Immune checkpoint inhibitors (ICIs) have dramatically improved patient outcomes in a variety of tumor types, but with variable efficacy. Recent research has suggested that antibiotic-induced ...disruption of the microbiota may impact ICI efficacy. We performed a systematic review and meta-analysis of studies that assessed the impact of antibiotic use on the survival of patients diagnosed with NSCLC and treated with ICI. We systematically searched Medline, the Cochrane Library, and major oncology conferences proceedings. Eligible studies mentioned hazard ratio or Kaplan–Meier curves for progression-free survival (PFS) or overall survival (OS) based on antibiotic exposure before or during ICI treatment. We identified 23 eligible studies. The impact of antibiotics was then evaluated in 2208 patients for PFS and 5560 for OS. For both PFS and OS meta-analyses, the between-study heterogeneity was high (Higgins and Thompson I2 of 69% and 80%, respectively). The pooled hazard ratio was 1.47 (95% confidence interval CI: 1.13–1.90) for PFS and 1.69 (95% CI: 1.25–2.29) for OS revealing a significantly reduced survival in patients with NSCLC exposed to antibiotics. The median OS was reduced on average by 6.7 months (95% CI: 5.1–8.4) in the patients exposed to antibiotics. The effect seems to depend on the time window of exposure with stronger effects reported when the patients took antibiotics −60 days; +60 days around ICI initiation. In patients with NSCLC, the findings of the meta-analysis indicate that antibiotic use before or during treatment with ICI leads to a median OS decreased by more than 6 months. Specifically, exposure shortly before or after ICI initiation seems to be particularly detrimental, whereas antibiotic use later during disease course does not seem to alter survival. Because PFS and OS were difficult to compare between studies owing to heterogeneity and the multiple confounding factors identified, further studies are needed to strengthen the understanding of this phenomenon.
Summary 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/m2 pemetrexed plus 75 mg/m2 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).
The Ras association domain family protein1 isoform A (RASSF1A) is a well-known tumor-suppressor protein frequently inactivated in various human cancers. Consistent with its function as a molecular ...scaffold protein, referred to in many studies, RASSF1A prevents initiation of tumorigenesis, growth, and dissemination through different biological functions, including cell cycle arrest, migration/metastasis inhibition, microtubular stabilization, and apoptosis promotion. As a regulator of key cancer pathways, namely Ras/Rho GTPases and Hippo signaling without ignoring strong interaction with microtubules, RASSF1A is indeed one of the guardians of cell homeostasis. To date, as we approach the two decade anniversary of RASSF1A's discovery, this review will summarize our current knowledge on the RASSF1A key interactions as a tumor suppressor and discuss their impact on cell fate during carcinogenesis. This could facilitate a deeper understanding of tumor development and provide us with new strategies in cancer treatment by targeting the RASSF1A pathway.
Lung cancer in never smokers – A review Couraud, Sébastien; Zalcman, Gérard; Milleron, Bernard ...
European journal of cancer (1990),
06/2012, Letnik:
48, Številka:
9
Journal Article
Recenzirano
Abstract An estimated 10–25% of lung cancers worldwide occur in never smokers, i.e. individuals having smoked less than 100 cigarettes in their lifetime. Lung cancer in never smokers (LCINS) is more ...frequent in women, although large geographic variations are found. Histologically, adenocarcinomas predominate. The mere existence of LCINS suggests that risk factors other than smoking must be present. Exposure to environmental tobacco smoke (particularly in women) and exposure to workplace carcinogens (particularly in men) are the two most important alternative risk factors. However, a history of either is absent in more than a third of LCINS. The large proportion of women in LCINS suggest a hormonal element that may interact with other identified factors such as hereditary risks, a history of respiratory infections or disease, exposure to air pollution, cooking and heating fumes, or exposure to ionising radiation. The study of genomic polymorphisms finds constitutive DNA variations across subjects according to their smoking status, particularly in genes coding for enzymes that participate in the metabolism of certain carcinogens, in those coding for DNA repair enzymes, or in genes associated with tobacco addiction, or inflammatory processes. The type of molecular mutation in p53 or KRAS varies with smoking status. EGFR mutations are more frequent in never smokers, as are EML4-ALK fusions. The mutually exclusive nature of certain mutations is a strong argument in favour of separate genetic paths to cancer for ever smokers and never smokers. In the present paper we review current clinical and molecular aspects of LCINS.
Approved systemic treatments for malignant pleural mesothelioma (MPM) have been limited to chemotherapy regimens that have moderate survival benefit with poor outcomes. Nivolumab plus ipilimumab has ...shown clinical benefit in other tumour types, including first-line non-small-cell lung cancer. We hypothesised that this regimen would improve overall survival in MPM.
This open-label, randomised, phase 3 study (CheckMate 743) was run at 103 hospitals across 21 countries. Eligible individuals were aged 18 years and older, with previously untreated, histologically confirmed unresectable MPM, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to nivolumab (3 mg/kg intravenously once every 2 weeks) plus ipilimumab (1 mg/kg intravenously once every 6 weeks) for up to 2 years, or platinum plus pemetrexed chemotherapy (pemetrexed 500 mg/m2 intravenously plus cisplatin 75 mg/m2 intravenously or carboplatin area under the concentration-time curve 5 mg/mL per min intravenously) once every 3 weeks for up to six cycles. The primary endpoint was overall survival among all participants randomly assigned to treatment, and safety was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02899299, and is closed to accrual.
Between Nov 29, 2016, and April 28, 2018, 713 patients were enrolled, of whom 605 were randomly assigned to either nivolumab plus ipilimumab (n=303) or chemotherapy (n=302). 467 (77%) of 605 participants were male and median age was 69 years (IQR 64–75). At the prespecified interim analysis (database lock April 3, 2020; median follow-up of 29·7 months IQR 26·7–32·9), nivolumab plus ipilimumab significantly extended overall survival versus chemotherapy (median overall survival 18·1 months 95% CI 16·8–21·4 vs 14·1 months 12·4–16·2; hazard ratio 0·74 96·6% CI 0·60–0·91; p=0·0020). 2-year overall survival rates were 41% (95% CI 35·1–46·5) in the nivolumab plus ipilimumab group and 27% (21·9–32·4) in the chemotherapy group. Grade 3–4 treatment-related adverse events were reported in 91 (30%) of 300 patients treated with nivolumab plus ipilimumab and 91 (32%) of 284 treated with chemotherapy. Three (1%) treatment-related deaths occurred in the nivolumab plus ipilimumab group (pneumonitis, encephalitis, and heart failure) and one (<1%) in the chemotherapy group (myelosuppression).
Nivolumab plus ipilimumab provided significant and clinically meaningful improvements in overall survival versus standard-of-care chemotherapy, supporting the use of this first-in-class regimen that has been approved in the USA as of October, 2020, for previously untreated unresectable MPM.
Bristol Myers Squibb.
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.
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.
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).
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.
French Cooperative Thoracic Intergroup.
Tailoring clinical trial methods and design according to drug class and gathering systematically long‐term real‐life clinical data from national early access programs might be options to improve the ...reliability of drug development in metastatic melanoma.
Approximately 1% of lung adenocarcinomas are driven by oncogenic ROS1 rearrangement. Crizotinib is a potent inhibitor of both ROS1 and ALK kinase domains.
In the absence of a prospective clinical ...trial in Europe, we conducted a retrospective study in centers that tested for ROS1 rearrangement. Eligible patients had stage IV lung adenocarcinoma, had ROS1 rearrangement according to fluorescent in situ hybridization, and had received crizotinib therapy through an individual off-label use. Best response was assessed locally using RECIST (version 1.1). All other data were analyzed centrally.
We identified 32 eligible patients. One patient was excluded because next-generation sequencing was negative for ROS1 fusion. Median age was 50.5 years, 64.5% of patients were women, and 67.7% were never-smokers. Thirty patients were evaluable for progression-free survival (PFS), and 29 patients were evaluable for best response. We observed four patients with disease progression, two patients with stable disease, and objective response in 24 patients, including five complete responses (overall response rate, 80%; disease control rate, 86.7%). Median PFS was 9.1 months, and the PFS rate at 12 months was 44%. No unexpected adverse effects were observed. Twenty-six patients received pemetrexed (either alone or in combination with platinum and either before or after crizotinib) and had a response rate of 57.7% and a median PFS of 7.2 months.
Crizotinib was highly active at treating lung cancer in patients with a ROS1 rearrangement, suggesting that patients with lung adenocarcinomas should be tested for ROS1. Prospective clinical trials with crizotinib and other ROS1 inhibitors are ongoing or planned.
The French pulmonary hypertension (PH) registry allows the survey of epidemiological trends. Isolated cases of precapillary PH have been reported in patients who have chronic myelogenous leukemia ...treated with the tyrosine kinase inhibitor dasatinib.
This study was designed to describe incident cases of dasatinib-associated PH reported in the French PH registry. From the approval of dasatinib (November 2006) to September 30, 2010, 9 incident cases treated by dasatinib at the time of PH diagnosis were identified. At diagnosis, patients had moderate to severe precapillary PH with functional and hemodynamic impairment. No other incident PH cases were exposed to other tyrosine kinase inhibitors at the time of PH diagnosis. Clinical, functional, or hemodynamic improvements were observed within 4 months of dasatinib discontinuation in all but 1 patient. Three patients required PH treatment with endothelin receptor antagonist (n=2) or calcium channel blocker (n=1). After a median follow-up of 9 months (min-max 3-36), the majority of patients did not demonstrate complete clinical and hemodynamic recovery, and no patients reached a normal value of mean pulmonary artery pressure (≤20 mm Hg). Two patients (22%) died at follow-up (1 of unexplained sudden death and 1 of cardiac failure in the context of septicemia, respectively, 8 and 12 months after dasatinib withdrawal). The lowest estimate of incident PH occurring in patients exposed to dasatinib in France was 0.45%.
Dasatinib may induce severe precapillary PH fulfilling the criteria of pulmonary arterial hypertension, thus suggesting a direct and specific effect of dasatinib on pulmonary vessels. Improvement is usually observed after withdrawal of dasatinib.
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