mediastinal teratoma in a 44-year-old man. Presentation symptoms were chest pain, hoarseness and a cough. Diagnosis was fortuitous, performed by the histological and immunohistochemical study of a mediastinal tumour biopsy specimen that showed embryonal carcinoma and yolk sac tumour components associated with the rhabdomyosarcoma. After cisplatin-based chemotherapy (bleomycin-etoposide-cisplatin), surgical resection of the residual mediastinal tumour was performed. Histological and immunohistochemical study of this tumour confirmed the presence of mature teratoma and embryonal rhabdomyosarcoma. Evolution was marked by a local extension of the mediastinal tumour, occurrence of multiple metastases and bone marrow involvement. The patient died 8 months after diagnosis despite chemotherapy and radiotherapy. A review of the literature reveals that the development of rhabdomyosarcoma in primary mediastinal teratomas is unusual in adults. The diagnostic, therapeutic and prognostic implications of such an association are reviewed.

Purpose: To determine if the timing of whole brain radiotherapy (WBRT) with respect to chemotherapy with cisplatin and vinorelbine would influence survival in patients with non-small-cell lung cancer (NSCLC) and concurrent brain metastasis., Patients and Methods: One hundred seventy-six patients with brain metastasis from NSCLC were included in the study between July 1995 and October 1997. All patients received chemotherapy with cisplatin 100 mg/m2 on day 1 and vinorelbine 30 mg/m2 on days 1, 8, 15, 22. Cycles were repeated every four weeks. Evaluation of response was performed after two, four or six cycles. After two cycles, chemotherapy was administered to the responders to a maximum of six cycles. Patients were randomised to receive WBRT 30 Gy/10 fx/12 days and delayed corticosteroids. (arm A) for the intracranial nonresponders, or early on day 1 to 12 during the first cycle of chemotherapy (arm B)., Results: One hundred seventy-one patients were eligible: eighty-six in arm A and eighty-five in arm B; none had received prior chemotherapy; seventy-six and seventy-three, respectively, were assessable for response. There was a 21% overall objective response rate (OR) (with 1 complete response and 17 partial responses) after two cycles of chemotherapy alone (arm A) and a 20% OR (with 17 partial responses) to chemotherapy and early WBRT (arm B). The intracranial OR was 27% and 33%, respectively (P = 0.12). The six months survival rate (46% and 40%) and the median survival duration (24 and 21 weeks, respectively) were not significantly different between the two arms (P = 0.83, log-rank test). The major toxicity was severe or life-threatening neutropenia (grade 4), which occurred in 35% of arm A patients and 36% of arm B patients. There were thirteen treatment-related deaths (six in arm A and seven in arm B). There was no difference between the arms for haematological and neuro-toxicities., Conclusions: These results confirm the efficacy of chemotherapy in brain metastases of NSCLC and suggest that the timing (early or delayed) of WBRT did not influence survival of NSCLC with brain metastasis treated with concurrent chemotherapy.