Lorlatinib for advanced ROS1+ non-small-cell lung cancer: results of the IFCT-1803 LORLATU study.

INTRODUCTION: ROS1-rearranged (ROS1+) non-small-cell lung cancer (NSCLC) is a rare lung cancer with limited treatment options. Phase I-II studies with ROS1-tyrosine kinase inhibitors (TKIs) included small numbers of patients and real-world data are lacking. We investigate the efficacy and safety of lorlatinib, a third-generation TKI targeting ALK and ROS1, in patients with ROS1+ NSCLC treated through an expanded access program. METHODS: Consecutive patients with advanced ROS1+ NSCLC treated with lorlatinib between October 2015 and June 2019 were included. Data were collected from medical records. The primary endpoint was progression-free survival. RESULTS: Out of the 80 patients included, 47(59%) were female, 49(62%) never smokers (less than 100 cigarettes over the lifetime), and 68(85%) had stage IV NSCLC at diagnosis. Most frequent histology was adenocarcinoma (95%) and median age was 58.2 years. At the time of lorlatinib initiation, 51(64%) patients had brain metastases and 55(81%) were PS 0-1. Lorlatinib was administered as second/third/fourth/fifth+ line in 29%/28%/18%/26% of patients. All patients previously received at least one ROS1 TKI, and 55(69%) previously received chemotherapy. Median follow-up from lorlatinib initiation was 22.2 months. Median progression-free survival and overall survival from lorlatinib initiation were 7.1 months [95% confidence interval (CI) 5.0-9.9 months] and 19.6 months (95% CI 12.3-27.5 months). Median duration of treatment with lorlatinib was 7.4 months (95% CI 6.5-13.1 months). Overall response and disease control rates were 45% and 82%, respectively. The central nervous system response rate was 72%. Treatment was stopped due to toxicity in 10 patients (13%). The safety profile was consistent with previously published data. CONCLUSIONS: Lorlatinib is a major treatment option for advanced refractory ROS1+ NSCLC in treatment strategy.

Serum total periostin is an independent marker of overall survival in bone metastases of lung adenocarcinoma.

More than 35% of lung adenocarcinoma patients have bone metastases at diagnosis and have a poor survival. Periostin, a carboxylated matrix protein, mediates lung cancer cell dissemination by promoting epithelial-mesenchymal transition, and is involved in bone response to mechanical stress and bone formation regulation. This suggests that periostin may be used as a biomarker to predict survival in lung cancer patients. Serum periostin was assessed at diagnosis in a prospective cohort of 133 patients with lung adenocarcinoma of all stages. Patients were divided into localized and bone metastatic groups. Both groups were matched to healthy controls. Survival analysis and Cox proportional hazards models were conducted in the total population and in bone metastatic group. The median serum periostin level was higher in bone metastatic (n = 67; median: 1752 pmol/L) than in the localized group (n = 66; 861 pmol/L; p < 0.0001). Patients with high periostin (>median) had a poorer overall survival in the whole population (33.3 weeks vs. NR; p < 0.0001) and the bone metastatic group (24.4 vs. 66.1 weeks; p < 0.001). In multivariate analysis, patients with high periostin had increased risk of death (HR = 2.09, 95%CI [1.06-4.13]; p = 0.03). This was also found in the bone metastatic group (HR = 3.62, 95%CI [1.74-7.52]; p = 0.0005). Immunohistochemistry on bone metastasis biopsies showed periostin expression in the bone matrix and nuclear and cytoplasmic staining in cancer cells. Serum periostin was an independent survival biomarker in all-stage and in bone metastatic lung adenocarcinoma patients. IHC data suggest that periostin might be induced in cancer cells in bone metastatic niche in addition to bone microenvironment expression.

NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents.

Oncogenic gene fusions are hybrid genes that result from structural DNA rearrangements, leading to deregulated activity. Fusions involving the neuregulin-1 gene (NRG1) result in ErbB-mediated pathway activation and therefore present a rational candidate for targeted treatment. The most frequently reported NRG1 fusion is CD74-NRG1, which most commonly occurs in patients with invasive mucinous adenocarcinomas (IMAs) of the lung, although several other NRG1 fusion partners have been identified in patients with lung cancer, including ATP1B1, SDC4, and RBPMS. NRG1 fusions are also present in patients with other solid tumors, such as pancreatic ductal adenocarcinoma. In general, NRG1 fusions are rare across different types of cancer, with a reported incidence of <1%, with the notable exception of IMA, which represents ≈2%-10% of lung adenocarcinomas and has a reported incidence of ≈10%-30% for NRG1 fusions. A substantial proportion (≈20%) of NRG1 fusion-positive non-small-cell lung cancer cases are nonmucinous adenocarcinomas. ErbB-targeted treatments, such as afatinib, a pan-ErbB tyrosine kinase inhibitor, are potential therapeutic strategies to address unmet treatment needs in patients harboring NRG1 fusions.

Do systemic treatments delivered after Nivolumab result in better outcomes? A bicentric case-control study.

BACKGROUND: Immune checkpoint inhibitors (ICI) are now widely used at different stages of non-small cell lung cancers (NSCLC). Some clinical studies suggest that chemotherapy and immunotherapy have synergic activities, raising the question of the best therapeutic sequence. We studied the effect of chemotherapy in advanced NSCLC when administered after immunotherapy by nivolumab. METHODS: We performed a bicentric, retrospective, case-control study in two French hospitals. Patients with NSCLC treated with chemotherapy after nivolumab between January 2015 and January 2016 were included. Each case was matched on age and number of previous lines to one lung cancer patient who had not received nivolumab. Each CT-scanner has been reviewed and the objective response to chemotherapy was assessed for each patient according to the RECIST 1.1 criteria. RESULTS: Thirty-one patients with advanced NSCL who had at least received one cycle of chemotherapy after progression under nivolumab in the inclusion period were matched to 31 controls. The median age for cases was 59 yo and the predominant tumoral histology was adenocarcinoma (77%). The progression free survival (PFS) was 2.95 months in the studied group vs 2.69 months (P=0.18) in the control group. At best response, disease control (DC=partial response and stable disease) was better in the case group than in the control group (58% vs 39%, P=0.127). Cases were about five times more likely to get objective response to best evaluation than controls (OR=5.043 [95% CI: 0.975-26.086]; P=0.054). The overall survival (OS) was 7.3 months in the case group and 3.3 months in the control group (P=0.074). Patients who have been treated with targeted therapy instead of chemotherapy and patients with squamous lung cancer had worst PFS and OS. CONCLUSION: In advanced NSCLC, the chemotherapy progression free survival does not seem higher when administered after nivolumab. However, when administered post-nivolumab, traditional chemotherapy has 5 times more chances to achieve objective response and seems to improve overall survival of cases. Pooled analysis with other similar studies might be interesting for a next step.

Proposals for managing patients with thoracic malignancies during COVID-19 pandemic.

The objective of this document is to formalize a degraded mode management for patients with thoracic cancers in the context of the COVID-19 pandemic. The proposals are based on those of the French High Council for Public Health, on published data outside the context of COVID-19, and on a concerted analysis of the risk-benefit ratio for our patients by a panel of experts specialized on thoracic oncology under the aegis of the French-Language Society of Pulmonology (SPLF)/French-language oncology group. These proposals are evolving (10 April 2020) according to the situations encountered, which will enrich it, and are to be adapted to our institutional organisations and to the evolution of resources during the COVID-19 epidemic. Patients with symptoms and/or COVID-19+ are not discussed in this document and are managed within the framework of specific channels.

Impact of systematic advanced care planning in lung cancer patients: A prospective study.

BACKGROUND: End-of-life (EOL) communication is crucial, particularly for cancer patients. While advanced care planning is still uncommon, we sought to investigate its impact on care intensity in case of organ failure in lung cancer patients. METHODS: We prospectively included consecutive lung cancer patients hospitalised at the Grenoble University Hospital, France, between January 1, 2014 and March 31, 2016. Patients could be admitted several times and benefited from advanced care planning based on three care intensities: intensive care, maximal medical care, and exclusive palliative care. Patients' wishes were addressed. RESULTS: Data of 739 hospitalisations concerning 482 patients were studied. During the three first admissions, 173 (25%) patients developed organ failure, with intensive care proposed to 56 (32%), maximal medical care to 104 (60%), and exclusive palliative care to 13 (8%). Median time to organ failure was 9 days [IQR 25%-75%: 3-13]. All patients benefited from care intensity that was either equal to or lower than the care proposed. Specific wishes were recorded for 158 (91%) patients, with a discussion about EOL conditions held in 116 (73%). CONCLUSIONS: In case of organ failure, advanced care planning helps provide reasonable care intensity. The role of the patient's wishes as to the proposed care must be further investigated. CLINICAL TRIAL REGISTRATION: The study was registered at www.ClinicalTrials.gov with the identifier NCT02852629.

[Residents in respiratory medicine: Assessment of the course and wishes regarding their career]. / Appréciation du cursus et vœux relatifs à l'exercice futur des internes en pneumologie.

INTRODUCTION: The aim of this study was to assess the feelings of residents in respiratory medicine regarding the quality and organization of their training and towards their career prospects. METHODS: A prospective survey conducted over the Internet among all the members of the French Young Pulmonologists Association (AJPO2). RESULTS: One hundred and thirty-two (71.5%) members responded. The rating given to theoretical training was 6 [5-7] whereas the practical training was rated at 7 [6-8] out of 10. The majority of the residents considered that the length of their course should be adapted (80.3%). Of them, 74.2% wanted to add a mandatory semester. The proposed mandatory semester was in bronchoscopy (40.3%). Seventy-two percent of the resident wanted to acquire a specialisation, the most common of which was in oncology (36.6%). Among the residents, 96.2% wanted to conduct a fellowship. The main reason for this was their feeling of inability to correctly handle patients at the end of their residency. Of the residents, 55.3% were considering working in a public hospital. CONCLUSION: There are opportunities to improve the French respiratory residency training both in its theory and practical aspects. The modalities of this training could also be adapted. Access to a fellowship is a major concern for the residents.

Clinical and molecular features in patients with advanced non-small-cell lung carcinoma refractory to first-line platinum-based chemotherapy.

Most of the cases of non-small-cell lung cancer (NSCLC) are diagnosed at an advanced stage and are treated with platinum-doublet chemotherapy. However, some patients are refractory to this treatment. The aim of this study was to identify the clinical and molecular characteristics of patients with refractory disease. All consecutive patients between 2003 and 2006, who received a platinum-doublet chemotherapy as first-line treatment for stage IIIb-IV NSCLC, were included. Refractory patients were defined as early progressive disease (PD) at the first evaluation of chemotherapy according to WHO criteria. The clinical, histo-pathological, and molecular characteristics (EGFR: exon 19, 20, 21 and KRAS: exon 2 by PCR sequencing; ALK by immunohistochemistry) and survival of refractory patients with initial PD (r-patients) and controlled disease (c-patients) were compared by univariate analyses. Factors that differed between the two groups (p-value <0.25 in univariate analyses) were entered into multivariate analysis. In this study, 178 patients were included. The first tumor assessment was carried out after a median of three cycles (range 1-4). Forty-six (25.8%) patients were refractory. Clinical presentation was similar between r- and c-patients. The sarcomatoid histological subtype was more common in r-patients than c-patients (10.9% vs. 1.5%, respectively; p=0.057). The proportion of EGFR (5.2% vs. 9.6%, p=0.224) and KRAS mutations (11.1% vs. 5.7%, p=0.357), and the expression of ALK (6.3% vs. 2.5%, p=0.327) did not differ significantly between the two groups. In multivariate analysis, sarcomatoid histological subtype was the only factor associated with early PD (OR=7.50; 95%CI: 1.02-55.45; p=0.048). r-Patients had significantly shorter survival than c-patients (median 5 months (IQR 3.2-9.9) vs. 15.4 months (IQR 9.9-22.5), respectively; p<0.0001). In conclusion, patients with early PD under platinum-doublet chemotherapy had shorter survival than c-patients. Sarcomatoid histological subtype was the only independent factor associated with early PD.

[Regional recurrence of triple-negative breast cancer: interest of systematic adjuvant lymph node irradiation?]. / Récidives régionales chez les patientes présentant un cancer du sein triple-négatif : intérêt d'une irradiation ganglionnaire adjuvante systématique ?

OBJECTIVE: To evaluate the percentage of regional recurrence (RR) in patients with triple-negative (TN) N0 breast cancer in order to consider the interests of a systematic adjuvant nodal irradiation. PATIENTS AND METHODS: Between February 1996 and June 2009, 249 patients were treated for TN breast cancer in Léon-Bérard center (Lyon, France). All patients received first surgical treatment followed or not by chemotherapy or radiotherapy. We excluded patients with metastasis at diagnosis, patients who were initially irradiated regional lymph node, patients which ER, PR and/or HER2 status was not known and patients who didn't have standard treatment. Ultimately, 100 patients were included. RESULTS: Two patients (2%) developed regional recurrence (1 sub and supraclavicular recurrence and 1 supraclavicular recurrence). The median follow-up was 34 months (95% CI: 29,2 to 37,4). The survival rate at 3 years was 98% (95% CI: 90-99). Our study showed no differences in terms of RR between TN cancers and not TN cancers for a median followed up of 34 months. CONCLUSION: The results of our study do not suggest that patients with TN breast cancer should receive systematic nodal adjuvant radiotherapy.

Influenza vaccination in patients with haematologic malignancies: analysis of practices in 200 patients in a single center.

GOALS OF WORK: Despite recent studies demonstrating immunogenicity and tolerance of influenza vaccine in patients with haematologic malignancies, practices are still heterogeneous. The aim of this study was to analyse practices and factors influencing vaccination in a single centre, in the light of recent literature data. PATIENTS AND METHODS: Two hundred patients with haematologic malignancies were included and filled out a standardized questionnaire about influenza vaccination. They were observed prospectively during the epidemic season. MAIN RESULTS: Our study revealed a poor uptake of influenza vaccination (vaccinal rate: 25.5%), in particular in patients younger than 65 y and those with no comorbidities. The main reasons for not being vaccinated were: the vaccination was not suggested to patients (53.7%), vaccination was contraindicated by doctors (24.2%), the patient refused it (21.5%). The main reasons for physicians for contraindicating the vaccine were: haematologic malignancy could be worsened by vaccination (33.3%), vaccination could generate illness or asthenia (27.8%), vaccination would not be efficient (16.7%), unknown (22.2%). CONCLUSIONS: We believe that a better knowledge by physicians of tolerance and efficiency of the vaccine could enhance the vaccination coverage.