Clinical benefit of anti-PD-(L)1 immunotherapies in advanced cancer in France: a population-based estimate from 2014 to 2021.

BACKGROUND: In France, the potential benefit of new treatments is initially evaluated by the Haute Autorité de Santé to determine reimbursement and pricing, but rarely afterwards. Although immunotherapies (ITs) have considerably improved the survival of patients, few data are available on their long-term benefit at a population-treated level. The present retrospective study aimed to assess the clinical benefit of ITs compared to the previous standards of care (SoCs) in France from 2014 to 2021. MATERIALS AND METHODS: To do this, we analyzed all ITs from the anti-programmed cell death protein 1/programmed death-ligand 1 [anti-PD-(L)1] class used in monotherapy or in association with another treatment available in early access or reimbursed in France between 2014 and 2021, regardless of indication. The number of patients initiating an IT was retrieved by year, drug and indication. Using extrapolated Kaplan-Meier curves, utility scores and the population treated, the clinical benefit was expressed as the number of deaths prevented (DP), life-years (LYs) and quality-adjusted life years (QALYs) gained compared to previous SoC. RESULTS: Across the period, five ITs were marketed in 21 indications related to eight primary tumor sites. Between 2014 and 2021, 132 924 patients initiated an IT. By December 2021, 16 173 (13 804-17 141) deaths were delayed compared to previous SoC, mainly in lung cancer. Compared to their SoC, ITs provided a gain of 37 316 (33 581-41 048) additional LYs and 27 709 (23 784-30 450) additional QALYs. Lung cancer was the driver indication with 70.6% of LYs and 68.4% of QALYs gained followed by melanoma with 18.7% and 20.4% of the gain, respectively. CONCLUSIONS: Significant gains in DP, LYs and QALYs have been observed in France following the introduction of ITs.

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.

Nivolumab-refractory patients with advanced non-small-cell lung cancer.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have revolutionised cancer care especially in lung cancer. New response patterns have been described under ICIs such as pseudo-progression or hyper-progressive disease (HPD). The definition of HPD is yet to be consensual. The aim of this study was to suggest a clinical definition of nivolumab-refractory patients and find factors associated with this entity. METHODS: We performed a multi centric retrospective study including all patients who received nivolumab for the treatment of advanced non-small cell lung cancer (NSCLC) during the French authorisation for temporary use in 2015. RESULTS: 303 patients were included in the cohort and 292 had details on the number of nivolumab injections received. 57 patients (20%) were nivolumab-refractory. These patients had worse PS at nivolumab initiation (p < 0.0001), shorter duration of treatment before nivolumab (p = 0.028) and had dramatically shorter nivolumab overall survival (p < 0.0001) than patients who did not present with refractory disease. CONCLUSION: Nivolumab-refractory disease can affect up to 20% of patients treated with nivolumab for advanced NSCLC with dramatically shortened survival rates. Further studies are needed to understand the precise mechanisms leading to refractory disease as well as its management.

[Role of the Sonic Hedgehog pathway in thoracic cancers]. / Rôle de la voie Sonic Hedgehog dans les cancers thoraciques.

INTRODUCTION: Sonic Hedgehog (Shh) pathway is physiologically activated during embryogenesis and development. It plays a role in idiopathic lung fibrosis and is also activated in several solid cancers. STATE OF THE ART: Shh pathway is reactivated in thoracic cancers, as small cell lung carcinoma, non-small cell lung carcinoma and malignant pleural mesothelioma. Shh pathway is associated with cancer stem cells and seems to have a crucial role in tumor proliferation, aggressiveness and chemoresistance in these cancers. This review describes the activation mode of Shh pathway in thoracic cancers and its role in small cell lung carcinoma, non-small cell lung carcinoma and malignant pleural mesothelioma, using in vitro and in vivo models. Notably, data from literature show that inhibition of Shh pathway has an antitumor action and sensitizes to chemotherapy. PERSPECTIVES: These results incite to develop targeted therapies against Shh pathway in the treatment of thoracic cancers.

[A new drug in thoracic oncology: MetMab (onartuzumab)]. / Un nouveau médicament en oncologie thoracique: le MetMab (onartuzumab).

Met pathway is activated in many solid cancers. In advanced non-small cell lung cancer (NSCLC), Met amplification is involved in 5 to 20% of acquired resistance to EGFR tyrosine kinase inhibitors (TKI) in tumors with initially sensitive EGFR mutation. MetMab (onartuzumab) is a monoclonal single-arm humanized anti-Met antibody. Its fixation on the Met receptor prevents the binding of the ligand (Hepatocyte Growth factor [HGF]) and the signal transduction. After promising results in preclinical and phase I trials, a randomized phase II trial has been conducted in advanced NSCLC in 2nd or 3rd line treatment. One hundred and twenty-eight patients have been randomized between an association of erlotinib+placebo and erlotinib+MetMab (15mg/kg IV every 3 weeks) until progression or toxicity. Patients with overexpression of Met in immunohistochemistry (IHC) had a progression-free survival (PFS) and an overall survival (OS) two-fold (median 1.5 versus 2.9 months; HR=0.53; P=0.04) and three-fold (median 3.8 versus 12.6 months; HR=0.37; P=0.002) longer, respectively, than patients with negative IHC score. The erlotinib+MetMab association had a worse effect on SSP and OS than the control arm in patients with negative IHC. The toxicity profile of MetMab is very good, and the main adverse effect is the occurrence of peripheral edemas, most of the time of low grade. A randomized phase III is on going to validate these results.

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.

[Non-small cell lung cancer: risk factors of radiation pneumonitis]. / Cancers bronchiques non à petites cellules : facteurs prédictifs de survenue de pneumopathie radique.

PURPOSE: To evaluate the predictors of acute radiation pneumonitis after conformal thoracic radiotherapy in the treatment of locally advanced non-small cell lung cancer. PATIENTS AND METHODS: Forty-seven consecutive patients were treated with conformal thoracic irradiation for locally advanced non-small cell lung cancer and retrospectively analysed. The mean total dose of radiotherapy was 65 Gy with respiratory gating in 19 cases. Neoadjuvant and concomitant chemotherapy was performed in 33 patients (70%) and 41 patients (87%) respectively. RESULTS: Eleven patients (23%) had an acute radiation pneumonitis, resulting in death for one patient. In univariate analysis, age, sex, pretherapeutic value of forced expiratory volume, non-gated radiotherapy and type of concomitant chemotherapy did not appear as contributing factors in contrast to the administration of neoadjuvant gemcitabine (P=0.03). The occurrence of acute radiation pneumonitis was significantly associated with non-tumour lung volumes irradiated to 13 Gy (V13, P=0.04), 20 Gy (V20, P=0.02) and 25 Gy (V25, P=0.006), the mean lung dose (P=0.008) and lung normal tissue complication probability (P=0.004). In multivariate logistic regression analysis, the occurrence of acute radiation pneumonitis was significantly associated with age above 75 years (odds ratio [OR]=16.72 ; P=0.02) and with administration of neoadjuvant gemcitabine (OR=18.08, P=0.04). CONCLUSION: Acute radiation pneumonitis is a common acute side effect of the conformal thoracic radiotherapy of locally advanced non-small cell lung cancer, requiring close post-treatment follow-up, particularly for elderly patients. The use of gemcitabine before radiation should be avoided. The benefits and risks of conformal thoracic radiotherapy must be carefully analyzed in view of the dosimetric parameters obtained.

[Biomarkers and targeted therapies in non-small cell lung cancer: present and future treatments]. / Biomarqueurs et thérapies ciblées dans le cancer bronchique non à petites cellules: traitement d'aujourd'hui et de demain.

Since several years, the perception of lung cancer has considerably evolved. Indeed, we have proceeded from a simple classification based on histology to a molecular dismemberment, with a lot of subtypes of tumors according to there molecular alteration profile. Mutations of the EGFR receptor define so a group of cancers particularly sensitive to EGFR tyrosine kinase inhibitors (TKI). Gefitinib has shown its efficacy in term of response and survival in first line treatment of NSCLC arboring EGFR mutations. Recently, the ALK-AML4 translocation has been found in approximately 5% of NSCLC, accessible to a specified targeted therapy (crizotinib) with response rate around 60%. NSCLC with HER2 mutation or amplification could be treated with trastuzumab, whereas treatments targeting Met pathway are currently in development. At last, several drugs active in case of DNA repair dysfunction, like PARP inhibitors, have already shown there efficacy in particular types of NSCLC. In a very near future, molecular screening of these molecular alterations should be systematic from the diagnostic, to allow a personalized treatment according to the mutation profile.

[Sampling and search for the EGFR mutation: what's taking, when and how to test?]. / Prélèvement et recherche de la mutation EGFR: quoi prélever, quand et comment tester?

Since the IPASS study, that has shown a benefit in term of progression-free survival in first line of treatment in non-small cell lung cancer (NSCLC) with activating EGFR mutations, and the restricted prescription of this treatment to the presence of these mutations, the determination of the mutational status has became necessary at the diagnosis. This research study of these mutations, present in about 10% of non-selected NSCLC, has to be preferred in case of clinical factors predictive of mutations (sex, race, tobacco status, adenocarcinoma), but don't have to be exclusive, the correlation between these clinical factors and the presence of the mutations being imperfect. Also, the research study of the EGFR mutations should be performed for patients non eligible for chemotherapy (PS>2). Molecular testing could be performed on biopsies, and also on cytology, knowing that there is a mismatch between the tumor and the metastasis for EGFR status. Samples should be prepared according to standardized protocols, avoiding fixation with Bouin. The gold-standard for molecular testing is still sequencing, but alternative targeted tests (allele-specific PCR...) seem to be more sensitive. Some immunohistochemistry tests are in development for EGFR mutations, but have to be validated on large prospective cohorts. At last, new tumoral sampling have to be performed in case of progression under gefitinib in first line, to look for acquired resistance EGFR mutations, or for other resistance molecular markers (Met amplification).

[Association between thymic MALT lymphoma and Sjögren's syndrome]. / Association d'un lymphome thymique de type MALT et d'un syndrome de Gougerot-Sjögren.

INTRODUCTION: Thymic mucosa-associated lymphoid tissue (MALT) lymphoma is a rare pathology, often associated with autoimmune diseases. The authors report the case of an Asian woman with Sjögren's syndrome. OBSERVATION: A 48-year-old Chinese woman, without past medical history and a non-smoker, presented an alteration in her overall condition, dyspnoea at exercise, inflammatory polyarthralgia, and a dry eye and mouth syndrome over the last few months. Thoracic tomodensitometry detected an anterior heterogenic cystic mediastinal mass. A mediastinotomy was performed. The diagnosis of the surgical biopsy was thymic MALT lymphoma. The authors also diagnosed Sjögren's syndrome with the presence of four diagnostic criteria. Chemotherapy by rituximab, cyclophosphamide, vincristine, prednisone induced major tumoral regression. The patient declined surgery and will be monitored. CONCLUSION: Thymic MALT lymphoma is a rare pathology. There is a high correlation with autoimmune diseases, like Sjögren's syndrome. Its appearance is that of an anterior mediastinal mass with a cystic component. The treatment is not well codified and is most often based on surgical resection, eventually followed by chemotherapy or radiotherapy. As far as the authors know, this is the second case of thymic MALT lymphoma treated by exclusive chemotherapy.

Echocardiographic features, mortality, and adrenal function in patients with cirrhosis and septic shock.

OBJECTIVES: Cirrhosis of the liver is associated with an increased susceptibility to bacterial infections capable of causing septic shock and with a basal hyperdynamic circulatory state. The primary objective of this study was to delineate the echocardiographic characteristics and outcomes of septic shock in patients with liver cirrhosis. The secondary objective was to determine whether adrenal insufficiency, which may contribute to hyperdynamic syndrome, was more marked in patients with cirrhosis than in other patients with septic shock. DESIGN: Prospective single-center cohort study. PATIENTS AND METHODS: Thirty-four patients admitted to the intensive care unit (ICU) for septic shocks were included, 14 with and 20 without liver cirrhosis. Echocardiography was performed within the first 24 h to measure the cardiac index (CI), systolic index (SI), and left ventricular ejection fraction (LVEF). A Synacthen test was performed. RESULTS: Patients with cirrhosis had higher values for the CI (3.69+/-1.0 vs. 2.86+/-0.8 l/min/m(2); P=0.02), SI (37.5+/-8 vs. 32.4+/-7 ml/m(2); P=0.04), and LVEF (67+/-7 vs. 55.9+/-12%; P=0.005). ICU mortality was 53% overall, 64% in patients with cirrhosis, and 45% in patients without cirrhosis (P=0.27). Serum cortisol levels under basal conditions (H0) and after stimulation (H1) showed no significant differences between patients with and without cirrhosis. The proportion of patients with no response to Synacthen was 77% among patients with cirrhosis and 50% among patients without cirrhosis (P=0.18). CONCLUSION: In a population with septic shock, left ventricular function was more hyperdynamic in the subset with cirrhosis. Relative adrenal insufficiency occurred in similar proportions of patients with and without cirrhosis.