Summary Purpose To establish a transborder virtual tumor board (VTB) fostering state-of-the-art management of cancer patients by exchanging knowledge and expertise among oncologists in Central and Southeastern Europe (CEE). Methods We established and implemented a VTB based on the WebEx platform. This allowed for password-protected and secure upload of patient cases to be presented and discussed among colleagues from various oncology centers scattered throughout CEE in order to arrive at a recommendation for further diagnoses and/or treatment. Results A total of 73 cases from 16 oncology centers located in 11 CEE countries were uploaded by 22 physicians; 71 were discussed over the course of 17 virtual meetings between June 2018 and May 2019 and 12 different kinds of malignant diseases were discussed with lung cancer (46.6%), melanoma (19.2%) and bladder cancer (13.6%) being the most commonly presented tumor entities. Of the discussed patients, 93.3% had stage IV disease at the time of presentation, 62.6% received chemotherapy or targeted treatment and 67.1% were treated with immune checkpoint inhibitors (ICPIs). The most common causes for presentation and discussion of patient cases were related to the use of ICPIs (80%). Conclusion When the need for expertise exceeds locally available resources, web-based VTBs provide a feasible way to discuss patient cases and arrive at conclusions regarding diagnoses and/or treatment across large geographic distances. Moreover, VTBs provide an innovative way for proper, state-of-the-art management of patients with malignant diseases in times of social distancing and the resulting need for restricted interaction during the current SARS-CoV‑2 (severe acute respiratory syndrome coronavirus type 2) pandemic.

BACKGROUND Transformation of EGFR (epidermal growth factor receptor) - mutant non-small cell lung cancer (NSCLC) into small-cell lung cancer (SCLC) is one mechanism of resistance to tyrosine kinase inhibitor (TKI) treatment, seen in approximately 3-10% cases. Such transformed SCLC often retains the original EGFR mutation (EGFRM), which is not otherwise observed in SCLC. CASE REPORT We present a 67 y/o woman with pulmonary adenocarcinoma (AC) and EGFRM deletion on exon 19. After initial treatment with whole brain radiotherapy and 7 months of TKI afatinib, progression was observed. Liquid biopsy detected deletion on exon 19 and T790M mutation. Chemotherapy carboplatin plus pemetrexed was administered, with no response. Genetics from a rebiopsy of lung revealed deletion on exon 19. After 12 months treatment with TKI osimertinib, a progression in lung and pancreas lesions was detected, docetaxel was used, with followig progression. The lung biopsy revealed SCLC. Significant elevation of serum markers carcinoembryonic antigen (CEA) and neuron-specific enolase (NSE) was observed at the time of the SCLC diagnosis. Treatment with carboplatin and etoposide was not effective. The next biopsy found two populations of cells: SCLC and AC. The biopsy from the pancreatic lesion revealed metastasis of SCLC. PCR confirmed EGFRM deletion on exon 19 in the lung SCLC tissue sample. The following treatment lines of topotecan, erlotinib were not effective. The patient survived 36 months from diagnosis, 7 months from detection of SCLC. CONCLUSION Screening for transformation of EGFR-mutant NSCLC to SCLC should be considered in resistance to TKI. In the presented case, this rare transformation was confirmed by histopathologic examination and by PCR. EGFRM in the lung SCLC, identical to that found in the original lung AC, was detected. Further, the observed elevation of serum tumor markers NSE and CEA can indicate this infrequent transformation and help to decide on rebiopsy.

New immunotherapeutics, PD-1 and PD-L1 checkpoint signalling inhibitors, have improved the prospects of patients with advanced non-small cell lung cancer (NSCLC). The purpose of this study was to assess the first results achieved with the PD-L1 inhibitor atezolizumab in the treatment of advanced NSCLC in Slovakia. The data of patients who entered the pre-approval access programme with atezolizumab between June 2017 and September 2017 were reviewed in the retrospective multicentre study. Data regarding patients were obtained from the databases of participating institutions and patient files. Statistical analyses were performed using MedCalc®software. PFS and OS were estimated using the Kaplan–Meier method, based on the data available by the end of March 2019. Altogether 22 patients were included. Characteristics of patients: median age, years (range): 63 (41 - 85), female/male: 3/19, ECOG PS: 0, 1, 2, 3 in 6, 11, 3, 2 patients, respectively. Histology: 8 squamous, 14 non-squamous. Patients with locally advanced disease: 1, with metastatic disease: 21. Treatment lines before atezolizumab: median: 2 (range: 1 - 3). Median PFS: 5 months (95%CI: 4 - 10). Median OS: 11 months (95%CI: 8 – 20). Complete/partial response: 1/4 patients. Median PFS in patients with complete or partial response was not achieved but will be over 19 months (range: 13 – 21+). Two patients only had to discontinue atezolizumab due to toxicities (pneumonitis and hepatitis). Results from our retrospective study are similar to those seen in the phase III trial OAK, excepting PFS. However, the different CT scanning schedules for the response evaluations and follow up in the different participating institutions could influence numerically better PFS seen in our patients.

BACKGROUND:Treatment of non-small cell lung cancer (NSCLC) improved substantially in the last decades. Novel targeted and immune-oncologic drugs were introduced into routine treatment. Despite accelerated development and subsequent drug registrations by the European Medicinal Agency (EMA), novel drugs for NSCLC are poorly accessible in Central and Eastern European (CEE) countries.MATERIAL AND METHODS:The Central European Cooperative Oncology Group conducted a survey among experts from 10 CEE countries to provide an overview on the availability of novel drugs for NSCLC and time from registration to reimbursement decision in their countries.RESULTS:Although first-generation epidermal growth factor receptor tyrosine kinase inhibitors were reimbursed and available in all countries, for other registered therapies-even for ALK inhibitors and checkpoint inhibitors in first-line-there were apparent gaps in availability and/or reimbursement. There was a trend for better availability of drugs with longer time from EMA marketing authorization. Substantial differences in access to novel drugs among CEE countries were observed. In general, the availability of drugs is not in accordance with the Magnitude of Clinical Benefit Scale (MCBS), as defined by the European Society for Medical Oncology (ESMO). Time spans between drug registrations and national decisions on reimbursement vary greatly, from less than 3 months in one country to more than 1 year in the majority of countries.CONCLUSION:The access to novel drugs for NSCLC in CEE countries is suboptimal. To enable access to the most effective compounds within the shortest possible time, reimbursement decisions should be faster and ESMO MCBS should be incorporated into decision making.

Median PFS in the key phase III trials with gefitinib or erlotinib for advanced NSCLC with EGFR sensitizing mutations was less than 12 months. There are only a few data about the treatment results and toxicity of long-term treatment lasting 5 years or over. Purpose of this study was to find patients treated with either gefitinib or erlotinib for at least 5 years and to evaluate the treatment results in this group of patients. Retrospective multicentre study, approved by the Ethics Committee of the Specialised Hospital of St Zoerardus Zobor, Nitra. All thoracic oncology centres in Slovakia were involved. For this update also the other hospitals and oncology outpatient departments were asked to participate. Data regarding patients were obtained from the databases of participating institutions and patient files. Descriptive statistics was used for the data analysis. At the IASLC WCLC 2018 we presented data about seven patients included in the study. Here we present the data about another two patients, and updated data about the previously found seven patients. Characteristics of patients and the treatment results are summarised in the Table. Median PFS in this exceptional group was not reached, but it will be over 80 months. There was only one patient with the decreased dose of erlotinib (from 150 to 100 mg QD) due to skin toxicities. All the other patients had the common and manageable grade I – II toxicities only, and there were no unexpected drug-related AEs.TablePatients characteristics and treatment resultsGender (M/W)Age (yrs)Smoking statusPSHistology,CytologyNSCLC stageEGFR mutationTreatment line/TKIResponsePFS (mo)W72Ex2ACIVDel 19*1st/gefitinibSD67W53Smoker1ACIVNK1st/erlotinibSD112+W58Never1AC/SQIIIBNK2nd/erlotinibPR94+W69Never1ACIVNK2nd erlotinibSD87+W72Never1ACIVDel 192nd erlotinibPR75+W59Never1ACIVL858R1st/erlotinibPR72M64Never1AC/SQIVNK2nd/erlotinibPR108+M70Ex1SQIVNK2nd/erlotinibSD102+W50Never1ACIVDel 191st/gefitinibPR66*Del 19 and T790M Open table in a new tab *Del 19 and T790M The treatment was safe and effective in our group of patients with advanced NSCLC treated with gefitinib or erlotinib for over 5 years. The NGS analysis of the available samples will be done after approval of the submitted Protocol by the Ethics Committee.

BACKGROUND:The introduction of targeted treatments for subsets of non-small cell lung cancer (NSCLC) has highlighted the importance of accurate molecular diagnosis to determine if an actionable genetic alteration is present. Few data are available for Central and Eastern Europe (CEE) on mutation rates, testing rates, and compliance with testing guidelines.METHODS:A questionnaire about molecular testing and NSCLC management was distributed to relevant specialists in nine CEE countries, and pathologists were asked to provide the results of EGFR and ALK testing over a 1-year period.RESULTS:A very high proportion of lung cancer cases are confirmed histologically/cytologically (75-100%), and molecular testing of NSCLC samples has been established in all evaluated CEE countries in 2014. Most countries follow national or international guidelines on which patients to test for EGFR mutations and ALK rearrangements. In most centers at that time, testing was undertaken on request of the clinician rather than on the preferred reflex basis. Immunohistochemistry, followed by fluorescent in situ hybridization confirmation of positive cases, has been widely adopted for ALK testing in the region. Limited reimbursement is a significant barrier to molecular testing in the region and a disincentive to reflex testing. Multidisciplinary tumor boards are established in most of the countries and centers, with 75-100% of cases being discussed at a multidisciplinary tumor board at specialized centers.CONCLUSIONS:Molecular testing is established throughout the CEE region, but improved and unbiased reimbursement remains a major challenge for the future. Increasing the number of patients reviewed by multidisciplinary boards outside of major centers and access to targeted therapy based on the result of molecular testing are other major challenges.

Median PFS in the key phase III trials with gefitinib or erlotinib for advanced NSCLC with EGFR sensitizing mutations was less than 12 months. There are only a few data about the treatment results and toxicity of long-term treatment lasting 5 years or over. Purpose of this study was to find patients treated with either gefitinib or erlotinib for at least 5 years and to evaluate the treatment results in this group of patients. Retrospective multicentre study, approved by the Ethical Committee of the Specialised Hospital of St Zoerardus Zobor, Nitra. All thoracic oncology centres in Slovakia were involved. Data regarding patients were obtained from the databases of participating institutions and patient files. Descriptive statistics was used for the data analysis. Seven patients were included. Patients characteristics and the treatment results are summarised in the Table. Median PFS in this exceptional group was not reached, but it will be over 75 months. There was only one patient with the decreased dose of erlotinib (from 150 to 100 mg QD) due to skin toxicities. All the other patients had the common and manageable grade I – II toxicities only, and there were no unexpected drug-related AEs. In our group of patients with advanced NSCLC treated with gefitinib or erlotinib for over 5 years the treatment was safe and effective. The NGS analysis of the available samples will be retrospectively done to assess the specific genetic features of these long-term responders.

Primary EGFR dual mutations comprising T790M and exon 19 or 21 mutation (SM, sensitizing mutations) are rare when common diagnostic methods are used. There are limited data about the treatment results with EGFR-TKIs in this setting. Purpose of this study was to find out the prevalence of primary dual EGFR mutations T790M and SM in the Caucasian population of NSCLC patients in Slovakia, and to evaluate treatment results with EGFR-TKIs in these patients. Retrospective multicenter study. The databases of the molecular/genetic diagnostic centers were searched for patients with dual EGFR mutations T790M and SM. Data regarding patients were obtained from the databases of participating institutions and patient files. Descriptive statistics was used for data analysis. Altogether 3883 patients were tested for EGFR mutation from 2010 through 2015. Allele specific PCR was used in majority, high resolution melting analysis, Sanger sequencing and mutant-enriched PCR were also used. Double mutations T790M and SM were found in only six cases, i.e. the observed period prevalence was 0.15%. Patients' characteristics and the treatment results are in the Table. PS was improved after two months of treatment in patients with initial PS over 1, and remained unchanged in those with PS 1. There were no unexpected AEs. The prevalence of the dual EGFR mutations T790M and SM is very low in Caucasian population in Slovakia when common testing methods are used. Treatment results seen in this study suggest good effectiveness of the first or second generation EGFR-TKIs even in NSCLC with primary dual T790M and SM mutations. The quantitative analysis of these mutations using the blood sample is available at present. It might be useful in decision making about the use of the first – second or the third generation EGFR-TKI, based on the prevailing mutation.

Primary EGFR dual mutations comprising T790M and exon 19 or 21 mutation (SM, sensitizing mutations) are rare in the Caucasian population, and there are only limited data about the treatment results with EGFR-TKIs in this setting. In 2016 we published results of the Slovakian retrospective study, in which six cases of the primary EGFR dual mutations T790M and SM were found among 3883 patients with NSCLC tested for EGFR mutations. Here we present the treatment results with updated PFS and OS data.

In Slovakia, since October 2012, crizotinib has been available for the treatment of adults with previously treated ALK-positive advanced NSCLC, based on the therapeutic indication approved by the European Medicines Agency. The purpose of this study was to assess the results achieved with crizotinib in the treatment of NSCLC in clinical practice in Slovakia, and to compare them with the results from the key clinical trial PROFILE 1007. In the multicenter retrospective study, approved by the Ethical Committee of the Specialized Hospital of St Zoerardus Zobor, the data of 34 ALK-positive patients from 8 centers were reviewed. Data regarding ALK testing and results were obtained from the central laboratory database (Comenius University Jessenius Medical Faculty and Martin's Biopsy Centre). Data regarding patients were obtained from the databases of participating institutions and patient files. Fluorescence in situ hybridization (FISH) with break-apart probes was used for the confirmation of ALK rearrangement in all cases. Response to treatment was evaluated using RECIST criteria v. 1.1. Statistical analyses were performed using MedCalc® software. PFS and OS were estimated using the Kaplan–Meier method. Between October 2012 and December 2015, 34 ALK-positive patients with locally advanced or metastatic NSCLC were treated with crizotinib, 31 of them after the first-line chemotherapy. Characteristics of patients: median age, years (range): 58 (23-77), ECOG/WHO PS: 0, 1, 2, 3 in 1, 23, 6, and 4 patients, respectively. Histology: adenocarcinoma in 33 cases, NSCLC, NOS in one. Patients with locally advanced disease: 2, with metastatic disease: 32. Median PFS was 18 months (95% CI: 13 - 22), median OS (number of events: 13, 38,24%): 32 months (95% CI: 18 - 32), response rates: CR + PR: 3 + 23, 76,5% (95% CI 50-100%), SD: 7, 21,5%, PD: 3, 8,8%, not stated: 1. There was a significant improvement in PS within 2 month, mean difference: - 0,62, p = 0,0025. Grade 3/4 toxicities occurred in 15/2 patients. Crizotinib was permanently discontinued due to AEs in 2 patients only. PFS and OS in our study were numerically better in comparison with PROFILE 1007. On the other hand, common grade 3 toxicities occurred also more often. Our study provides real-world evidence of the efficacy of crizotinib in patients with ALK-positive NSCLC, treated outside of clinical trials.

Development of the target therapies of lung cancer was a rapid process which fundamentally changed the pathological diagnosis as well. Furthermore, molecular pathology became essential part of the routine diagnostics of lung cancer. These changes generated several practical problems and in underdeveloped countries or in those with reimbursement problems have been combined with further challenges. The central and eastern region of Europe are characterized by similar problems in this respect which promoted the foundation of NSCLC Working Group to provide up to date protocols or guidelines. This present paper is a summary of the molecular pathology and target therapy guidelines written with the notion that it has to be upgraded continuously according to the development of the field.

The ImplementatioN of perSonalized medicine In NSCLC in Central Europe: EGFR testing, Histopathology, and clinical feaTures (INSIGHT) observational study assessed both implementation of epidermal growth factor receptor (EGFR) mutation testing and treatment of patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC) in a real-world setting in Central Europe. A total of 1785 patients from 14 cancer centers of six Central European countries were enrolled. EGFR mutations were detected in tumors of 13.8% of the patients. More than 70% of patients with advanced EGFR mutation-positive NSCLC received EGFR tyrosine kinase inhibitors as first-line therapy. The INSIGHT study demonstrated the establishment of EGFR mutation testing, a mutation rate consistent with other Caucasian patients populations, and adherence to current guidelines regarding treatment of patients with EGFR mutation-positive tumors in Central Europe.

Background Crizotinib was approved and authorized for use in the European Union in October 2012. Since then crizotinib has been available in Slovakia for treatment of advanced metastatic non-small cell lung cancer (NSCLC) after failure of standard chemotherapy only, based on the wording of the therapeutic indications by the European Medicines Agency. Purpose of this study was to assess results achieved with crizotinib in the treatment of advanced, metastatic NSCLC in clinical practice in Slovakia.