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INTRODUCTION: The safety of first-line (1L) durvalumab in patients with advanced nonsmall-cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 (PS2) is unknown. This is an interim unplanned safety analysis of the study SAKK 19/17 for patients with metastatic NSCLC with programmed death-ligand 1 (PD-L1) expression in ≥ 25% of tumor cells and an ECOG PS2 treated with 1L durvalumab. This safety analysis was triggered by the SAKK data and safety monitoring board due to a high mortality rate observed after the recruitment of the first 21 patients. METHODS: This single-arm phase II study recruited patients with metastatic NSCLC with PD-L1 in ≥ 25% and ECOG PS2. Patients received durvalumab 1500 mg every four weeks. The trial aims to recruit 48 patients in total. This report includes safety analyses only. Adverse events (AEs) were assessed using National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) Version 5.0. Efficacy data including the primary endpoint overall survival at 6 months and secondary endpoints (objective response rate, progression-free survival, and quality of life) will be reported at a later time point. RESULTS: The data from 21 patients were available at this interim safety analysis. Among these, 13 deaths (13/21; 62%) were reported, including one treatment-related fatal colonic perforation at 9 months after treatment initiation (1/13; 8%). Twelve deaths were not treatment-related (12/13; 92%), and mostly attributed to tumor progression (10/13; 77%). Of note, seven deaths (7/13; 54%) occurred during the first 5 weeks (range 0.6-4.7 weeks) after treatment initiation. Four (4/7; 57%) were respiratory failures attributed to tumor progression. One of these patients (25%) had pre-existing COPD, and three (75%) had baseline dyspnea grade 2-3 related to the tumor. Grade ≥ 3 treatment-related AEs (TRAEs) included colonic perforation (grade 5), abdominal pain, and colitis (grade 3 each) in one patient, and fatigue (grade 3) in another. Other Grade ≥ 3 AEs unrelated to treatment were all of pulmonary origin: lung infections (19%), dyspnea (24%), cough (5%), and bronchial obstruction (5%). CONCLUSIONS: 1L durvalumab in patients with ECOG PS2 and metastatic NSCLC with PD-L1 expression ≥ 25% resulted in an unexpectedly high number of fatal early events due to rapid tumor progression. We recommend to avoid treatment with 1 L durvalumab of patients who are highly symptomatic from the tumor, particularly those with respiratory symptoms. The study is continuing its accrual after an amendment excluding these patients.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Antibodies, Monoclonal/adverse effects , Antineoplastic Agents, Immunological/adverse effects , B7-H1 Antigen/metabolism , Carcinogenesis , Carcinoma, Non-Small-Cell Lung/complications , Carcinoma, Non-Small-Cell Lung/mortality , Drug-Related Side Effects and Adverse Reactions , Female , Humans , Intestinal Perforation/etiology , Lung Neoplasms/complications , Lung Neoplasms/mortality , Male , Neoplasm Metastasis , Neoplasm Staging , Respiratory Insufficiency/etiology , Survival Analysis , Treatment OutcomeABSTRACT
BACKGROUND: The use of Nasal Continuous Positive Airway Pressure Ventilation (NCPAP) has begun to increase and is progressively replacing conventional mechanical ventilation (MV), becoming the cornerstone treatment for newborn respiratory distress syndrome (RDS). However, NCPAP use in Lower-Middle Income Countries (LMICs) is poor. Moreover, bubble NCPAP (bNCPAP), for efficacy, cost effectiveness, and ease of use, should be the primary assistance technique employed in newborns with RDS. OBJECTIVE: To measure the impact on in-hospital newborn mortality of using a bNCPAP device as the first intervention on newborns requiring ventilatory assistance. DESIGN: Prospective pre-intervention and post-intervention study. SETTING: The largest Neonatal Intensive Care Unit (NICU) in Nicaragua. PARTICIPANTS: In all, 230 (2006) and 383 (2008) patients were included. INTERVENTION: In May 2006, a strategy was introduced to promote the systematic use of bNCPAP to avoid intubation and MV in newborns requiring ventilatory assistance. Data regarding gestation, delivery, postnatal course, mortality, length of hospitalisation, and duration of ventilatory assistance were collected for infants assisted between May and December 2006, before the project began, and between May and December 2008, two years afterwards. OUTCOME MEASURES: The pre- vs post-intervention proportion of newborns who died in-hospital was the primary end point. Secondary endpoints included rate of intubation and duration of NICU stay. RESULTS: Significant differences were found in the rate of intubation (72 vs 39%; p < 0.0001) and the proportion of patients treated exclusively with bNCPAP (27% vs 61%; p <0.0001). Mortality rate was significantly reduced (40 vs 23%; p < 0.0001); however, an increase in the mean duration of NICU stay was observed (14.6 days in 2006 and 17.5 days in 2008, p = 0.0481). The findings contribute to the evidence that NCPAP, particularly bNCPAP, is the first-line standard of care for efficacy, cost effectiveness, and ease of use in newborns with respiratory distress in LMICs. CONCLUSIONS: This is the first extensive survey performed in a large NICU from a LMICs, proving the efficacy of the systematic use of a bNCPAP device in reducing newborn mortality. These findings are an incentive for considering bNCPAP as an elective strategy to treat newborns with respiratory insufficiency in LMICs.
Subject(s)
Continuous Positive Airway Pressure/economics , Continuous Positive Airway Pressure/methods , Developing Countries , Intensive Care Units, Neonatal , Respiratory Distress Syndrome, Newborn/therapy , Cost-Benefit Analysis , Delivery, Obstetric , Female , Gestational Age , Hospital Mortality , Humans , Infant, Newborn , Length of Stay , Male , Nicaragua , Prospective Studies , Respiratory Distress Syndrome, Newborn/mortalityABSTRACT
INTRODUCTION: The safety and efficacy of first-line durvalumab in PS2 patients with advanced NSCLC is unknown. Here, we present the primary analysis of first-line durvalumab in PS2 patients, unsuitable for combination chemotherapy. METHODS: In this single-arm, multicenter, phase II trial patients with PD-L1 positive (tumor proportional score ≥25%), advanced NSCLC with PS2, received four-weekly durvalumab 1500 mg. The primary endpoint was overall survival (OS) at 6 months. RESULTS: Forty-eight patients were included. Median follow-up was 23.3 months (95% CI: 14.3-28.6). OS at 6 months was 60% (95% CI: 45-74%). Median OS was 8.5 months (95%CI: 4.4-16.7). Objective response rate and median progression free survival were 17% (95% CI: 8-30%) and 2.5 months (95% CI: 1.8-7.1), respectively. Thirty-three deaths were observed at the time point of the analysis. Seven early fatal events considered not treatment-related occurred during the first 5 weeks of treatment. Four out of the first 7 early fatal events (4/7; 57%) were respiratory failure in patients with advanced symptomatic primary lung tumors. Three more early fatal events occurred after exclusion of patients with grade ≥ 3 dyspnea. Treatment-related AEs ≥G3 were reported in 9 patients (19%) and included colonic perforation in one patient (grade 5), colitis in 4 patients (8%), increased lipase in 3 patients (6%), and hepatitis in 2 patients (4%). CONCLUSIONS: First-line durvalumab in PS2 patients with advanced PD-L1 positive NSCLC results in a high number of early fatal events. When patients with grade ≥ 3 dyspnea are excluded a promising 6-month OS with an acceptable toxicity profile can be observed. Durvalumab could be an option instead of single agent chemotherapy for PS2 patients who are not candidates for platinum doublet chemotherapy provided they are well selected.
Subject(s)
Antibodies, Monoclonal , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/pathology , B7-H1 Antigen/metabolism , Dyspnea , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
BACKGROUND: The prognostic role of programmed death-ligand 1 (PD-L1) expression in patients with localised and locally advanced non-small cell lung cancer has not been fully elucidated. This information could help to better interpret recent and upcoming results of phase III adjuvant or neoadjuvant anti-PD-1/PD-L1 immunotherapy studies. METHODS: In a cohort of 146 patients with early or locally advanced non-small cell lung cancer treated with curative intent (by surgery or radiotherapy), we investigated the prognostic value of PD-L1 expression and its correlation with other biological and clinical features. PD-L1 expression was stratified by quartiles. Primary endpoints were overall and disease-free survival. We also analysed the prognostic impact of the presence of actionable mutations, implemented treatment modality and completion of the treatment plan. Neither type of patient received neoadjuvant or adjuvant immunotherapy or target therapy. RESULTS: Of the 146 selected patients, 32 (21.9%) presented disease progression and 15 died (10.3%) at a median follow-up of 20 months. In a univariable analysis, PD-L1 expression ≥25% was associated with significantly lower disease-free survival (hazard ratio [HR]) 1.9, 95% confidence interval [CI] 1.0-3.9, p = 0.049). PD-L1 expression ≥50% did not lead to disease-free survival or overall survival benefits (HR 1.2 and 1.1, respectively; 95% CI 0.6-2.6 and 0.3-3.4, respectively; pnot significant). In a multivariate analysis, a stage >I (HR 2.7, 95% CI 1.2-6, p = 0.012) and having an inoperable tumour (HR 3.2, 95% CI 1.4-7.4, p = 0.005) were associated with lower disease-free survival. CONCLUSION: The population of patients with early-stage non-small cell lung cancer and PD-L1 expression ≥25% who were treated with curative intent during the pre-immunotherapy era exhibited a worse prognosis. This finding provides justification for the utilisation of adjuvant immunotherapy in this subgroup of patients, based on the current evidence derived from disease-free survival outcomes. However, for patients with PD-L1 expression <25%, opting to wait for the availability of the overall survival results may be a prudent choice.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/therapy , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/therapy , Lung Neoplasms/drug therapy , B7-H1 Antigen , Prognosis , Retrospective StudiesABSTRACT
In non-small cell lung cancer (NSCLC) the most common alterations are identified in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, accounting for approximately 30% of cases in Caucasian patients. The majority of mutations are located in exon 2, with the c.34G > T (p.G12C) change being the most prevalent. The clinical relevance of KRAS mutations in NSCLC was not recognized until a few years ago. What is now emerging is a dual key role played by KRAS mutations in the management of NSCLC patients. First, recent data report that KRAS-mutant lung AC patients generally have poorer overall survival (OS). Second, a KRAS inhibitor specifically targeting the c.34G > T (p.G12C) variant, Sotorasib, has been approved by the U.S. Food and Drug Administration (FDA) and by the European Medicines Agency. Another KRAS inhibitor targeting c.34G > T (p.G12C), Adagrasib, is currently being reviewed by the FDA for accelerated approval. From the description of the biology of KRAS-mutant NSCLC, the present review will focus on the clinical aspects of KRAS mutations in NSCLC, in particular on the emerging efficacy data of Sotorasib and other KRAS inhibitors, including mechanisms of resistance. Finally, the interaction between KRAS mutations and immune checkpoint inhibitors will be discussed.
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BACKGROUND: Immune checkpoint inhibitors (ICIs) targeting PD-1 or PD-L1 improved the survival of non-small cell lung cancer (NSCLC) patients with PD-L1 expression ≥50% and without alterations in EGFR, ALK, ROS1, RET. However, markers able to predict the efficacy of ICIs, in combination with PD-L1 expression are still lacking. Our aim in this hypothesis-generating pilot study was to evaluate whether the KRAS G12C variant may predict the efficacy of ICIs in advanced NSCLC patients with PD-L1 ≥ 50%. METHODS: Genomic DNA or tissue sections of 44 advanced ICI-treated NSCLC cases with PD-L1 ≥ 50% without EGFR, ALK, ROS1, RET alterations were tested using Next Generation Sequencing, Fluorescence in Situ Hybridization and immunohistochemistry. Statistical analyses were carried out fitting univariate and multivariate time to event models. RESULTS: KRAS G12C mutant patients (N = 11/44) showed a significantly longer progression-free survival (PFS) at univariate and multivariate analyses (p = 0.03). The Kaplan-Meier plot of the PFS time-to-event supports that G12C positive patients have a longer time to progress. PFS improvement was not observed when any KRAS mutations were compared to wild-type cases. CONCLUSIONS: Given the limitations due to the small sample size and exploratory nature of this study, we tentatively conclude the KRAS G12C mutation should be considered in future trials as a predictive marker of prolonged response to first-line ICIs in NSCLC patients overexpressing PD-L1. This finding could be relevant as anti-KRAS G12C therapies enter the therapeutic landscape of NSCLC.
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BACKGROUND: KRAS mutations are found in 20-25 % of non-squamous non-small cell lung cancer (NSCLC) and therapies targeting the RAS/MEK/ERK pathway are in development. We performed a multicenter open-label phase 1B trial to determine the recommended phase 2 dose and early antitumor activity of the MEK-inhibitor binimetinib combined with cisplatin and pemetrexed. METHODS: Eligible patients (pts) had stage III-IV NSCLC unsuitable for curative treatment, KRAS exon 2 or 3 (codon 12, 13 or 61) mutations, no prior systemic therapy. Pts were enrolled into part 1: 3â¯+â¯3 design with dose escalation in 2 dose levels (DL) of binimetinib and part 2: expansion cohort at the maximum tolerated dose (MTD). Pts received 4 cycles of cisplatin 75â¯mg/m2, pemetrexed 500â¯mg/m2and binimetinib 30 (DL1)/45â¯mg (DL2) orally twice a day (bid) d1-14 q3w followed by pemetrexed and binimetinib until progressive disease (PD) or unacceptable toxicity. RESULTS: From May 2017 to Dec 2019, 18 pts (13 dose escalation, 5 expansion cohort) were enrolled. Median age was 60 (48-73, range). KRAS mutations were 87.5 % at codon 12. No DLT occurred in the dose escalation cohort. Median number of cycles was 2 (1-17, range). Treatment discontinuation was mainly due to PD (33 %) or pts/physicians' decision (27 %). Together with the expansion cohort, 16 pts were evaluable for safety. Most frequent treatment-related grade 3 AEs were lung infection (25 %), fatigue (19 %), anemia (19 %). Overall response rate among 9 evaluable pts receiving binimetinib at MTD (45â¯mg bid) was 33 % (7-70 %, 95 % CI). Median progression-free survival was 5.7 months (1.1-14.0, 95 % CI) and overall survival 6.5 months (1.8-NR, 95 % CI). CONCLUSIONS: Pts treated with combination of cisplatin, pemetrexed and binimetinib presented no unexpected toxicity. No early signal of increased antitumor activity of binimetinib added to chemotherapy was observed in our pts population.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Benzimidazoles , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Cisplatin/therapeutic use , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Middle Aged , Mutation , Pemetrexed/therapeutic use , Proto-Oncogene Proteins p21(ras)/geneticsABSTRACT
PURPOSE: For patients with resectable stage IIIA(N2) non-small-cell lung cancer, neoadjuvant chemotherapy with cisplatin and docetaxel followed by surgery resulted in a 1-year event-free survival (EFS) rate of 48% in the SAKK 16/00 trial and is an accepted standard of care. We investigated the additional benefit of perioperative treatment with durvalumab. METHODS: Neoadjuvant treatment consisted of three cycles of cisplatin 100 mg/m2 and docetaxel 85 mg/m2 once every 3 weeks followed by two doses of durvalumab 750 mg once every 2 weeks. Durvalumab was continued for 1 year after surgery. The primary end point was 1-year EFS. The hypothesis for statistical considerations was an improvement of 1-year EFS from 48% to 65%. RESULTS: Sixty-eight patients were enrolled, 67 were included in the full analysis set. Radiographic response rate was 43% (95% CI, 31 to 56) after neoadjuvant chemotherapy and 58% (95% CI, 45 to 71) after sequential neoadjuvant immunotherapy. Fifty-five patients were resected, of which 34 (62%) achieved a major pathologic response (MPR; ≤ 10% viable tumor cells) and 10 (18%) among them a complete pathologic response. Postoperative nodal downstaging (ypN0-1) was observed in 37 patients (67%). Fifty-one (93%) resected patients had an R0 resection. There was no significant effect of pretreatment PD-L1 expression on MPR or nodal downstaging. The 1-year EFS rate was 73% (two-sided 90% CI, 63 to 82). Median EFS and overall survival were not reached after 28.6 months of median follow-up. Fifty-nine (88%) patients had an adverse event grade ≥ 3 including two fatal adverse events that were judged not to be treatment-related. CONCLUSION: The addition of perioperative durvalumab to neoadjuvant chemotherapy in patients with stage IIIA(N2) non-small-cell lung cancer is safe and exceeds historical data of chemotherapy alone with a high MPR and an encouraging 1-year EFS rate of 73%.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Immune Checkpoint Inhibitors/therapeutic use , Lung Neoplasms/drug therapy , Neoadjuvant Therapy , Adult , Aged , Antibodies, Monoclonal/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Chemotherapy, Adjuvant , Cisplatin/therapeutic use , Docetaxel/therapeutic use , Female , Humans , Immune Checkpoint Inhibitors/adverse effects , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Neoadjuvant Therapy/adverse effects , Neoadjuvant Therapy/mortality , Neoplasm Staging , Pneumonectomy , Progression-Free Survival , Switzerland , Time FactorsABSTRACT
Lung cancer prevention may include primary prevention strategies, such as corrections of working conditions and life style - primarily smoking cessation - as well as secondary prevention strategies, aiming at early detection that allows better survival rates and limited resections. This review summarizes recent developments and advances in secondary prevention, focusing on recent technological tools for an effective early diagnosis.
Subject(s)
Biomarkers, Tumor/analysis , Early Detection of Cancer/methods , Lung Neoplasms/diagnosis , Mass Screening/methods , Secondary Prevention/methods , Antineoplastic Agents/therapeutic use , Breath Tests , Bronchoscopy/methods , Bronchoscopy/trends , Early Detection of Cancer/trends , Humans , Lung/diagnostic imaging , Lung Neoplasms/mortality , Lung Neoplasms/therapy , Machine Learning , Mass Screening/trends , Pneumonectomy/methods , Pneumonectomy/trends , Radiographic Image Interpretation, Computer-Assisted/methods , Radiosurgery/methods , Radiosurgery/trends , Secondary Prevention/trends , Sputum/chemistry , Survival Rate , Tomography, X-Ray Computed/methods , Volatile Organic Compounds/analysisABSTRACT
Lorlatinib is a third-generation tyrosine-kinases inhibitor (TKI) targeting ALK/ROS1 fusions. The FDA has approved lorlatinib for TKI-pretreated ALK(+) NSCLC, while its approval for ROS1(+) is still pending. Here we present the largest real-world data of NSCLC patients harboring ALK/ROS1 rearrangements treated with lorlatinib. METHODS: 123 patients were enrolled retrospectively (data cut-off 1/1/2019). Lorlatinib was administered through an early access program for patients with no other available therapy. Outcome and response were defined by each investigator upon RECIST 1.1 criteria. RESULTS: 106 ALK(+) and 17 ROS1(+) patients recruited from 8 different countries. The ALK(+) cohort included 50 % males, 73 % never-smokers and 68 % with brain metastases. Extracranial (EC) and intracranial (IC) response rates (RR) were 60 % and 62 %, with disease control rates (DCR) of 91 % and 88 % respectively. Mean duration of therapy (DoT) was 23.9⯱â¯1.6 months and median overall survival (mOS) was 89.1⯱â¯19.6 months. ROS1 cohort enrolled 53 % males, 65 % never-smokers and 65 % had brain metastases. EC and IC RR were 62 % and 67 % with DCR of 92 % and 78 % respectively. Median DoT was 18.1⯱â¯2.5 months and mOS of 90.3⯱â¯24.4 months. OS and DoT in both cohorts were not significantly correlated with line of therapy nor other parameters. The most common adverse events of any grade were peripheral edema (48 %), hyperlipidemia (47 %), weight gain (25 %) and fatigue (30 %). CNS adverse events such as cognitive effect of grade 1-2 were reported in 18 % of patients. CONCLUSION: Lorlatinib shows outstanding EC/IC efficacy in ALK/ROS1(+) NSCLC. The observed mOS of 89⯱â¯19 months in ALK(+) NSCLC supports previous reports, while mOS from of 90⯱â¯24 months is unprecedented for ROS1(+) NSCLC.
Subject(s)
Lung Neoplasms , Protein-Tyrosine Kinases , Aminopyridines , Female , Humans , Lactams , Lactams, Macrocyclic , Lung Neoplasms/drug therapy , Male , Proto-Oncogene Proteins , Pyrazoles , Receptor Protein-Tyrosine Kinases/genetics , Retrospective StudiesSubject(s)
Biomarkers, Tumor/genetics , Bronchial Neoplasms/genetics , Gene Rearrangement , Hemothorax/etiology , Proto-Oncogene Proteins/genetics , Repressor Proteins/genetics , Sarcoma, Synovial/genetics , Aged, 80 and over , Bronchial Neoplasms/complications , Bronchial Neoplasms/pathology , Bronchial Neoplasms/surgery , Hemothorax/diagnosis , Hemothorax/surgery , Humans , In Situ Hybridization, Fluorescence , Male , Pneumonectomy , Sarcoma, Synovial/complications , Sarcoma, Synovial/pathology , Sarcoma, Synovial/surgery , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
Background: Molecular imaging methods are currently used in the management of patients with lung cancer. Compared to non-small cell lung cancer, less data are available about the impact of molecular imaging using fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in staging patients with small cell lung cancer (SCLC). Performing a systematic review and meta-analysis, we aimed to provide quantitative data about the impact of 18F-FDG PET/CT in staging SCLC. Methods: A comprehensive literature search of studies on the use of 18F-FDG PET/CT in patients with SCLC was performed. Three different databases were screened (PubMed/MEDLINE, EMBASE, and Cochrane library databases) until June 2019. Only articles describing the impact of 18F-FDG PET/CT in staging patients with SCLC were selected. A pooled analysis evaluating the change of binary SCLC staging (limited-stage vs. extensive-stage disease) using 18F-FDG PET/CT was carried out. Results: Nine articles including 721 patients with SCLC were included in the systematic review. Compared to conventional staging, a superior diagnostic accuracy of 18F-FDG PET/CT was found. A change of binary SCLC staging using 18F-FDG PET/CT was demonstrated in 15% (95% confidence interval, 9-21%) of patients with SCLC. Currently, it is not clearly demonstrated that the use of 18F-FDG PET/CT for staging may improve the survival outcome of patients with SCLC. Conclusions: 18F-FDG PET/CT is a useful molecular imaging method for staging patients with SCLC because it can change the management in a significant number of patients. More large prospective studies and cost-effectiveness analyses on the impact of 18F-FDG PET/CT in staging patients with SCLC are needed.
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INTRODUCTION: There is no approved second-line treatment for malignant pleural mesothelioma (MPM). On the basis of promising early results, pembrolizumab was used off-label in Switzerland and Australia. We investigated outcomes in association with clinicopathological features and expression of programmed death ligand 1 (PD-L1). METHODS: Registry data in Australia and Switzerland were pooled. Patient characteristics, including age, sex, histological subtype, and previous treatments were captured. Outcomes were assessed locally. PD-L1 expression was categorized as negative (<5%), intermediate (5%-49%), and high (≥50%). RESULTS: A total of 93 patients (48 from Switzerland and 45 from Australia) were treated; 68 patients (73%) had epithelioid MPM, and 67 (72%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. Pembrolizumab was the second-line treatment in 48 of 93 patients (52%). PD-L1 expression results were available for 66 patients (71%). Most (68%) were negative, 18% were intermediate, and 14% were high for PD-L1 expression. In the full cohort, the overall response rate (ORR) was 18%, the median progression-free survival (mPFS) was 3.1 months, and the median overall survival was 7.2 months. In patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 and only one previous systemic treatment (n = 35), the ORR was 37%, the mPFS was 3.7 months, and the median overall survival was 10.2 months. The nonepitheloid histological subtype showed an improved ORR (24% versus 16% [p = 0.54) and mPFS (5.6 versus 2.8 months [p = 0.02]). Compared with intermediate and negative PD-L1 expression, high PD-L1 expression was associated with an improved ORR (44% versus 42% versus 11% [p = 0.01]) and mPFS (6.2 versus 3.9 versus 2.7 months [p = 0.04]). Toxicity was as expected. CONCLUSION: These real-world data demonstrate similar response rates but inferior survival compared with those in early-phase trials. High PD-L1 expression and nonepitheloid histological subtype were associated with greater activity. Anti-PD-L1 immunotherapy is a reasonable second-line therapy in patients with MPM.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Lung Neoplasms/drug therapy , Mesothelioma/drug therapy , Pleural Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Female , Humans , Immunotherapy/methods , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Male , Mesothelioma/immunology , Mesothelioma/pathology , Mesothelioma, Malignant , Middle Aged , Pleural Neoplasms/immunology , Pleural Neoplasms/pathologyABSTRACT
Most ocular adnexal lymphomas (OAL) are extranodal marginal zone B-cell lymphomas (EMZL) of mucosa-associated lymphoid tissue (MALT)-type. Chronic antigen stimulation has been suggested to have a pathogenetic role in EMZL and Chlamydia psittaci chronic infection has been recently associated with the development of OAL in a series of patients from Italy. To assess this association, an evaluation of the presence of C. psittaci was made in a different OAL population. DNA samples were obtained from formalin-fixed, paraffin-embedded sections samples of 26 patients with OAL, 20 non-OAL and 20 benign ocular lesions, diagnosed and treated between 1998 and 2003 at National Institute of Oncology in Havana, Cuba. All samples were histologically reviewed by an expert pathologist. Fluorescence in situ hybrization (FISH) analysis of translocations involving MALT1 was performed. The presence of bacterial DNA was assessed with a multiplex touchdown enzyme time release polymerase chain reaction. DNA sequencing was performed to confirm suspicious bands. Seventy-three percent of the OAL cases were EMZL and 81% were in stage IE. FISH analysis was performed in 13 OAL cases and none of them evidenced MALT1 translocations. DNA of C. psittaci was detected in 11% of the 46 lymphomas: two orbital EMZL and three non-OAL. All 20 benign ocular lesions were negative for C. psittaci. The low prevalence of C. psittaci in OAL suggests geographical differences in the etiology of this entity. International studies are needed to clarify the role of C. psittaci in OALs.
Subject(s)
Chlamydophila psittaci/isolation & purification , Eye Neoplasms/microbiology , Lymphoma, B-Cell/microbiology , Psittacosis/complications , Adult , Aged , Aged, 80 and over , Caspases/genetics , Chlamydophila psittaci/genetics , Cuba/epidemiology , DNA, Bacterial/isolation & purification , Eye Neoplasms/complications , Eye Neoplasms/genetics , Female , Humans , Lymphoma, B-Cell/complications , Lymphoma, B-Cell/genetics , Male , Middle Aged , Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein , Neoplasm Proteins/genetics , Prevalence , Psittacosis/epidemiology , Retrospective StudiesABSTRACT
INTRODUCTION: NSCLC with de novo anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangements and EGFR or KRAS mutations co-occur very rarely. Outcomes with tyrosine kinase inhibitors (TKIs) in these patients are poorly understood. METHODS: Outcomes of patients with metastatic NSCLC de novo co-alterations of ALK/EGFR or ALK/KRAS detected by fluorescence in situ hybridization (ALK) and sequencing (EGFR/KRAS) from six Swiss centers were analyzed. RESULTS: A total of 14 patients with adenocarcinoma were identified. Five patients had ALK/EGFR co-alterations and nine had ALK/KRAS co-alterations. Six of seven patients with ALK/KRAS co-alterations (86%) were primary refractory to crizotinib. One patient has had ongoing disease stabilization for 26 months. Of the patients with ALK/EGFR co-alterations, one immediately progressed after receiving crizotinib for 1.3 months and two had a partial response for 5.7 and 7.3 months, respectively. Three of four patients with ALK/EGFR co-alterations treated with an EGFR TKI achieved one or more responses in different lines of therapy: four patients had a partial response, three with afatinib and one with osimertinib. One patient achieved a complete remission with osimertinib, and one patient was primary refractory to erlotinib. Median PFS during treatment with a first EGFR TKI was 5.8 months (range 3.0-6.9 months). CONCLUSIONS: De novo concurrent ALK/KRAS co-alterations were associated with resistance to ALK TKI treatment in seven out of eight patients. In patients with ALK/EGFR co-alterations, outcomes with ALK and EGFR TKIs seem inferior to what would be expected in patients with either alteration alone, but further studies are needed to clarify which patients with ALK/EGFR co-alterations may still benefit from the respective TKI.
Subject(s)
Carcinoma, Non-Small-Cell Lung/mortality , Drug Resistance, Neoplasm , ErbB Receptors/genetics , Mutation , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins p21(ras)/genetics , Receptor Protein-Tyrosine Kinases/genetics , Adenocarcinoma/drug therapy , Adenocarcinoma/genetics , Adenocarcinoma/mortality , Adenocarcinoma/secondary , Adult , Afatinib , Aged , Aged, 80 and over , Anaplastic Lymphoma Kinase , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/secondary , Crizotinib , Female , Follow-Up Studies , Gene Rearrangement , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Staging , Prognosis , Pyrazoles/administration & dosage , Pyridines/administration & dosage , Quinazolines/administration & dosage , Survival RateABSTRACT
BACKGROUND: Pemetrexed and bevacizumab as single agents have been approved for maintenance therapy after platinum-based induction in patients with advanced nonsquamous non-small-cell lung cancer. It is currently unknown whether bevacizumab plus pemetrexed is superior to pemetrexed alone. PATIENTS AND METHODS: We conducted a nonrandomized phase II trial with 2 sequential cohorts. In the first cohort, 77 patients were treated with 4 cycles of cisplatin, bevacizumab, and pemetrexed every 3 weeks, followed by bevacizumab plus pemetrexed maintenance until progression. In the second cohort, we treated 52 patients without bevacizumab, using maintenance with pemetrexed alone. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), adverse events, and the treatment costs of the 2 cohorts were compared. RESULTS: The median PFS from the time of registration was 6.9 months in cohort 1 and 5.6 months in cohort 2. The ORR was 62.3% in cohort 1% and 44.2% in cohort 2. The PFS (hazard ratio, 0.7; 95% confidence interval [CI], 0.5-1.0; P = .041) and ORR (odds ratio, 2.1; 95% CI, 1.0-4.3; P = .049) were better in cohort 1 than in cohort 2. No OS difference was found (hazard ratio, 1.0; 95% CI, 0.7-1.6; P = .890) after a median follow-up period of 47 months for cohort 1 and 27 months for cohort 2. The rate of grade ≥ 3 adverse events was greater in cohort 1. The treatment costs per patient were on average 1.4 times greater for cohort 1. CONCLUSION: The addition of bevacizumab increased the ORR and PFS, but not OS, in our nonrandomized trial. Furthermore, the addition of bevacizumab was associated with greater toxicity and higher costs.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bevacizumab/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Pemetrexed/therapeutic use , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/economics , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Cohort Studies , Cost-Benefit Analysis , Female , Follow-Up Studies , Humans , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Survival Analysis , Switzerland , Treatment OutcomeABSTRACT
Purpose In addition to prospective trials for non-small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response to targeted therapies. Here, we present the results of an international registry of patients with RET-rearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. Methods A global, multicenter network of thoracic oncologists identified patients with pathologically confirmed NSCLC that harbored a RET rearrangement. Molecular profiling was performed locally by reverse transcriptase polymerase chain reaction, fluorescence in situ hybridization, or next-generation sequencing. Anonymized data-clinical, pathologic, and molecular features-were collected centrally and analyzed by an independent statistician. Best response to RET tyrosine kinase inhibition administered outside of a clinical trial was determined by RECIST v1.1. Results By April 2016, 165 patients with RET-rearranged NSCLC from 29 centers across Europe, Asia, and the United States were accrued. Median age was 61 years (range, 29 to 89 years). The majority of patients were never smokers (63%) with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent rearrangement was KIF5B-RET (72%). Of those patients, 53 received one or more RET tyrosine kinase inhibitors in sequence: cabozantinib (21 patients), vandetanib (11 patients), sunitinib (10 patients), sorafenib (two patients), alectinib (two patients), lenvatinib (two patients), nintedanib (two patients), ponatinib (two patients), and regorafenib (one patient). The rate of any complete or partial response to cabozantinib, vandetanib, and sunitinib was 37%, 18%, and 22%, respectively. Further responses were observed with lenvantinib and nintedanib. Median progression-free survival was 2.3 months (95% CI, 1.6 to 5.0 months), and median overall survival was 6.8 months (95% CI, 3.9 to 14.3 months). Conclusion Available multikinase inhibitors had limited activity in patients with RET-rearranged NSCLC in this retrospective study. Further investigation of the biology of RET-rearranged lung cancers and identification of new targeted therapeutics will be required to improve outcomes for these patients.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/enzymology , Lung Neoplasms/drug therapy , Lung Neoplasms/enzymology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-ret/antagonists & inhibitors , Proto-Oncogene Proteins c-ret/genetics , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/epidemiology , Carcinoma, Non-Small-Cell Lung/genetics , Gene Rearrangement , Humans , International Cooperation , Lung Neoplasms/epidemiology , Lung Neoplasms/genetics , Middle Aged , Molecular Targeted Therapy , Prospective Studies , Registries , Treatment OutcomeABSTRACT
BACKGROUND: The tyrosine kinase inhibitor erlotinib improves the outcomes of patients with advanced non-small-cell lung carcinoma (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations. The coexistence of the T790M resistance mutation with another EGFR mutation in treatment-naive patients has been associated with a shorter progression-free survival to EGFR inhibition than in the absence of the T790M mutation. To test this hypothesis clinically, we developed a proof-of-concept study, in which patients with EGFR-mutant NSCLC were treated with the combination of erlotinib and bevacizumab, stratified by the presence of the pretreatment T790M mutation. METHODS: BELIEF was an international, multicentre, single-arm, phase 2 trial done at 29 centres in eight European countries. Eligible patients were aged 18 years or older and had treatment-naive, pathologically confirmed stage IIIB or stage IV lung adenocarcinoma with a confirmed, activating EGFR mutation (exon 19 deletion or L858R mutation). Patients received oral erlotinib 150 mg per day and intravenous bevacizumab 15 mg/kg every 21 days and were tested centrally for the pretreatment T790M resistance mutation with a peptide nucleic acid probe-based real-time PCR. The primary endpoint was progression-free survival. The primary efficacy analysis was done in the intention-to-treat population and was stratified into two parallel substudies according to the centrally confirmed pretreatment T790M mutation status of enrolled patients (T790M positive or negative). The safety analysis was done in all patients that have received at least one dose of trial treatment. This trial was registered with ClinicalTrials.gov, number NCT01562028. FINDINGS: Between June 11, 2012, and Oct 28, 2014, 109 patients were enrolled and included in the efficacy analysis. 37 patients were T790M mutation positive and 72 negative. The overall median progression-free survival was 13·2 months (95% CI 10·3-15·5), with a 12 month progression-free survival of 55% (95% CI 45-64). The primary endpoint was met only in substudy one (T790M-positive patients). In the T790M-positive group, median progression-free survival was 16·0 months (12·7 to not estimable), with a 12 month progression-free survival of 68% (50-81), whereas in the T790M-negative group, median progression-free survival was 10·5 months (9·4-14·2), with a 12 month progression-free survival of 48% (36-59). Of 106 patients included in the safety analysis, five had grade 4 adverse events (one acute coronary syndrome, one biliary tract infection, one other neoplasms, and two colonic perforations) and one died due to sepsis. INTERPRETATION: The BELIEF trial provides further evidence of benefit for the combined use of erlotinib and bevacizumab in patients with NSCLC harbouring activating EGFR mutations. FUNDING: European Thoracic Oncology Platform, Roche.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , ErbB Receptors/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab/administration & dosage , Disease-Free Survival , Erlotinib Hydrochloride/administration & dosage , Female , Humans , Intention to Treat Analysis , International Cooperation , Male , Middle Aged , Mutation , Proof of Concept Study , Response Evaluation Criteria in Solid TumorsABSTRACT
Most developed countries accepted the chronological age of 70 years as the definition of "elderly" and there is a general consensus in clinical practice to consider this age as the threshold in risk assessment. This has a strong impact in the choice of treatment of these lung cancer patients. Indeed, more than 50% of these patients are over 70 and nearly 30% are over 75 years old. Because of the increasing number of elderly patients that are generally fitter than in the past, the treatment options should rather be based on individual fitness, taking into account risks and benefits of the diagnostic and therapeutic procedures. This means considering biological rather than chronological age to make decisions. For these reasons, we developed a simplified short comprehensive geriatric assessment (sCGA), including a standardised evaluation of activity of daily living, depression, cognitive status, comorbidities and geriatric syndromes. This allowed us the classification of these patients into 3 categories: frail, vulnerable and fit. Through the emblematic case of a fit elderly man affected by NSLCC, we present the multidisciplinary assessment and discussions to identify the best treatment options for this patient.