Immune checkpoint inhibitors in patients aged 80 or older with advanced non-small cell lung cancer or melanoma: a real-life multicentre study.

BACKGROUND: Data regarding characteristics, safety and survival outcomes of patients aged 80 or older treated with immune checkpoint inhibitors (ICI) in routine oncology practice are limited. MATERIALS AND METHODS: We retrospectively collected data of patients aged 80 and older with advanced non-small cell lung cancer (NSCLC) or melanoma treated with anti-PD1, anti-PD-L1 or anti-CTLA-4 regardless of the treatment line, in 14 institutions, between January 2014 and June 2017. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan Meier method. Toxicity was assessed according to CTCAE 5.0. Multivariate analyses were performed with the Cox model. RESULTS: Eighty-two patients were included (36 with NSCLC, 45 with melanoma). Their median age was 82 years (range 80-93). Nivolumab and pembrolizumab were mainly used. In the NSCLC group, median PFS and OS were 2.3 months (95%CI 1.8-6.1) and 8.8 months (95%CI 5.5-18.1), respectively. In the melanoma group, median PFS and OS were 10.2 months (95%CI 4.5-20.0) and 24.5 months (95%CI 14.1-NR), respectively. The albumin level was found to be independently associated with a better OS in both groups. Grade 3-4 toxicities occurred in 15 patients (18.5%). One patient died from ICI-induced pulmonary toxicity. CONCLUSION: Our study findings suggest that treatment with ICI in elderly patients with NSCLC and melanoma has a risk-benefit ratio that supports its use. However, we report in this cohort that one in five patients has a grade 3-4 IRAEs leading to treatment discontinuation. Geriatric assessment prior to initiation of therapy and during therapy should be routine in patients aged 80 years and older.

Implementation of a molecular tumor board at a regional level to improve access to targeted therapy.

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.

Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial.

BACKGROUND: 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. METHODS: 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 vs <3 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: French Cooperative Thoracic Intergroup.

MST1/Hippo promoter gene methylation predicts poor survival in patients with malignant pleural mesothelioma in the IFCT-GFPC-0701 MAPS Phase 3 trial.

BACKGROUND: The Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS/NCT00651456) phase 3 trial demonstrated the superiority of bevacizumab plus pemetrexed-cisplatin triplet over chemotherapy alone in 448 malignant pleural mesothelioma (MPM) patients. Here, we evaluated the prognostic role of Hippo pathway gene promoter methylation. METHODS: Promoter methylations were assayed using methylation-specific polymerase chain reaction in samples from 223 MAPS patients, evaluating their prognostic value for overall survival (OS) and disease-free survival in univariate and multivariate analyses. MST1 inactivation effects on invasion, soft agar growth, apoptosis, proliferation, and YAP/TAZ activation were investigated in human mesothelial cell lines. RESULTS: STK4 (MST1) gene promoter methylation was detected in 19/223 patients tested (8.5%), predicting poorer OS in univariate and multivariate analyses (adjusted HR: 1.78, 95% CI (1.09-2.93), p = 0.022). Internal validation by bootstrap resampling supported this prognostic impact. MST1 inactivation reduced cellular basal apoptotic activity while increasing proliferation, invasion, and soft agar or in suspension growth, resulting in nuclear YAP accumulation, yet TAZ cytoplasmic retention in mesothelial cell lines. YAP silencing decreased invasion of MST1-depleted mesothelial cell lines. CONCLUSIONS: MST1/hippo kinase expression loss is predictive of poor prognosis in MPM patients, leading to nuclear YAP accumulation and electing YAP as a putative target for therapeutic intervention in human MPM.

Characteristics of Lung Cancer in Patients Younger than 40 Years: A Prospective Multicenter Analysis in France.

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.

Effect of Continuous versus Intermittent Subglottic Suctioning on Tracheal Mucosa by the Mallinckrodt TaperGuard Evac Oral Tracheal Tube in Intensive Care Unit Ventilated Patients: A Prospective Randomized Study.

BACKGROUND AND AIMS: A risk of tracheal mucosa injury induced by subglottic suctioning has been raised. Therefore, this prospective randomized study aims to compare the effect of continuous suctioning of subglottic secretions versus intermittent suctioning of subglottic secretions (CSSS vs. ISSS) secretions on tracheal mucosa in front of the suctioning port of the endotracheal tube. PATIENTS AND METHODS: Patients requiring intubation or reintubation in Intensive Care Unit with an expected ventilation duration > 24 h were eligible. Participants received CSSS at -20 mmHg or ISSS at -100 mmHg during 15 s and no suction during 8 s. The effect on tracheal mucosa in front of the suction port was assessed after intubation (T0) and before extubation (T1) using bronchoscopy. Tracheal mucosa damages were graded into five categories (no injury, erythema, edema, ulceration, or necrosis). The occurrence (no injury observed at T0 but present at T1) or the worsening (injury observed at T0 exacerbating at T1) was studied. RESULTS: Seventy-three patients were included and 53 patients (CSSS, n = 26 and ISSS, n = 27) were evaluable on the primary endpoint. The occurrence or worsening of tracheal mucosal damages did not differ between the two groups (CSSS, n = 7 [27%] vs. ISSS, n = 5 [17%], P = 0.465). Daily average volume of suctioned secretion was higher with ISSS (74 ± 100 ml vs. 20 ± 25 ml, P < 0.001). Impossibility to aspirate was higher with CSSS (0.14 ± 0.16 per day vs. 0.03 ± 0.07 per day, P < 0.001). CONCLUSIONS: Our results suggest that tracheal mucosal damages did not differ between CSSS and ISSS. The aspirated volume was higher and impossibility to aspirate was lower with ISSS. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01555229.

Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial.

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 Cancérologie Thoracique (IFCT).

Afatinib or Bevacizumab in combination with Osimertinib efficiently control tumor development in orthotopic murine models of non-small lung cancer.

Lung cancer is one of the most common and deadliest cancers. Preclinical models are essential to study new therapies and combinations taking tumor genetics into account. We have established cell lines expressing the luciferase gene from lines with varied genetic backgrounds, commonly encountered in patients with pulmonary adenocarcinoma. We have characterized these lines by testing their response to multiple drugs. Thus, we have developed orthotopic preclinical mouse models of NSCLC with very high engraftment efficiency. These models allow the easy monitoring of tumor growth, particularly in response to treatment, and of tumor cells dissemination in the body. We show that concomitant treatment with osimertinib (3rd generation tyrosine kinase inhibitor targeting mutated EGFR) and bevacizumab (anti-angiogenic targeting VEGF) can have a beneficial therapeutic effect on EGFR-mutated tumors. We also show that the addition of afatinib to osimertinib-treated tumors in escape leads to tumor growth inhibition. No such effect is observed with selumetinib or simvastatin. These preclinical mouse models therefore make it possible to test innovative therapeutic combinations and are also a tool of choice for studying resistance mechanisms.

Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.

BACKGROUND: Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations. We aimed to assess the safety and efficacy of erlotinib compared with standard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC. METHODS: We undertook the open-label, randomised phase 3 EURTAC trial at 42 hospitals in France, Italy, and Spain. Eligible participants were adults (> 18 years) with NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease (neoadjuvant or adjuvant chemotherapy ending ≥ 6 months before study entry was allowed). We randomly allocated participants (1:1) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of standard intravenous chemotherapy of cisplatin 75 mg/m(2) on day 1 plus docetaxel (75 mg/m(2) on day 1) or gemcitabine (1250 mg/m(2) on days 1 and 8). Carboplatin (AUC 6 with docetaxel 75 mg/m(2) or AUC 5 with gemcitabine 1000 mg/m(2)) was allowed in patients unable to have cisplatin. Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status (0 vs 1 vs 2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed safety in all patients who received study drug (≥ 1 dose). This study is registered with ClinicalTrials.gov, number NCT00446225. FINDINGS: Between Feb 15, 2007, and Jan 4, 2011, 174 patients with EGFR mutations were enrolled. One patient received treatment before randomisation and was thus withdrawn from the study; of the remaining patients, 86 were randomly assigned to receive erlotinib and 87 to receive standard chemotherapy. The preplanned interim analysis showed that the study met its primary endpoint; enrolment was halted, and full evaluation of the results was recommended. At data cutoff (Jan 26, 2011), median PFS was 9·7 months (95% CI 8·4-12·3) in the erlotinib group, compared with 5·2 months (4·5-5·8) in the standard chemotherapy group (hazard ratio 0·37, 95% CI 0·25-0·54; p < 0·0001). Main grade 3 or 4 toxicities were rash (11 [13%] of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group), neutropenia (none vs 18 [22%]), anaemia (one [1%] vs three [4%]), and increased amino-transferase concentrations (two [2%] vs 0). Five (6%) patients on erlotinib had treatment-related severe adverse events compared with 16 patients (20%) on chemotherapy. One patient in the erlotinib group and two in the standard chemotherapy group died from treatment-related causes. INTERPRETATION: Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors. FUNDING: Spanish Lung Cancer Group, Roche Farma, Hoffmann-La Roche, and Red Temática de Investigacion Cooperativa en Cancer.

Reaching multidisciplinary consensus on the management of non-bulky/non-infiltrative stage IIIA N2 non-small cell lung cancer.

INTRODUCTION: The optimal management of patients with non-bulky/non-infiltrative stage IIIA N2 non-small cell lung cancer (NSCLC) remains controversial. In this modified Delphi study from France, we aimed to generate agreement through multidisciplinary decision-making on the clinical management of patients with non-bulky/non-infiltrative N2 NSCLC. METHODS: An expert panel of 30 physicians from different specialities completed two Delphi rounds of a 76-item questionnaire, pertaining to: pathological confirmation of N2 disease; initial treatment approach; treatment approach in case of disease progression/stability following neoadjuvant chemotherapy; treatment approach taking into account various patient and tumour characteristics. Each questionnaire item was scored using a 9-point Likert scale. Consensus in agreement was achieved if ≥ 80 % of responses to a questionnaire item were scored between 7 and 9 and if the median value of the score to the item was ≥ 7. RESULTS: Regarding the pathologic confirmation of N2 disease, agreement (up to 100 %) was reached on endobronchial ultrasound/endoscopic ultrasound as the preferred method of initial mediastinal staging for paratracheal lymph nodes. There was also panellist agreement (up to 93 %) on the adoption as first-line treatment of surgery and (neo)adjuvant chemotherapy in patients with single-station disease, and of concurrent chemoradiotherapy followed by adjuvant immunotherapy in those with multi-station N2 disease. Panellists further agreed on the use of a non-surgical strategy, i.e., concurrent chemoradiotherapy with adjuvant immunotherapy, in patients with single-station N2 disease in case of: involvement of ≥ 2 mediastinal lymph nodes; disease progression following neoadjuvant chemotherapy; compromised cardiopulmonary function if compatible with radiotherapy; anticipated right pneumonectomy. CONCLUSIONS: This Delphi study reinforces the importance of multidisciplinary discussions leading to the best individual approach to the clinical management of patients with non-bulky/non-infiltrative N2 NSCLC, a challenging heterogeneous population.

Safety and efficacy of second-line metronomic oral vinorelbine-atezolizumab combination in stage IV non-small-cell lung cancer: An open-label phase II trial (VinMetAtezo).

OBJECTIVE: To evaluate the safety and efficacy of second-line metronomic oral vinorelbine-atezolizumab combination for stage IV non-small-cell lung cancer. METHODS: This was a multicenter, open-label, single-arm Phase II study performed in patients with advanced NSCLC without activating EGFR mutation or ALK rearrangement who progressed after first-line platinum-doublet chemotherapy. Combination treatment was atezolizumab (1200 mg IV day 1, every 3 weeks) and oral vinorelbine (40 mg, 3 times by week). The primary outcome was progression-free survival (PFS) during the 4-month follow-up from the first dose of treatment. Statistical analysis was based on the exact single-stage Phase II design defined by A'Hern. Based on literature data, the Phase III trial threshold was set at 36 successes in 71 patients. RESULTS: 71 patients were analyzed (median age, 64 years; male, 66.2%; ex-smokers/active smokers, 85.9%; ECOG performance status 0-1, 90.2%; non-squamous NSCLC, 83.1%; PD-L1 ≥ 50%, 4.4%). After a median follow-up of 8.1 months from treatment initiation, 4-month PFS rate was 32% (95% CI, 22-44), i.e. 23 successes out 71 patients. OS rate was 73.2% at 4 months and 24.3% at 24 months. Median PFS and OS were 2.2 (95% CI, 1.5-3.0) months and 7.9 (95% CI, 4.8-11.4) months, respectively. Overall response rate and disease control rate at 4 months were 11% (95% CI, 5-21) and 32% (95% CI, 22-44), respectively. No safety signal was evidenced. CONCLUSION: Metronomic oral vinorelbine-atezolizumab in the second-line setting did not achieve the predefined PFS threshold. No new safety signal was reported for vinorelbine-atezolizumab combination.

Real-life second-line epirubicin-paclitaxel regimen as treatment of relapsed small-cell lung cancer: EpiTax study.

BACKGROUND: Few therapeutic options are approved as second-line treatment after failure of platinum-based chemotherapy for patients with extensive-stage small-cell lung cancer (ES-SCLC). Topotecan widespread use remains challenged by the risk of severe toxicities in a pretreated population. Little is known about the efficacy and safety of epirubicin-paclitaxel doublet in second-line and beyond and especially cerebral outcomes. METHODS: EpiTax is a retrospective multicenter observational real-life study. We evaluated the efficacy of epirubicin 90 mg/m2 combined with paclitaxel 175 mg/m2 every 3 weeks in SCLC patients after failure of at least one line of platinum-based chemotherapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), intracranial control rate (ICR), and safety. RESULTS: A total of 29 patients were included. The median of previous systemic therapy lines was 2 (1-4). Eleven patients received the treatment in the second line. Characteristics of patients were a median age of 60 years (45-77), 65.5% of males with 72.4% of PS 0-1. Fifteen patients had a history of brain metastases. Median PFS and OS achieved 11.0 (95% CI, 8.1-16.3) and 23 (95% CI, 14.1-29.6) weeks, respectively. ORR was 34.5% and DCR was 55.2%. ICR was 3/15 (20%). Grade 3-4 adverse events were mainly hematological and concerned 7 patients. No case of febrile neutropenia or toxic death was reported. CONCLUSION: Epirubicin-paclitaxel association highlighted promising efficacy with PFS and OS of 11 and 23 weeks, respectively, ORR of 34.5%, and a tolerable safety profile. This doublet could represent another valuable therapeutic option for ES-SCLC patients treated in the second line and beyond.

Predictors of three-month mortality and severe chemotherapy-related adverse events in patients aged 70 years and older with metastatic non-small-cell lung cancer: A secondary analysis of ESOGIA-GFPC-GECP 08-02 study.

INTRODUCTION: Predictors for mortality and toxicity in older patients with cancer are mainly studied in cohorts with various cancers at different stages. This study aims to identify predictive geriatric factors (PGFs) for early death and severe chemotherapy related adverse events (CRAEs) in patients aged ≥70 years with metastatic non-small-cell lung cancer (mNSCLC). MATERIAL AND METHODS: This is a secondary analysis of the multicenter, randomized, phase 3 ESOGIA trial that compared, for patients ≥70 years with mNSCLC, a treatment algorithm based on performance status and age to another algorithm based on geriatric assessment. To identify PGFs of three-month mortality and grade 3, 4, or 5 CRAEs, multivariate Cox models and logistic models, adjusted for treatment group and center, and stratified by randomization arm, were constructed. RESULTS: Among 494 included patients, 145 (29.4%) had died at three months and 344 (69.6%) had severe chemotherapy toxicity. For three-month mortality, multivariate analyses retained mobility (Test Get up and Go), instrumental activity of daily living (IADL) dependence and weight loss as PGFs. The combined effect of IADL ≤2/4 and weight loss ≥3 kg was strongly associated with three-month mortality (adjusted hazard ratio: 5.71 [95% confidence interval [CI]: 2.64-12.32]). For chemotherapy toxicity, Charlson Comorbidity Index ≥2 was independently associated with grade3, 4, or 5 CRAEs (adjusted odds ratio [95% CI]: 1.94 [1.06-3.56]). DISCUSSION: Mobility, IADL dependence, and weight loss were predictive of three-month mortality in a population aged ≥70 years treated for mNSCLC, while comorbidities were independently associated with severe chemotherapy toxicity.

Real-World Treatment Outcomes of MET Exon14 Skipping in Non-small Cell Lung Cancer: GFPC 03-18 Study.

BACKGROUND: MET-targeted tyrosine kinase inhibitors (TKIs) demonstrated efficacy in advanced non-small cell lung cancer (aNSCLC) with MET exon14 skipping mutations (METexon14); yet, data on the management of these patients in clinical practice is sparse. OBJECTIVE: The aim of this study was to describe the management of METexon14 aNSCLC patients. PATIENTS AND METHODS: This real-life, retrospective study analyzed the management of METexon14 aNSCLC. The primary endpoint was the median overall survival (mOS). Secondary endpoints were to assess investigator-progression-free survival (PFS) and mOS in different subgroups: patients treated with (a) crizotinib, regardless of treatment line; (b) anti-MET TKIs (crizotinib, tepotinib, capmatinib); and (c) immunotherapy. RESULTS: A total of 118 patients were included between December 2015 and January 1, 2020 in 13 centers. Median age was 73 years, 62.7% were female, 83.9% had adenocarcinoma, 92.4% at stage IV, and 27% had more than three metastatic sites. The majority of the patients (106, 89.8%) received at least one systemic treatment; 73% received at least one anti-MET TKI: crizotinib (68.6%), tepotinib (16%), capmatinib (10%). Only 10% received two anti-MET TKIs in their treatment sequences. With a median follow-up of 16 months (95% CI 13.6-29.7), mOS was 27.1 months (95% CI 18-31.4). There was no significant difference between mOS of patients treated and never treated with crizotinib, 19.7 (95% CI 13.6-29.7) and 28 (95% CI 16.4-NR) months, respectively (p = 0.16); mOS of the TKI cohort and of the TKI-naïve patient cohort were 27.1 (95% CI 18-29.7) and 35.6 (95% CI 8.6-NR) months respectively, with no significant difference (p = 0.7). CONCLUSIONS: In this real-life study, there was no evidence of benefit in mOS with anti-MET TKIs.

Pembrolizumab plus pemetrexed-carboplatin combination in first-line treatment of advanced non-squamous non-small cell lung cancer: a multicenter real-life study (CAP29).

Background: Pembrolizumab combined with chemotherapy is now first-line standard of care in advanced non-small cell lung cancer. This real-life study aimed to assess efficacy and safety of carboplatin-pemetrexed plus pembrolizumab in advanced non-squamous non-small cell lung cancer. Methods: CAP29 is a retrospective, observational, multicenter real-life study conducted in 6 French centers. We evaluated efficacy of first-line setting chemotherapy plus pembrolizumab (November 2019 to September 2020) in advanced (stage III-IV) non-squamous non-small cell lung cancer patients without targetable alterations. Primary endpoint was progression-free survival. Secondary endpoints were overall survival, objective response rate and safety. Results: With a median follow-up of 4.5 months (0 to 22 months), a total of 121 patients were included. Baseline characteristics were: median age of 59.8 years with 7.4% ≥75 years, 58.7% of males, 91.8% PS 0-1, 87.6% of stage IV with ≥3 metastatic sites in 62% of cases. Patients had brain and liver metastases in 24% and 15.7% of cases, respectively. PD-L1 was <1% (44.6%), 1-49% (28.1%) and ≥50% (21.5%). Median progression-free survival and overall survival achieved 9 and 20.6 months, respectively. Objective response rate was 63.7% with 7 prolonged complete responses. Survival benefit seemed to be correlated with PD-L1 expression. Brain and liver metastases were not statistically associated with decreased overall survival. Most common adverse events were asthenia (76%), anemia (61.2%), nausea (53.7%), decreased appetite (37.2%) and liver cytolysis (34.7%). Renal and hepatic disorders were the main causes of pemetrexed discontinuation. Grade 3-4 adverse events concerned 17.5% of patients. Two treatment-related deaths were reported. Conclusions: First-line pembrolizumab plus chemotherapy confirmed real-life efficacy for patients with advanced non-squamous non-small cell lung cancer. With median progression-free survival and overall survival of 9.0 and 20.6 months, respectively and no new safety signal, our real-life data are very close to results provided by clinical trials, confirming the benefit and the manageable toxicity profile of this combination.

Clinical Characteristics of Patients with Advanced ALK-Translocated Non-small Cell Lung Cancers and Long-Term Responses to Crizotinib (CRIZOLONG GFPC 05-19 Study).

BACKGROUND: Although ALK-translocated (ALK+) advanced non-small cell lung cancers (aNSCLCs) are currently treated with second- or third-generation ALK inhibitors (ALK-TKIs), some patients respond durably to the first-generation ALK-TKI crizotinib. OBJECTIVE: This study aimed to describe the clinical characteristics of these long-term responders. PATIENTS AND METHODS: This national, multicenter, retrospective, non-interventional study included patients with ALK+ aNSCLCs and long-term responses to first (L1)- or subsequent (≥ L2)-line crizotinib, defined, respectively, as treatments lasting > 18 and > 10 months. Median treatment duration (mDOT) was the primary endpoint. RESULTS: A total of 85 patients (32 L1 and 53 ≥ L2 responders) from 23 centers were included (receiving crizotinib between 10/24/2011-10/02/2018): median age of 59 years, 83.6% non-smokers or ex-smokers, 85.9% performance status (PS) 0/1, 94.1% with adenocarcinomas, median of one metastatic site, and 22.4% with brain metastases (BMs). After median follow-up of 73.4 [95% confidence interval, 67.5-79.9] months, respective L1 and ≥ L2 mDOTs were 43.3 [26.7-56.8] and 29.6 [22.6-35.8] months, with overall survival (OS) not reached (NR) and 116.2 [83.4-NR] months. BM presence or absence did not affect mDOT (31.4 versus 32.9 months) but significantly impacted median OS (70.6 versus 158.6 months; p = 0.0008). Progression on crizotinib was paucisymptomatic (74.1%) and oligometastatic (34.8%), especially BMs (42.4%). After crizotinib discontinuation, 65 (76.5%) patients received subsequent systemic therapy: 57 (67.1%) with second-generation ALK-TKIs. Respective mDOTs of first- and second-line post-crizotinib ALK-TKIs lasted 19.4 [14.9-25.6] and 11.1 [4.8-17.9] months, respectively. CONCLUSIONS: Most ALK+ aNSCLC patients with prolonged crizotinib efficacy had paucisymptomatic and oligometastatic disease without BMs. They subsequently benefited from a sequential strategy with other ALK-TKIs.

Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output.

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 < .001). Median cardiac index at 6 months was significantly lower than before treatment (4.1 L/min/m(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.

[Semantic analysis of online conversations on lung cancer: The WE-Lung research]. / Analyse sémantique de conversations sur le web portant sur le cancer du poumon : étude Web Ethnography-Lung.

INTRODUCTION: Today, patients with lung cancer and their relatives can easily search information on the Internet and express themselves online. METHODS: Within this web-ethnographic research, we found, based on 246 search terms related to lung cancer, and collected, a sample of 136 online conversations that were published between January 2004 and September 2018, including 1220 messages by 762 authors. RESULTS: The authors of messages, many of them close relatives of patients (35%), share their experience (34%). Seven areas of worrying concern, each of them prominent in 10 to 24% of the corpus, can be grouped under three headings: accepting the disease in order for the patient or their caregiver to fight it ("decide on the prognosis", "managing the treatments", "stopping the progression"), conjuring fate ("naming the guilty ones", "conjuring powerlessness"), asserting resilience ("adopt the right attitude" and "telling one's story in order to survive"). The question of time - disrupted, lost, to be caught up with or controlled - runs through all the issues. DISCUSSION: The patients' and caregivers' concerns go beyond the pace of medical treatment and beyond death. Their mental representations of the disease influence their adherence to the care pathway. Welcoming them in our care and dialogue goes hand in hand with personalized treatment.

Machine Learning-Based Analysis of Treatment Sequences Typology in Advanced Non-Small-Cell Lung Cancer Long-Term Survivors Treated With Nivolumab.

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

Targeted Therapy for Older Patients with Non-Small Cell Lung Cancer: Systematic Review and Guidelines from the French Society of Geriatric Oncology (SoFOG) and the French-Language Society of Pulmonology (SPLF)/French-Language Oncology Group (GOLF).

Systematic molecular profiling and targeted therapy (TKI) have changed the face of Non-Small Cell Lung Cancer (NSCLC) treatment. However, there are no specific recommendations to address the prescription of TKI for older patients. A multidisciplinary task force from the French Society of Geriatric Oncology (SoFOG) and the French Society of Pulmonology/Oncology Group (SPLF/GOLF) conducted a systematic review from May 2010 to May 2021. Protocol registered in Prospero under number CRD42021224103. Three key questions were selected for older patients with NSCLC: (1) to whom TKI can be proposed, (2) for whom monotherapy should be favored, and (3) to whom a combination of TKI can be proposed. Among the 534 references isolated, 52 were included for the guidelines. The expert panel analysis concluded: (1) osimertinib 80 mg/day is recommended as a first-line treatment for older patients with the EGFR mutation; (2) full-dose first generation TKI, such as erlotinib or gefitinib, is feasible; (3) ALK and ROS1 rearrangement studies including older patients were too scarce to conclude on any definitive recommendations; and (4) given the actual data, TKI should be prescribed as monotherapy. Malnutrition, functional decline, and the number of comorbidities should be assessed primarily before TKI initiation.