Publications by authors named "Dariusz Kowalski"

55 Publications

Predictive factors testing proposal for NSCLC patients during the COVID-19 pandemic.

Expert Rev Anticancer Ther 2021 Mar 25:1-4. Epub 2021 Mar 25.

Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland.

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http://dx.doi.org/10.1080/14737140.2021.1901585DOI Listing
March 2021

Tissue MicroRNA Expression as a Predictor of Response to Immunotherapy in NSCLC Patients.

Front Oncol 2020 8;10:563613. Epub 2021 Feb 8.

Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland.

Introduction: Expression of PD-L1 protein on tumor cells, which is so far the only validated predictive factor for immunotherapy, is regulated by epigenetic and genetic factors. Among the most important ones that regulate gene expression are microRNAs.

Materials And Methods: The study included 60 patients with NSCLC who underwent first or second line immunotherapy with pembrolizumab or nivolumab. FFPE materials were collected before the start of immunotherapy. We examined relative expression of microRNAs (miR-141, miR-200a, miR-200b, miR-200c, miR-429, miR-508-3p, miR-1184, miR-1255a) and mRNA expression. Copy number variation (CNV) of gene by qPCR and FISH methods were assessed. Two single nucleotide polymorphisms (SNPs) in promoter region of gene (rs822335 and rs822336) were examined. Expression of PD-L1 protein on tumor cells was assessed by immunohistochemistry (IHC). The response rate to immunotherapy and progression free survival (PFS) measured in weeks and overall survival (OS) measured in months from the start of immunotherapy were evaluated.

Results: Response to immunotherapy was observed in nine patients (15%, including one complete response), disease stabilization in 22 patients (36.7%), and progression in 29 patients (48.3%). Significantly higher (p=0.015) expression of miR-200b and significantly lower (p=0.043) expression of miR-429 were observed in responders compared to patients who did not respond to immunotherapy. The median PFS in the whole group of patients was 16 weeks, and the median OS was 10.5 month. In univariate analysis, the median PFS was significantly higher in patients with high miR-200b expression (HR=0.4253, 95%CI: 0.1737-1.0417, p=0.05) and high miR-508 expression (HR=0.4401, 95%CI: 0.1903-1.0178, p=0.05) and with low expression of miR-429 (HR=0.1288, 95%CI: 0.01727-0.9606, p=0.0456) compared to patients with low and high expression of these molecules, respectively. The median OS was higher in patients with low expression of miR-429 (HR=0,6288, 95%CI: 0,3053-1,2949, p=0.06) compared with patients with high expression of this microRNA. In multivariate analysis, we found that patients with PD-L1 expression on ≥1% of tumor cells compared to patients without PD-L1 expression on cancer cells had a significantly lower risk of progression (HR=0.3857, 95%CI: 0.1612-0.9226, p=0.0323) and death (HR=0.377, 95%CI: 0.1636-0.8688, p=0.022).

Conclusion: The miR-200b and miR-429 molecules in tumor cells seem to have greatest impact on the effectiveness of immunotherapy in NSCLC patients.
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http://dx.doi.org/10.3389/fonc.2020.563613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897665PMC
February 2021

First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial.

Lancet 2021 01 21;397(10272):375-386. Epub 2021 Jan 21.

Bichat-Claude Bernard University Hospital, AP-HP, Université de Paris, Paris, France.

Background: 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.

Methods: 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/m intravenously] plus cisplatin [75 mg/m 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.

Findings: 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).

Interpretation: 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.

Funding: Bristol Myers Squibb.
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http://dx.doi.org/10.1016/S0140-6736(20)32714-8DOI Listing
January 2021

Afatinib in EGFR TKI-naïve patients with locally advanced or metastatic EGFR mutation-positive non-small cell lung cancer: Interim analysis of a Phase 3b study.

Lung Cancer 2021 02 17;152:127-134. Epub 2020 Dec 17.

Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.

Objectives: Randomized controlled trials have demonstrated that afatinib is a suitable treatment option for patients with epidermal growth factor receptor mutation-positive (EGFRm +) non-small cell lung cancer (NSCLC). However, such studies often exclude patients treated in routine clinical practice. We report interim results from a Phase 3b, open-label, multicenter, single-arm, exploratory trial, in which afatinib was investigated in a real-world setting.

Materials And Methods: Patients with EGFRm + tyrosine kinase inhibitor (TKI)-naïve NSCLC received afatinib 40 mg orally, once-daily, until disease progression, or voluntary withdrawal. Primary objective was safety.

Results: Overall, 479 patients received afatinib: median age 65 years, 8 % of patients had an ECOG performance status ≥ 2, 17 % had brain metastases, and 13 % had tumors containing uncommon mutations only. All but one patient (99.8 %) had an adverse event (AE). Treatment-related AEs (TRAEs; any/grade ≥ 3) occurred in 97 %/44 % of patients; most common were diarrhea (87 %/16 %) and rash (51 %/11 %). AEs leading to afatinib dose-reduction were reported in 258 patients (54 %), and 37 patients (8 %) discontinued treatment due to a TRAE. Objective response rate was 45.5 %, median duration of response was 14.1 months (95 % CI: 12.2-16.4). Overall median time to symptomatic progression and progression-free survival were 14.9 months (95 % CI: 13.8-17.6) and 13.4 months (95 % CI: 11.8-14.5), respectively, in the overall population and 19.3 months (95 % CI: 15.6-21.8) and 15.9 months (95 % CI: 13.9-19.1) in patients with EGFR exon 19 deletions.

Conclusions: Afatinib administration in routine clinical practice was well tolerated with no new safety signals and demonstrated promising efficacy in patients with EGFRm + NSCLC. TRAEs were generally manageable with tolerability-guided dose reductions. Overall, these data independently support findings from randomized controlled trials of afatinib in EGFRm + NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2020.12.011DOI Listing
February 2021

Thymic epithelial tumors: Do we know all the prognostic factors?

Thorac Cancer 2021 02 2;12(3):339-348. Epub 2021 Jan 2.

Department of Pathology, National Tuberculosis and Lung Diseases Research Institute, Warsaw, Poland.

Background: Thymic epithelial tumors constitute a morphologically and clinically diverse group of rare neoplasm of the anterior mediastinum.

Methods: Here, we present an analysis of 188 patients diagnosed with primary thymic tumors between 1995 and 2015. The prognostic value of selected clinical and morphological factors was assessed in relation to overall survival and recurrence-free survival.

Results: The risk of recurrence increased significantly in thymic carcinoma diagnosis (P = 0.0036), co-occurrence of other diseases, and weight loss (P = 0.0012 and 0.0348, respectively). Multivariate analysis showed that the most important independent risk factor for disease recurrence was clinical stage IV (P = 0.0036). A total of 63 patients (33.5%) died. In the univariate analysis, the following factors were considered as independent prognostic factors for overall survival: clinical stage (P < 0.0001), histological type (P < 0.0001), lymph node involvement (P < 0.001), WHO performance status 2 (P < 0.0001), anemia (Hb <9.5 g/dL; P = 0.0002), leucocytosis (>12.5 G/L; P = 0.0011), LDH level (>185 U/L; P < 0.0001), concomitant diseases (P = 0.0012) and weight loss (P < 0.0001).The strongest independent risk factor for death was stage IV disease (P < 0.001).

Conclusions: The results confirmed a fairly good prognosis for patients with thymic epithelial tumors. Clinical stage was the most important prognostic factor, but, some additional clinical factors may also have prognostic value.
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http://dx.doi.org/10.1111/1759-7714.13750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862797PMC
February 2021

Influence of pipe material on biofilm microbial communities found in drinking water supply system.

Environ Res 2020 Nov 6:110433. Epub 2020 Nov 6.

Institute of Agrophysics, Polish Academy of Sciences, Doświadczalna 4, 20-290, Lublin, Poland.

The biofilms and water samples from a model installation built of PVC-U, PE-HD and cast iron pipes were investigated using standard heterotrophic plate count and 16S rRNA Next Generation Sequencing. The results of the high throughput identification imply that the construction material strongly influences the microbiome composition. PVC-U and PE-HD pipes were dominated with Proteobacteria (54-60%) while the cast pipe was overgrown by Nitrospirae (64%). It was deduced that the plastic pipes create a more convenient environment for the potentially pathogenic taxa than the cast iron. The 7-year old biofilms were described as complex habitats with sharp oxidation-reduction gradients, where co-existence of methanogenic and methanotrophic microbiota takes place. Furthermore, it was found that the drinking water distribution systems (DWDS) are a useful tool for studying the ecology of rare bacterial phyla. New ecophysiological aspects were described for Aquihabitans, Thermogutta and Vampirovibrio. The discrepancy between identity of HPC-derived bacteria and NGS-revealed composition of biofilm and water microbiomes point to the need of introducing new diagnostical protocols to enable proper assessment of the drinking water safety, especially in DWDSs operating without disinfection.
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http://dx.doi.org/10.1016/j.envres.2020.110433DOI Listing
November 2020

Real-world clinical outcomes of first-generation and second-generation epidermal growth factor receptor tyrosine kinase inhibitors in a large cohort of European non-small-cell lung cancer patients.

ESMO Open 2020 11;5(6):e001011

Department of Oncology and Radiotherapy, Gdanski Uniwersytet Medyczny, Gdansk, Poland.

Background: First-generation or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are commonly used in -mutation-positive advanced non-small-cell lung cancer (NSCLC) with no relevant differences in efficacy in randomised clinical trials (RCTs). Patients enrolled to RCTs may differ from NSCLC population in everyday practice. Limited real-world experience (RWE) exists on efficacy of EGFR TKIs in European patient cohorts.

Patients And Methods: In this retrospective study, real-world data of all patients who started first-line EGFR TKIs between 2012 and 2016 in Poland were analysed. The main endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints were an objective response rate and toxicity.

Results: A total of 620 treatment-naive mutated patients with stage III/IV NSCLC were analysed with follow-up time of 24.5 months. A significantly longer median PFS (p=0.005) and higher 1-year OS rate (p=0.004) for afatinib (16.4 months and 78.2%) vs gefitinib (10.3 months and 69.1%) and erlotinib (12.1 months and 71.6%) were observed. In multivariate analysis toxicity was predictive for PFS and OS. In patients with adverse events (AEs) versus those without AEs, improved median PFS (13.6 months vs 8.8 months) and median OS (23.6 vs 15.5 months) were observed. Median OS in the group with AE of grades 3-4 and those with AE of grades 1-2 were 42.1 months and 23.4 months, respectively.

Conclusion: This study represents the largest RWE of first-line TKI therapy in a European country with longer survival of patients receiving second-generation TKI. We confirmed in everyday practice the role of toxicity as a marker of clinical benefit.
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http://dx.doi.org/10.1136/esmoopen-2020-001011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640619PMC
November 2020

Nivolumab for Previously Treated Patients with Non-Small-Cell Lung Cancer-Daily Practice versus Clinical Trials.

J Clin Med 2020 Jul 17;9(7). Epub 2020 Jul 17.

Department of Lung Cancer and Chest Tumors, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland.

Based on the results of the CheckMate 017 and CheckMate 057 studies, nivolumab therapy has become a new standard treatment for both squamous and non-squamous non-small-cell lung cancer (NSCLC). However, due to the specific inclusion criteria of these clinical trials, the efficacy and safety of nivolumab in real-world practice were not certain. In general, the real-world results of nivolumab treatment have been consistent with those obtained in clinical trials. Additional analyses of the real-world data have made the identification of prognostic factors possible. Good performance status is the most significant predictor of clinical benefit. Brain metastases, liver metastases, mutation, malignant pleural effusion, and a high number of metastatic sites were identified as negative prognostic factors. By contrast, a longer time to disease progression (>6 months) from the beginning of prior chemotherapy and an objective response to chemotherapy seem to have positive prognostic value in the case of nivolumab treatment. In terms of patient age, the data are inconclusive. Some blood biomarkers can also be considered significant prognostic factors.
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http://dx.doi.org/10.3390/jcm9072273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408765PMC
July 2020

Effectiveness of osimertinib in patients with lung adenocarcinoma in clinical practice - the Expanded Drug Access Program in Poland.

Adv Respir Med 2020 ;88(3):189-196

Department of Lung Cancer and Chest Tumors, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.

Introduction: Osimertinib is a third-generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has demonstrated efficacy in the treatment of EGFR-mutant non-small-cell lung cancer (NSCLC) in prospective clinical trials.

Material And Methods: This retrospective analysis evaluated the outcomes of 32 pretreated patients with EGFR T790M mutation who received osimertinib in clinical practice at seven centers in Poland within the Expanded Drug Access Program. Osimertinib was used in the second line in 59% of patients and in later lines in 41%.

Results: Objective response was attained in 16 patients (50%), and 12 subjects (38%) had stable disease. Median progression -free survival was 11.3 months in the overall population, 12.6 months in patients with EGFR exon 19 mutation and 7.5 months in patients with EGFR exon 21 mutation (p = 0.045). Median overall survival (OS) was 18.3 months. Overall, 58.4% and 45.6% of patients remained in follow-up after 12 and 24 months, respectively. Median OS appeared longer for patients without cerebral metastases than for those with cerebral metastases (27.4 vs 9.4 months, respectively; p = 0.078), and for patients with the Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 than those with ECOG PS 2 (27.4 vs 11.8 months, respectively; p = 0.189), although neither result reached statistical significance. Median OS of patients with partial response, stable disease and progressive disease was 27.4, 12.7 and 4.5 months, respectively (p < 0.001). Age, comorbidities, line of treatment with osimertinib, and type of activating EGFR mutation did not impact on OS. Adverse events of any grade or grade 3/4 were reported in 38% and 9% of patients, respectively. One person discontinued due to interstitial pneumonia.

Conclusion: These results confirm the value of osimertinib in patients with previously treated EGFR T790M-mutant NSCLC. Clinical benefit was evident in patients with cerebral metastases and moderate performance status.
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http://dx.doi.org/10.5603/ARM.2020.0130DOI Listing
January 2020

Tepotinib in Non-Small-Cell Lung Cancer with Exon 14 Skipping Mutations.

N Engl J Med 2020 09 29;383(10):931-943. Epub 2020 May 29.

From Memorial Sloan Kettering Cancer Center, New York (P.K.P.); the Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (E.F.), and Dr. Rosell Oncology Institute, Dexeus University Hospital, Quirónsalud Group (S.V.), Barcelona; Centre Hospitaliere Universitaire (CHU) Bordeaux, Service des Maladies Respiratoires, Bordeaux (R.V.), Université de Lille, CHU Lille, Thoracic Oncology Department, Centre National de la Recherche Scientifique, INSERM, Institut Pasteur de Lille, UMR9020-UMR-S 1277-Canther, Lille (A.B.C.), CHU de Toulouse, Institut Universitaire du Cancer de Toulouse, Université Paul Sabatier, Toulouse (J.M.), and Institut de Cancérologie de l'Ouest Rene Gauducheau Centre, Saint-Herblain (H. Senellart) - all in France; Saitama Cancer Center, Saitama (H. Sakai), and the Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama (T.K.) - both in Japan; the Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (M.C.G.), and the Department of Surgery, Oncology and Gastroenterology, University of Padua and Oncologia Medica 2, Istituto Oncologico Veneto, IRCCS, Padua (P.C.) - both in Italy; Antwerp University Hospital, Edegem, Belgium (J.V.M., J.R.); Asklepios Lung Clinic, Munich-Gauting (N.R.), Pius Hospital Oldenburg, University Medicine Oldenburg, Oldenburg (F.G.), Translational Medicine, Department of Bioinformatics (D.J.), Translational Innovation Platform, Oncology (C.S.), the Department of Biostatistics (R.B.), Translational Medicine, Department of Clinical Biomarkers and Companion Diagnostics (J. Straub), and Global Clinical Development (A.J., J. Scheele), Merck, Darmstadt - all in Germany; the Department of Lung Cancer and Thoracic Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (D.K.); Yonsei Cancer Center, Yonsei University College of Medicine, Seoul (B.C.C.), the Center for Lung Cancer, National Cancer Center, Goyang (J.-Y.H.), and Chonnam National University Medical School and Hwasun Hospital, Hwasun (Y.-C.K.) - all in South Korea; Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago (J.D.P.); the Department of Medicine, Vanderbilt Ingram Cancer Center, Nashville (L.H.); the Faculty of Medicine, School of Medicine, National Yang-Ming University (G.-C.C.), the Division of Chest Medicine, Department of Internal Medicine, Tri-service General Hospital, National Defense Medical Center (C.-L.T.), National Taiwan University Hospital (J.C.-H.Y.), and the Department of Chest Medicine, Taipei Veterans General Hospital, and School of Medicine, National Yang-Ming University (Y.-M.C.), Taipei, and the Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung (G.-C.C.) - both in Taiwan; the Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam (E.F.S.), and the Department of Pulmonology, University of Groningen and University Medical Center Groningen, Groningen (A.J.W.) - both in the Netherlands; and M.D. Anderson Cancer Center, University of Texas, Houston (J.V.H., X.L.).

Background: A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population.

Methods: In this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmed exon 14 skipping mutation. The primary end point was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of a exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy.

Results: As of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% confidence interval [CI], 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% (95% CI, 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment.

Conclusions: Among patients with advanced NSCLC with a confirmed exon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.).
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http://dx.doi.org/10.1056/NEJMoa2004407DOI Listing
September 2020

Cardiovascular Complications of Systemic Therapy in Non-Small-Cell Lung Cancer.

J Clin Med 2020 Apr 27;9(5). Epub 2020 Apr 27.

Department of Pulmonary Circulation, Thromboembolic Diseases and Cardiology, Centre of Postgraduate Medical Education, European Health Centre, 05-400 Otwock, Poland.

Cardiovascular diseases may determine therapy outcomes of non-small-cell lung cancer (NSCLC). The evidence for how iatrogenic cardiovascular complications contribute to ceasing anticancer treatment, decreasing the quality of life or even premature death, is unclear. Older patients and smokers are at risk of atherosclerosis and arterial thromboembolic events (TE), such as myocardial infarction or stroke. Venous TE can be observed in up to 15% of NSCLC patients, but the risk increases three to five times in ALK (anaplastic lymphoma kinase)-rearranged NSCLC. ALK inhibitors are associated with electrophysiological disorders. Cytotoxic agents and anti-VEGF inhibitors mainly cause vascular complications, including venous or arterial TE. Cardiac dysfunction and arrhythmias seem to be less frequent. Chemotherapy is often administered in two-drug regimens. Clinical events can be triggered by different mechanisms. Among epidermal growth factor inhibitors, erlotinib and gefitinib can lead to coronary artery events; however, afatinib and osimertinib can be associated with the development of heart failure. During anti-PD1/anti-PDL1 therapy, myocarditis is possible, which must be differentiated from acute coronary syndrome and heart failure. Awareness of all possible cardiovascular complications in NSCLC encourages vigilance in early diagnostics and treatment.
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http://dx.doi.org/10.3390/jcm9051268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287714PMC
April 2020

Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study.

Lancet Oncol 2020 03 3;21(3):373-386. Epub 2020 Feb 3.

Department of Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address:

Background: Preclinical data suggest that EGFR tyrosine kinase inhibitors (TKIs) plus MET TKIs are a possible treatment for EGFR mutation-positive lung cancers with MET-driven acquired resistance. Phase 1 safety data of savolitinib (also known as AZD6094, HMPL-504, volitinib), a potent, selective MET TKI, plus osimertinib, a third-generation EGFR TKI, have provided recommended doses for study. Here, we report the assessment of osimertinib plus savolitinib in two global expansion cohorts of the TATTON study.

Methods: In this multi-arm, multicentre, open-label, phase 1b study, we enrolled adult patients (aged ≥18 years) with locally advanced or metastatic, MET-amplified, EGFR mutation-positive non-small-cell lung cancer, who had progressed on EGFR TKIs. We considered two expansion cohorts: parts B and D. Part B consisted of three cohorts of patients: those who had been previously treated with a third-generation EGFR TKI (B1) and those who had not been previously treated with a third-generation EGFR TKI who were either Thr790Met negative (B2) or Thr790Met positive (B3). In part B, patients received oral osimertinib 80 mg and savolitinib 600 mg daily; after a protocol amendment (March 12, 2018), patients who weighed no more than 55 kg received a 300 mg dose of savolitinib. Part D enrolled patients who had not previously received a third-generation EGFR TKI and were Thr790Met negative; these patients received osimertinib 80 mg plus savolitinib 300 mg. Primary endpoints were safety and tolerability, which were assessed in all dosed patients. Secondary endpoints included the proportion of patients who had an objective response per RECIST 1.1 and was assessed in all dosed patients and all patients with centrally confirmed MET amplification. Here, we present an interim analysis with data cutoff on March 29, 2019. This study is registered with ClinicalTrials.gov, NCT02143466.

Findings: Between May 26, 2015, and Feb 14, 2019, we enrolled 144 patients into part B and 42 patients into part D. In part B, 138 patients received osimertinib plus savolitinib 600 mg (n=130) or 300 mg (n=8). In part D, 42 patients received osimertinib plus savolitinib 300 mg. 79 (57%) of 138 patients in part B and 16 (38%) of 42 patients in part D had adverse events of grade 3 or worse. 115 (83%) patients in part B and 25 (60%) patients in part D had adverse events possibly related to savolitinib and serious adverse events were reported in 62 (45%) patients in part B and 11 (26%) patients in part D; two adverse events leading to death (acute renal failure and death, cause unknown) were possibly related to treatment in part B. Objective partial responses were observed in 66 (48%; 95% CI 39-56) patients in part B and 23 (64%; 46-79) in part D.

Interpretation: The combination of osimertinib and savolitinib has acceptable risk-benefit profile and encouraging antitumour activity in patients with MET-amplified, EGFR mutation-positive, advanced NSCLC, who had disease progression on a previous EGFR TKI. This combination might be a potential treatment option for patients with MET-driven resistance to EGFR TKIs.

Funding: AstraZeneca.
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http://dx.doi.org/10.1016/S1470-2045(19)30785-5DOI Listing
March 2020

Population morbidity in elderly lung cancer patients from Poland with specific trends in elderly women.

Prz Menopauzalny 2019 Dec 20;18(3):161-165. Epub 2019 Dec 20.

Department of Management and Logistics in Health Care, Medical University of Lodz, Lodz, Poland.

Introduction: Lung cancer remains a leading cause of morbidity and mortality in Poland and globally. The objective of the study was to assess lung cancer incidence among elderly patients in Poland, including data for urban and rural populations, with trend analysis between 2008 and 2012.

Material And Methods: Differences between lung cancer prevalence in the Polish population aged 65 years or older were assessed with respect to province, gender, and rural vs. urban areas during the 2008-2012 period. Data were extracted from the Polish National Health Authority and Statistical Bureau databases.

Results: Lung cancer morbidity among the elderly increased by 14.05% in urban areas but only by 4.01% in rural areas. A 22.41% overall increase was noted in the elderly female population, compared to a 7.29% increase among men aged 65 years and over. Regional differences in morbidity were observed.

Conclusions: The rationale behind the differences is likely to be multi-factorial. A change in risk factor exposure in the past is probably now being reflected in lung cancer morbidity. The difference between sexes can potentially be regarded as an unfortunate side-effect of increasing female empowerment. Urban vs. rural, as well as regional, variances are probably due to a multitude of factors, including differences in socio-economic status.
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http://dx.doi.org/10.5114/pm.2019.90811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970423PMC
December 2019

Randomized Phase III Study of Ganetespib, a Heat Shock Protein 90 Inhibitor, With Docetaxel Versus Docetaxel in Advanced Non-Small-Cell Lung Cancer (GALAXY-2).

J Clin Oncol 2020 02 12;38(6):613-622. Epub 2019 Dec 12.

Winship Cancer Institute, Emory University, Atlanta, GA.

Purpose: Ganetespib, a highly potent heat shock protein 90 inhibitor, blocks multiple oncogenic pathways, resulting in antitumor activity. We evaluated the combination of ganetespib and docetaxel for second-line therapy of patients with advanced adenocarcinoma of the lung.

Patients And Methods: In this international phase III trial, patients with stage IIIB or IV adenocarcinoma diagnosed > 6 months before study entry and 1 prior systemic therapy were randomly assigned (1:1) to ganetespib 150 mg/m on days 1 and 15 with docetaxel 75 mg/m on day 1 of a 21-day cycle or to docetaxel alone. The primary end point was overall survival (OS).

Results: Of 677 enrolled patients, 335 were randomly assigned to ganetespib and docetaxel and 337 were assigned to docetaxel. The trial was stopped early as a result of futility at a planned interim analysis. The median OS time was 10.9 months (95% CI, 9.0 to 12.3 months) in the ganetespib and docetaxel arm compared with 10.5 months (95% CI, 8.6 to 12.2 months) in docetaxel arm (hazard ratio [HR], 1.11; 95% CI, 0.899 to 1.372; = .329). Median progression-free survival was 4.2 months in the ganetespib and docetaxel arm and 4.3 months in the docetaxel arm (HR, 1.16; 95% CI, 0.96 to 1.403; = .119). The addition of ganetespib did not improve outcomes compared with docetaxel alone for any secondary end point, including survival in the elevated lactate dehydrogenase or EGFR and ALK wild-type populations. The most common grade 3 or 4 adverse event in both arms was neutropenia (30.9% with ganetespib and docetaxel 25% with docetaxel).

Conclusion: The addition of ganetespib to docetaxel did not result in improved survival for salvage therapy of patients with advanced-stage lung adenocarcinoma.
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http://dx.doi.org/10.1200/JCO.19.00816DOI Listing
February 2020

Health-Related Quality of Life With Carboplatin-Paclitaxel or nab-Paclitaxel With or Without Pembrolizumab in Patients With Metastatic Squamous Non-Small-Cell Lung Cancer.

J Clin Oncol 2020 01 21;38(3):271-280. Epub 2019 Nov 21.

Hospital Universitario 12 de Octubre, CNIO-H12o Lung Cancer Unit, Universidad Complutense and Ciberonc, Madrid, Spain.

Purpose: In the phase 3 KEYNOTE-407 study, the addition of pembrolizumab to carboplatin-paclitaxel/nab-paclitaxel significantly improved overall survival, progression-free survival, and objective response rate in patients with previously untreated metastatic squamous non-small-cell lung cancer (NSCLC), with little impact on severe toxicity. We present patient-reported outcomes (PROs) from KEYNOTE-407.

Methods: Patients were randomly assigned to receive 4 cycles of pembrolizumab 200 mg or placebo once every 3 weeks plus carboplatin plus paclitaxel or nab-paclitaxel, followed by pembrolizumab or placebo for an additional 31 cycles. Health-related quality of life (HRQoL) was evaluated using the European Organisation for Research and Treatment of Cancer Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) and Quality of Life Questionnaire-Lung Cancer Module 13 (QLQ-LC13). Key PRO endpoints were change from baseline to weeks 9 and 18 (during and after platinum therapy) in the QLQ-C30 global health status/quality of life (GHS/QoL) score and time to deterioration in the composite endpoint of cough, chest pain, or dyspnea from the QLQ-C30 and QLQ-LC13. Two-sided, nominal values are provided.

Results: A total of 554 and 553 patients completed ≥ 1 QLQ-C30 or ≥ 1 QLQ-LC13 assessment, respectively. GHS/QoL score improved for the pembrolizumab-combination group (least squares [LS] mean [95% CI] change from baseline: week 9, 1.8 [-0.9 to 4.4]; week 18, 4.3 [1.7 to 6.9]) and deteriorated in the placebo-combination group (week 9, -1.8 [-4.4 to 0.7]; week 18, -0.57 [-3.3 to 2.2]). Between-group differences were improved for the pembrolizumab-combination group (difference in LS mean scores: week 9, 3.6 [95% CI, 0.3 to 6.9], nominal = .0337; week 18, 4.9 [1.4 to 8.3], nominal = .0060). Median time to deterioration in cough, chest pain, or dyspnea was not reached in either group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06]; nominal = .125).

Conclusion: Addition of pembrolizumab to chemotherapy maintained or improved HRQoL measurements relative to baseline and improved HRQoL versus chemotherapy alone at weeks 9 and 18. These results support use of pembrolizumab plus chemotherapy as first-line therapy for metastatic squamous NSCLC.
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http://dx.doi.org/10.1200/JCO.19.01348DOI Listing
January 2020

Solitary fibrous tumour along with non-small-cell lung cancer and Doege-Potter syndrome.

Kardiochir Torakochirurgia Pol 2019 Mar 4;16(1):49-51. Epub 2019 Apr 4.

Department of Lung Cancer and Chest Tumours, Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.

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http://dx.doi.org/10.5114/kitp.2019.83948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491374PMC
March 2019

Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.

Lancet 2019 05 4;393(10183):1819-1830. Epub 2019 Apr 4.

Department of Medical Oncology, Sylvester Comprehensive Cancer Center at the University of Miami, Miami, FL, USA.

Background: First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater.

Methods: This randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (≥18 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (≥50% vs 1-49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0·0122, p=0·0120, and p=0·0124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at ClinicalTrials.gov, number NCT02220894.

Findings: From Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12·8 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (≥50% hazard ratio 0·69, 95% CI 0·56-0·85, p=0·0003; ≥20% 0·77, 0·64-0·92, p=0·0020, and ≥1% 0·81, 0·71-0·93, p=0·0018). The median surival values by TPS population were 20·0 months (95% CI 15·4-24·9) for pembrolizumab versus 12·2 months (10·4-14·2) for chemotherapy, 17·7 months (15·3-22·1) versus 13·0 months (11·6-15·3), and 16·7 months (13·9-19·7) versus 12·1 months (11·3-13·3), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively.

Interpretation: The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS.

Funding: Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S0140-6736(18)32409-7DOI Listing
May 2019

Phase II Study of Roniciclib in Combination with Cisplatin/Etoposide or Carboplatin/Etoposide as First-Line Therapy in Patients with Extensive-Disease Small Cell Lung Cancer.

J Thorac Oncol 2019 04 21;14(4):701-711. Epub 2019 Jan 21.

Washington University School of Medicine, St. Louis, Missouri.

Introduction: This phase II study evaluated the efficacy and safety of the pan-cyclin-dependent kinase inhibitor roniciclib with platinum-based chemotherapy in patients with extensive-disease SCLC.

Methods: In this randomized, double-blind study, unselected patients with previously untreated extensive-disease SCLC received roniciclib, 5 mg, or placebo twice daily according to a 3 days-on, 4 days-off schedule in 21-day cycles, with concomitant cisplatin or carboplatin on day 1 and etoposide on days 1 to 3. The primary end point was progression-free survival. Other end points included overall survival, objective response rate, and safety.

Results: A total of 140 patients received treatment: 70 with roniciclib plus chemotherapy and 70 with placebo plus chemotherapy. Median progression-free survival times was 4.9 months (95% confidence interval [CI]: 4.2-5.5) with roniciclib plus chemotherapy and 5.5 months (95% CI: 4.6-5.6) with placebo plus chemotherapy (hazard ratio [HR] = 1.242, 95% CI: 0.820-1.881, p = 0.8653). Median overall survival times was 9.7 months (95% CI: 7.9-11.1) with roniciclib plus chemotherapy and 10.3 months (95% CI: 8.7-11.9) with placebo plus chemotherapy (HR = 1.281, 95% CI: 0.776-1.912, p = 0.7858). The objective response rates were 60.6% with roniciclib plus chemotherapy and 74.6% with placebo plus chemotherapy. Common treatment-emergent adverse events in both groups included nausea, vomiting, and fatigue. Serious treatment-emergent adverse events were more common with roniciclib plus chemotherapy (57.1%) than with placebo plus chemotherapy (38.6%).

Conclusions: Roniciclib combined with chemotherapy demonstrated an unfavorable risk-benefit profile in patients with extensive-disease SCLC, and the study was prematurely terminated.
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http://dx.doi.org/10.1016/j.jtho.2019.01.010DOI Listing
April 2019

Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer.

N Engl J Med 2018 11 25;379(21):2040-2051. Epub 2018 Sep 25.

From Hospital Universitario 12 de Octubre, Spanish National Cancer Research Center, Universidad Complutense and Ciberonc, Madrid (L.P.-A.), and Hospital Universitario Virgen Macarena, Seville (D.V.) - both in Spain; Leningrad Regional Clinical Hospital, St. Petersburg, Russia (A.L.); Wollongong Oncology and Wollongong Private Hospital, Wollongong, NSW, Australia (A.T.); Istanbul Medeniyet University Hospital, Istanbul (M.G.), and Ankara University, Ankara (F.Ç.Ş.) - both in Turkey; Centre Hospitalier Universitaire de Toulouse, Université Paul Sabatier, Toulouse, France (J.M.); Universitätsklinikum Tübingen, Tübingen, Germany (B. Hermes); Jász-Nagykun-Szolnok County Hospital, Szolnok (T.C.), and Országos Korányi TBC és Pulmonológiai Intézet, Budapest (A.F.) - both in Hungary; Oncology Center, Medica Sur Hospital, Mexico City (J.R.-C.); Humber River Regional Hospital, Toronto (J.W.); Sendai Kousei Hospital, Sendai (S.S.), and the Kanagawa Cancer Center, Yokohama (T.K.) - both in Japan; Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheong-ju, South Korea (K.H.L.); Jilin Cancer Hospital, Changchun, China (Y.C.); University of Turin, Orbassano, Italy (S.N.); Montefiore Medical Center-Albert Einstein College of Medicine, New York (B. Halmos); Merck, Kenilworth, NJ (X.L., G.M.L., B.P.); and the Maria Skłodowska-Curie Institute of Oncology, Warsaw, Poland (D.M.K.).

Background: Standard first-line therapy for metastatic, squamous non-small-cell lung cancer (NSCLC) is platinum-based chemotherapy or pembrolizumab (for patients with programmed death ligand 1 [PD-L1] expression on ≥50% of tumor cells). More recently, pembrolizumab plus chemotherapy was shown to significantly prolong overall survival among patients with nonsquamous NSCLC.

Methods: In this double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, 559 patients with untreated metastatic, squamous NSCLC to receive 200 mg of pembrolizumab or saline placebo for up to 35 cycles; all the patients also received carboplatin and either paclitaxel or nanoparticle albumin-bound [nab]-paclitaxel for the first 4 cycles. Primary end points were overall survival and progression-free survival.

Results: After a median follow-up of 7.8 months, the median overall survival was 15.9 months (95% confidence interval [CI], 13.2 to not reached) in the pembrolizumab-combination group and 11.3 months (95% CI, 9.5 to 14.8) in the placebo-combination group (hazard ratio for death, 0.64; 95% CI, 0.49 to 0.85; P<0.001). The overall survival benefit was consistent regardless of the level of PD-L1 expression. The median progression-free survival was 6.4 months (95% CI, 6.2 to 8.3) in the pembrolizumab-combination group and 4.8 months (95% CI, 4.3 to 5.7) in the placebo-combination group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.45 to 0.70; P<0.001). Adverse events of grade 3 or higher occurred in 69.8% of the patients in the pembrolizumab-combination group and in 68.2% of the patients in the placebo-combination group. Discontinuation of treatment because of adverse events was more frequent in the pembrolizumab-combination group than in the placebo-combination group (13.3% vs. 6.4%).

Conclusions: In patients with previously untreated metastatic, squamous NSCLC, the addition of pembrolizumab to chemotherapy with carboplatin plus paclitaxel or nab-paclitaxel resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck Sharp & Dohme; KEYNOTE-407 ClinicalTrials.gov number, NCT02775435 .).
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http://dx.doi.org/10.1056/NEJMoa1810865DOI Listing
November 2018

Trastuzumab Emtansine (T-DM1) in Patients with Previously Treated HER2-Overexpressing Metastatic Non-Small Cell Lung Cancer: Efficacy, Safety, and Biomarkers.

Clin Cancer Res 2019 01 11;25(1):64-72. Epub 2018 Sep 11.

Duke Cancer Institute, Duke University School of Medicine, Durham, North Carolina.

Purpose: HER2-targeted therapy is not standard of care for HER2-positive non-small cell lung cancer (NSCLC). This phase II study investigated efficacy and safety of the HER2-targeted antibody-drug conjugate trastuzumab emtansine (T-DM1) in patients with previously treated advanced HER2-overexpressing NSCLC.

Patients And Methods: Eligible patients had HER2-overexpressing NSCLC (centrally tested IHC) and received previous platinum-based chemotherapy and targeted therapy in the case of mutation or gene rearrangement. Patients were divided into cohorts based on HER2 IHC (2+, 3+). All patients received T-DM1 3.6 mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was investigator-determined overall response rate (ORR) using RECIST v1.1.

Results: Forty-nine patients received T-DM1 (29 IHC 2+, 20 IHC 3+). No treatment responses were observed in the IHC 2+ cohort. Four partial responses were observed in the IHC 3+ cohort (ORR, 20%; 95% confidence interval, 5.7%-43.7%). Clinical benefit rates were 7% and 30% in the IHC 2+ and 3+ cohorts, respectively. Response duration for the responders was 2.9, 7.3, 8.3, and 10.8 months. Median progression-free survival and overall survival were similar between cohorts. Three of 4 responders had gene amplification. No new safety signals were observed.

Conclusions: T-DM1 showed a signal of activity in patients with HER2-overexpressing (IHC 3+) advanced NSCLC. Additional investigation into HER2 pathway alterations is needed to refine the target population for T-DM1 in NSCLC; however, HER2 IHC as a single parameter was an insufficient predictive biomarker.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1590DOI Listing
January 2019

Preventing central nervous system metastases in non-small cell lung cancer.

Expert Rev Anticancer Ther 2018 11 21;18(11):1077-1083. Epub 2018 Sep 21.

a Department of Pneumonology , Oncology and Allergology, Medical University of Lublin , Lublin , Poland.

Introduction: There are no effective central nervous system (CNS) metastases prevention methods in lung cancer patients. Prophylactic cranial irradiation has a limited effectiveness and relatively high toxicity. Systemic chemotherapy is not relevant in reducing the risk of CNS in lung cancer patients. The understanding of molecular background of brain metastases in non-small cell lung cancer (NSCLC) patients could contribute to the development of personalized treatments for such patients. Areas covered: This article summarizes the latest clinical trials concerning the use of radiotherapy, chemotherapy, molecularly targeted therapies, and immunotherapy in lung cancer patients, with particular consideration of brain lung cancer metastasis prevention. The literature search was undertaken via PubMed and EMBASE searches and relevant articles are included in this review. Expert commentary: The recent data supports that EGFR-TKIs and ALK inhibitors are clinically relevant for first-line treatment to prevent and treat CNS metastases in molecularly selected NSCLC patients. In the future, high hopes for the prevention of CNS metastases in NSCLC patients are associated with immunotherapy concerning immune check-points inhibitors.
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http://dx.doi.org/10.1080/14737140.2018.1521273DOI Listing
November 2018

Updated Efficacy Analysis Including Secondary Population Results for OAK: A Randomized Phase III Study of Atezolizumab versus Docetaxel in Patients with Previously Treated Advanced Non-Small Cell Lung Cancer.

J Thorac Oncol 2018 08 17;13(8):1156-1170. Epub 2018 May 17.

Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France.

Introduction: The efficacy and safety of atezolizumab versus the efficacy and safety of docetaxel as second- or third-line treatment in patients with advanced NSCLC in the primary (n = 850) and secondary (n = 1225) efficacy populations of the randomized phase III OAK study (respectively referred to as the intention-to-treat [ITT] 850 [ITT850] and ITT1225) at an updated data cutoff were assessed.

Methods: Patients received atezolizumab, 1200 mg, or docetaxel, 75 mg/m, intravenously every 3 weeks until loss of clinical benefit or disease progression, respectively. The primary end point was overall survival (OS) in the ITT population and programmed death-ligand 1-expressing subgroup. A sensitivity analysis was conducted to evaluate the impact of subsequent immunotherapy use in the docetaxel arm on the observed survival benefit with atezolizumab.

Results: Atezolizumab demonstrated an OS benefit versus docetaxel in the updated ITT850 (hazard ratio [HR] = 0.75, 95% confidence interval: 0.64-0.89, p = 0.0006) and the ITT1225 (HR = 0.80, 95% confidence interval: 0.70-0.92, p = 0.0012) after minimum follow-up times of 26 and 21 months, respectively. Improved survival with atezolizumab was observed across programmed death-ligand 1 and histological subgroups. In the immunotherapy sensitivity analysis, the relative OS benefit with atezolizumab was slightly greater in the ITT850 (HR = 0.69) and ITT1225 (HR = 0.74) than the conventional OS estimate. Fewer patients receiving atezolizumab experienced grade 3 or 4 treatment-related adverse events (14.9%) than did patients receiving docetaxel (42.4%); no grade 5 adverse events related to atezolizumab were observed.

Conclusions: The results of the updated ITT850 and initial ITT1225 analyses were consistent with those of the primary efficacy analysis demonstrating survival benefit with atezolizumab versus with docetaxel. Atezolizumab continued to demonstrate a favorable safety profile after longer treatment exposure and follow-up.
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http://dx.doi.org/10.1016/j.jtho.2018.04.039DOI Listing
August 2018

Consensus statement on a screening programme for the detection of early lung cancer in Poland.

Adv Respir Med 2018 ;86(1):53-74

Department of Thoracic Surgery, Medical University of Gdansk, Sklodowskiej Curie 3a, 80-210 Gdansk, Poland.

Introduction: Lung cancer is the most common cancer in Poland and worldwide, and the leading cause of cancer-related deaths. Compared to the present day, the annual number of new cases of lung cancer will have increased by approximately 50%, by 2030. The overall ratio of mortality to incidence totals 0.87 and is among the highest. The five-year survival rate in Poland has recently achieved 13.4%. In 2015, lung cancer screening using low-dose computed tomography (LDCT) was introduced to routine clinical practice in the United States following the publication of the largest randomised study, The National Lung Screening Trial. The implementation of screening programmes in Poland and the rest of Europe also seems unavoidable. Due to the differences, both in the socioeconomic considerations and healthcare funding, compared to that in the United States, the current approach comes down to the awaited results of the European randomised study, NELSON.

Material And Methods: During the meeting of an expert panel at the "Torakoneptunalia 2016" conference in Jastarnia, Poland, a decision was made to summarise and publish the current data on LDCT lung cancer screening in the form of recommendations, or a position statement. The document was prepared by a team composed of a radiologist, thoracic surgeons, pulmonologists, clinical oncologists, epidemiologists, internists, health prevention specialists and pathologists. It reflects the current body of knowledge about lung cancer, its diagnosis and treatment, and provides recommendations on early detection of lung cancer using LDCT. The recommendations address the screening procedure, the requirements for the teams conducting the screening, and the requirements for radiologists, pathologists and surgeons involved in the diagnosis and treatment of patients.

Results: While awaiting the results of the NELSON study and the European position statement on lung cancer screening methodology, the multidisciplinary group of experts presents their position, laying grounds for the development of an action plan for early detection of lung cancer in the upcoming future in Poland.

Conclusions: Primary and secondary prophylaxis are the principal ways to reduce lung cancer mortality. While smoking cessation is a task of utmost importance, it must be accompanied by an effective screening programme if the outcome of the disease is to be improved.
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http://dx.doi.org/10.5603/ARM.2018.0009DOI Listing
September 2018

Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial.

Lancet Oncol 2017 09 17;18(9):1261-1273. Epub 2017 Jul 17.

Department of Medicine, University of Chicago, Chicago, IL, USA.

Background: New therapeutic strategies for malignant mesothelioma are urgently needed. In the DETERMINE study, we investigated the effects of the cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody tremelimumab in patients with previously treated advanced malignant mesothelioma.

Methods: DETERMINE was a double-blind, placebo-controlled, phase 2b trial done at 105 study centres across 19 countries in patients with unresectable pleural or peritoneal malignant mesothelioma who had progressed after one or two previous systemic treatments for advanced disease. Eligible patients were aged 18 years or older with Eastern Cooperative Oncology Group performance status of 0 or 1 and measurable disease as defined in the modified Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 for pleural mesothelioma or RECIST version 1.1 for peritoneal mesothelioma. Patients were randomly assigned (2:1) in blocks of three, stratified by European Organisation for Research and Treatment of Cancer status (low risk vs high risk), line of therapy (second line vs third line), and anatomic site (pleural vs peritoneal), by use of an interactive voice or web system, to receive intravenous tremelimumab (10 mg/kg) or placebo every 4 weeks for 7 doses and every 12 weeks thereafter until a treatment discontinuation criterion was met. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. The trial is ongoing but no longer recruiting participants, and is registered with ClinicalTrials.gov, number NCT01843374.

Findings: Between May 17, 2013, and Dec 4, 2014, 571 patients were randomly assigned to receive tremelimumab (n=382) or placebo (n=189), of whom 569 patients received treatment (two patients in the tremelimumab group were excluded from the safety population because they did not receive treatment). At the data cutoff date (Jan 24, 2016), 307 (80%) of 382 patients had died in the tremelimumab group and 154 (81%) of 189 patients had died in the placebo group. Median overall survival in the intention-to-treat population did not differ between the treatment groups: 7·7 months (95% CI 6·8-8·9) in the tremelimumab group and 7·3 months (5·9-8·7) in the placebo group (hazard ratio 0·92 [95% CI 0·76-1·12], p=0·41). Treatment-emergent adverse events of grade 3 or worse occurred in 246 (65%) of 380 patients in the tremelimumab group and 91 (48%) of 189 patients in the placebo group; the most common were dyspnoea (34 [9%] patients in the tremelimumab group vs 27 [14%] patients in the placebo group), diarrhoea (58 [15%] vs one [<1%]), and colitis (26 [7%] vs none). The most common serious adverse events were diarrhoea (69 [18%] patients in the tremelimumab group vs one [<1%] patient in the placebo group), dyspnoea (29 [8%] vs 24 [13%]), and colitis (24 [6%] vs none). Treatment-emergent events leading to death occurred in 36 (9%) of 380 patients in the tremelimumab group and 12 (6%) of 189 in the placebo group; those leading to the death of more than one patient were mesothelioma (three [1%] patients in the tremelimumab group vs two [1%] in the placebo group), dyspnoea (three [1%] vs two [1%]); respiratory failure (one [<1%] vs three [2%]), myocardial infarction (three [1%] vs none), lung infection (three [1%] patients vs none), cardiac failure (one [<1%] vs one [<1%]), and colitis (two [<1%] vs none). Treatment-related adverse events leading to death occurred in five (1%) patients in the tremelimumab group and none in the placebo group. The causes of death were lung infection in one patient, intestinal perforation and small intestinal obstruction in one patient; colitis in two patients, and neuritis and skin ulcer in one patient.

Interpretation: Tremelimumab did not significantly prolong overall survival compared with placebo in patients with previously treated malignant mesothelioma. The safety profile of tremelimumab was consistent with the known safety profile of CTLA-4 inhibitors. Investigations into whether immunotherapy combination regimens can provide greater efficacy than monotherapies in malignant mesothelioma are ongoing.

Funding: AstraZeneca.
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http://dx.doi.org/10.1016/S1470-2045(17)30446-1DOI Listing
September 2017

Comparison of the effectiveness of erlotinib, gefitinib, and afatinib for treatment of non-small cell lung cancer in patients with common and rare gene mutations.

Oncol Lett 2017 Jun 3;13(6):4433-4444. Epub 2017 Apr 3.

Department of Lung Cancer and Chest Tumours, The Maria Skłodowska-Curie Memorial Cancer Center and Institute, 02-034 Warsaw, Poland.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are routinely used to treat non-small cell lung cancer (NSCLC) in patients with common activating mutations of the gene. The aim of the study was to compare the efficacies of EGFR-TKIs in patients with common (exon 19 deletions and exon 21 p.Leu858Arg) and rare mutations. A retrospective analysis of 180 NSCLC patients with common (n=167) and rare (n=13) mutations treated with erlotinib (n=98), gefitinib (n=66) and afatinib (n=16) was performed. mutations were determined using RT-PCR and the EntroGen EGFR Mutations Analysis kit. Partial and complete response (PR and CR), progression-free survival (PFS), and overall survival (OS) were analyzed. Demographic and clinical factors had no impact on PFS or OS in patients treated with EGFR-TKIs. Erlotinib, gefitinib, and afatinib showed similar efficacies based on treatment response, median PFS, and OS. The type of mutation had no impact on median OS; however, median PFS was significantly longer in patients with the exon 19 deletion compared to patients with the exon 21 p.Leu858Arg substitution and rare gene mutations (P=0.013). Patients with common mutations showed significantly longer median PFS than those with rare mutations (10 vs. 5 months; P=0.009). Erlotinib, gefitinib, and afatinib show similar efficacies in NSCLC patients with both common and rare mutations. When undergoing EGFR-TKI treatment, patients with rare mutations showed similar OS but poorer PFS. Further investigation into the associations between particular rare mutations and EGFR-TKIs treatment outcomes is required.
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http://dx.doi.org/10.3892/ol.2017.5980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453045PMC
June 2017

Two neoplasms rich in small lymphocytes, B1B2 thymoma and small lymphocytic lymphoma, intermingled in one tumor mass. A case report.

Pol J Pathol 2017;68(1):75-81

We present a case of a 52-year-old man with myasthenia gravis and a mediastinal tumor who was admitted to our hospital for surgical treatment. The pathologic examination of the resected tumor revealed a very rare case of a collision tumor: a B1B2 thymoma and a small lymphocytic lymphoma. Flow cytometry of the peripheral blood revealed the presence of a small number of leukemic cells. After postoperative irradiation of the mediastinum and chemotherapy a complete response in both diseases was achieved. The case confirms that a pathologist should always be aware that two different neoplasms can coexist in rare cases.
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http://dx.doi.org/10.5114/pjp.2017.67620DOI Listing
July 2017

Evaluation of miR-506 and miR-4316 expression in early and non-invasive diagnosis of colorectal cancer.

Int J Colorectal Dis 2017 Jul 12;32(7):1057-1060. Epub 2017 Apr 12.

Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Jaczewskiego 8, 20-954, Lublin, Poland.

Purpose: Examination of the entire colon by colonoscopy remains the golden standard for screening of colorectal cancer (CRC). However, patients are reluctant to perform invasive colonoscopies because of interference with their intimacy. Therefore, the potential use of non-invasive analysis of microRNAs expression in liquid biopsy as a novel biomarker for early CRC has investigated in several studies. In this study, we analyzed the expression of two novel microRNAs: miR-506 and miR-4316, which have never been examined in CRC.

Methods: Plasma samples were collected from 56 patients (median age of 68 years) with operable colorectal cancer and from 70 healthy individuals (median age of 59 years). Expression of plasma microRNAs was evaluated by quantitative reverse transcription polymerase chain reaction using Eco real-time PCR device (Illumina, USA).

Results: We found a significant elevated expression of both examined microRNAs in early CRC patients when compared to those in healthy individuals (p = 0.0054 for miR-506 and p = 0.0025 for miR-4316). The expression of miR-506 and miR-4316 did not depend on gender, age, disease stage, and tumor localization of CRC patients. ROC curve analysis showed that both examined microRNAs could differentiate early stage colorectal cancer from healthy individuals with 76.8% specificity and 60.7% sensitivity for miR-506 analysis and 76.8% specificity and 75% specificity for miR-4316 analysis.

Conclusion: Our study revealed that elevated expression of miR-506 and miR-4316 in peripheral blood were potential molecular markers for early colorectal cancer.
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http://dx.doi.org/10.1007/s00384-017-2814-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486640PMC
July 2017

Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.

Lancet 2017 01 13;389(10066):255-265. Epub 2016 Dec 13.

UC Davis Comprehensive Cancer Center, Sacramento, CA, USA. Electronic address:

Background: Atezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1 and B7-1 interactions, reinvigorating anticancer immunity. We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer.

Methods: We did a randomised, open-label, phase 3 trial (OAK) in 194 academic or community oncology centres in 31 countries. We enrolled patients who had squamous or non-squamous non-small-cell lung cancer, were 18 years or older, had measurable disease per Response Evaluation Criteria in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy regimens (one or more platinum based combination therapies) for stage IIIB or IV non-small-cell lung cancer. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded. Patients were randomly assigned (1:1) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m every 3 weeks by permuted block randomisation (block size of eight) via an interactive voice or web response system. Coprimary endpoints were overall survival in the intention-to-treat (ITT) and PD-L1-expression population TC1/2/3 or IC1/2/3 (≥1% PD-L1 on tumour cells or tumour-infiltrating immune cells). The primary efficacy analysis was done in the first 850 of 1225 enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02008227.

Findings: Between March 11, 2014, and April 29, 2015, 1225 patients were recruited. In the primary population, 425 patients were randomly assigned to receive atezolizumab and 425 patients were assigned to receive docetaxel. Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT population, overall survival was improved with atezolizumab compared with docetaxel (median overall survival was 13·8 months [95% CI 11·8-15·7] vs 9·6 months [8·6-11·2]; hazard ratio [HR] 0·73 [95% CI 0·62-0·87], p=0·0003). Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab (n=241) compared with docetaxel (n=222; median overall survival was 15·7 months [95% CI 12·6-18·0] with atezolizumab vs 10·3 months [8·8-12·0] with docetaxel; HR 0·74 [95% CI 0·58-0·93]; p=0·0102). Patients in the PD-L1 low or undetectable subgroup (TC0 and IC0) also had improved survival with atezolizumab (median overall survival 12·6 months vs 8·9 months; HR 0·75 [95% CI 0·59-0·96]). Overall survival improvement was similar in patients with squamous (HR 0·73 [95% CI 0·54-0·98]; n=112 in the atezolizumab group and n=110 in the docetaxel group) or non-squamous (0·73 [0·60-0·89]; n=313 and n=315) histology. Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90 [15%] of 609 patients) versus docetaxel (247 [43%] of 578 patients). One treatment-related death from a respiratory tract infection was reported in the docetaxel group.

Interpretation: To our knowledge, OAK is the first randomised phase 3 study to report results of a PD-L1-targeted therapy, with atezolizumab treatment resulting in a clinically relevant improvement of overall survival versus docetaxel in previously treated non-small-cell lung cancer, regardless of PD-L1 expression or histology, with a favourable safety profile.

Funding: F. Hoffmann-La Roche Ltd, Genentech, Inc.
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http://dx.doi.org/10.1016/S0140-6736(16)32517-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886121PMC
January 2017

A decrease in D-dimer concentration and an occurrence of skin rash as iatrogenic events and complementary predictors of survival in lung cancer patients treated with EGFR tyrosine kinase inhibitors.

Pharmacol Rep 2016 Dec 20;68(6):1140-1148. Epub 2016 Jul 20.

Department of Pulmonary Circulation and Thromboembolic Diseases, Centre of Postgraduate Medical Education, European Health Centre Otwock, Otwock, Poland. Electronic address:

Background: Progression of lung cancer is associated with some abnormalities in coagulation. The aim of the study was to determine the predictive and prognostic value of changes in D-dimer concentration in non-small cell lung cancer (NSCLC) patients on anti-EGFR targeted therapy.

Methods: The analysis included fifty two NSCLC patients treated with EGFR tyrosine kinase inhibitors (TKIs): erlotinib or gefitinib. All clinical data were collected before treatment and after 2 cycles (60days) of therapy and correlated with progression free and overall survival (PFS, OS).

Results: Two iatrogenic events were noted within the first 60days of anti-EGFR treatment: typical skin rash in 38 (73.1%) and a decrease in D-dimer concentration in 26 (50%) patients. Multivariate analysis revealed a decrease of D-dimer concentration as the strongest factor associated with longer PFS (HR=0.39; 95%CI: 0.16-0.91; p=0.029) and OS (HR=0.33; 95%CI: 0.13-0.82, p=0.017) independently of skin rash, baseline level of D-dimer and other clinical characteristics. Coexisting a decrease in D-dimer concentration with an occurrence of skin rash correlated significantly with the positive objective response after 60days of anti-EGFR therapy (p=0.0175) and indicated the longest PFS (HR=0.31; 95%CI: 0.16-0.60, p=0.0005) as well as OS (HR=0.30; 95%CI: 0.15-0.59, p=0.0005).

Conclusion: Adverse events may predict the outcomes of cancer patients. Apart from skin rash, change in D-dimer concentration may be valuable parameter in creation of predictive and prognostic models in NSCLC patients receiving anti-EGFR targeted therapy.
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http://dx.doi.org/10.1016/j.pharep.2016.07.003DOI Listing
December 2016