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Lung cancer holds a leading position in the cancer mortality pattern worldwide. The emergence of knowledge about driver mutations heralded a new era in the targeted therapy for lung carcinomas. ALK translocation is identified in 5–7% of non-small cell lung cancer cases. ALK-positive lung adenocarcinomas are associated with specific clinical features, including no or light smoking history and younger age. Alectinib is a novel ALK inhibitor that has been granted a breakthrough therapy status by the FDA to accelerate approval as a second-line therapy after progression during crizotinib therapy.Here, the case of a patient with metastatic ALK-positive lung adenocarcinoma treated with alectinib has been discussed. Molecular genetic testing for driver mutations makes it possible to personalize approaches to anticancer drug therapy. At the same time, the custom-compounded targeted therapy is more often accompanied by significant objective responses and moderate symptoms of toxicity, which is relevant for patients in critical condition. The experience in using alectinib demonstrates the possibility of its long-term administration with high efficiency and a controlled safety profile.

Introduction. Sufficient experience has been gained with the use of target drugs in patients with ALK-positive non-small cell lung cancer (NSCLC) over the past years. The multikinase inhibitor crizotinib was the first drug approved for use. The drug passed the accelerated registration in the United States, showing an indisputable advantage over standard chemotherapy both in untreated patients and patients, who had previously received cytostatic therapy. Brain metastasis is the manifestation of acquired resistance to crizotinib in almost half of patients, which requires local monitoring and/or prescription of the nextgeneration ALK inhibitors – ceritinib or alectinib. Experience has proven that it is sequential targeted therapy with the nextgeneration ALK inhibitors with a wider spectrum of anti-tumour activity and penetrating the blood-brain barrier that significantly improves the overall survival of these patients after disease progression on crizotinib. It appears then that the second generation drugs – ceritinib and particularly alectinib – show more impressive results when they are prescribed in the firstline therapy and have now replaced crisotinib in the clinical guidelines. Crizotinib has long remained the only target drug to treat ALK-positive patients in the Russian Federation. Material and methods. In our work, we analysed the crizotinib therapy outcomes in 104 patients with translocation in the ALK gene. The drug was prescribed in a standard dose of 250 mg orally twice per day. Treatment continued until disease progression or intolerable toxicity. Results. The objective response was 56.8%. The median time to progression was 13 months; the median overall survival was 46 months. Conclusion. The obtained data are consistent with previously published data and confirm the effectiveness of the drug in comparison with the previously available universal standard – combination chemotherapy.

Background: Disease-specific Graded Prognostic Assessment (DS-GPA) is the most validated prognostic tool for patients with brain metastasized lung cancer. The Lung-molGPA scoring system was recently introduced for oncogenic-driven brain metastasized lung cancer, but has not yet been validated in cohorts including only ALK-translocated tumors. Methods: We designed a retrospective cohort study consisting of 44 patients with brain metastasized ALK-positive, non-small cell lung cancer (NSCLC) who were treated between January 2009 and November 2019 at Karolinska University Hospital in Stockholm, Sweden. Information about demographics and clinicopathological parameters were collected. Predictors of overall survival (OS) were identified by Cox regression analyses. A bootstrap validation with 1000 samples was performed in order to compare the different prognostic scores. Results: The variables found to independently influence OS in the multivariate analysis, i.e., PS, sex and brain metastases at diagnosis, were used as prognostic variables in our new prognostic index (ALK-BPI). Patients were divided into two prognostic groups. The median OS was 65.7 months for the good prognostic group and 22.7 months for the poor prognostic group (p = 0.0068). In the univariate analysis of the different prognostic scores, ALK-BPI performed better than the others (HR = 3.6, 95% CI: 1.3&ndash, 9.9). The mean C-statistics of the different prognostic scores were compared to each other, and no significant difference was observed. Conclusion: We propose the ALK-BPI score as a new prognostic tool that can easily be applied for ALK-positive lung cancer patients with brain metastases in daily clinical practice, as it has at least the same prognostic value as Lung-molGPA.

Introduction: Based on the high incidence of thromboembolic events (TEs) observed in lung adenocarcinomas with ALK translocations and taking into account the biological proximity of ROS1 and ALK, we conducted a retrospective analysis of patients with advanced lung carcinoma carrying rearrangements in ROS1 from 23 centres in Spain and one centre in Portugal. Methods: The main objective of the study was to analyse the incidence of TE in this population, looking for predictive risk factors, and its impact on overall survival. Results: A total of 58 patients were included. The incidence of TEs throughout the disease was 46.6% (n = 27) with a median follow-up of 19 months (range: 1-78 months) and a median overall survival of 52 months in the total population and 50 months for the patients presenting TEs, with a hazards ratio of 1.12 (95% confidence interval: 0.47-2.65) p = 0.78. The majority of the events were venous (n = 24; 89%) and occurred in the ambulatory setting (n = 18; 67%). Almost half of the patients (n = 13; 48%) presented the TE in the peri-diagnostic period. Conclusions: The high incidence of thrombosis, especially during the cancer diagnosis process, requires special attention from a clinician. Despite the limitations of such a small descriptive study, its results are in accordance with previously reported data. It would be important to design prospective studies of antithrombotic prophylaxis in this population because of their possible impact in reducing the risk of TEs. (C) 2020 Elsevier Ltd. All rights reserved.

In January 2003, a 55-year old, non-smoking woman visited our hospital to undergo treatment for T4N0M0 pulmonary adenocarcinoma of the left lung. Until death in October 2015, she received over 20 lines of treatment including a second line therapy with gefitinib, which showed long response. In March 2014, she noticed the left axillar lymph node swelling. Aspiration cytology of the lymph node revealed the presence of adenocarcinoma harboring EGFR exon 19 deletion (Ex19del) but not T790M. Concomitant ALK translocation of variant 1 was also detected. Crizotinib and alectinib showed marked decrease of serum CEA value from 731.9 to 122.2 and moderate radiologic response. In contrast, both Ex19del and T790M, but not ALK translocation, were detected in the metastasis to the left anterior chest wall.

A 35-year-old woman with shortness of breath and cough was referred to our hospital and agreed to receive therapy for lung tumor in our hospital. Based on the findings from a bronchoscopic biopsy, she was suspected of having pulmonary inflammatory myofibroblastic tumor (IMT), but a correct diagnosis was not indicated. Right upper wedge lobectomy was performed. The findings of a pathological examination of the permanent surgical resected tissue, the ultimate diagnosis was pulmonary IMT. The immunohistochemistry of ALK using the intercalated antibody-enhanced polymer (iAEP) method was positive. We extracted the RNA from frozen surgical resected tumor tissue and proved the tropomyosin alpha-4 chain (TPM4)-ALK by 5' rapid amplification of cDNA end (5' RACE) and reverse transcription polymerase chain reaction. The preoperative bronchial biopsy specimen was also found to be positive for anti-ALK immunohistochemistry with the iAEP method. A molecular therapeutic drug may be useful as personalized therapy for tumors with ALK translocation as oncogenic drivers. We should examine the ALK protein expression and translocation in cases of lung cancer and IMT using an adequate ALK immunohistochemistry system. We experienced a case of pulmonary IMT with TPM4-ALK translocation.

Patients with brain metastases (BM) are a population of high clinical need for new therapeutic approaches due to, as yet, very impaired survival prognosis. However, only few clinical trials have specifically addressed this prognostically highly heterogeneous patient population. New developments in the treatment of BM patients aim to reduce the side effects of local therapies, for example, by redefining the indications for stereotactic radiosurgery and whole-brain radiotherapy (WBRT) or introducing new applications like hippocampal sparing WBRT. Furthermore, systemic therapies become a more important treatment approach in patients harboring targetable mutations, as recent BM-specific endpoints in several phase III trials have shown promising intracranial efficacy. In addition, immune-checkpoint inhibitors show promising intracranial efficacy, particularly in patients with melanoma and non-small lung cancer BM. Here, we provide a review on the recent new developments in the local and systemic therapy approaches in BM patients.

e20579Background: The evaluation of ALK rearrangement in non-small-cell lung cancer (NSCLC) is a useful and significant tool for the decision of crizotinib treatment. However, tumor biopsy in patie...

Aims To study the ALK translocation in patients with advanced non-small-cell lung carcinomas (NSCLCs) seen at a European cancer centre, and its association with EGFR mutations, KRAS mutations and MET amplification. Methods and results The study included samples from 86 patients diagnosed with advanced NSCLC. ALK fluorescence in-situ hybridization (FISH) was performed using the ALK break-apart probe set (Vysis). ALK FISH-positive cases were defined as those with more than 15% break-apart signals or isolated red signals in 50 cells. EGFR and KRAS mutations were determined by direct sequencing. All ALK-positive cases were analysed retrospectively for MET amplification using a FISH assay, and for ALK mutations by sequencing. We found nine (10.5%) ALK-positive cases, all in adenocarcinomas and the majority in female patients (88.9%). Signet ring cells were observed in four (44.4%) of the nine patients. None of the ALK translocated cases showed MET amplifications or EGFR, KRAS and ALK mutations. Conclusions The prevalence of ALK translocation in an unselected population of European patients with advanced NSCLCs was 10%. This alteration was mutually exclusive with EGFR and KRAS mutations, as well as with MET amplification. If multiplexing is considered at the preanalytical phase, lung biopsy specimens are sufficient for performing several predictive assays.

e19084 Background: Targeted therapies have considerably improved the prognosis of patients with non-small cell lung cancer (NSCLC) ,RESIST criteria was the most often used response assessment method to reflecting the clinical benefits. We propose a non-invasive, folate receptor (FR)–based circulating tumor cell (CTC) detection approach to interpret treatment response of targeted therapy between baseline and follow-up CTC values in EGFR mutation/ALK translocation advanced NSCLC. Methods: CTCs were collected from 4 ml of blood based on negative enrichment by immunomagnetic beads in blood from 51 advanced NSCLC patients before the start of targeted therapy and after one month, three months of therapy. The change of CTCs value, radiological response and patient reported outcome(PRO) were compared. Sequential analyses were conducted to monitor CTC signals during therapy and correlate radiological effects with treatment outcome. Results: CTCs were detected in pretreatment and protreatment blood samples from all...

e13516 Background: Targeted lung cancer therapy has undoubtedly made a difference to the treatment of EGFR mutation and ALK translocation carriers. However, targeted therapies for other subgroups l...

e19025 Background: Targeted therapy with tyrosine kinase inhibitor (TKI) crizotinib against EML4-ALK (ALK+) non-small cell lung cancer (NSCLC) have impacted cancer therapy as a new paradigm. However, there is still an unmet need to develop affordable and robust technology platforms to assay circulating tumor cells (CTCs), which may form the basis of distant hematogenous metastases. There are relative advantages and pitfalls with various CTC platforms. Methods: We performed pilot studies utilizing two different platforms of CTC detection and enrichment. First, we adopted the CellSearch “positive-selection” platform to profile 11 pts with ALK(+) NSCLC who were treated with crizotinib prospectively. Blood samples were collected (i) pretreatment, (ii) on TKI with CR/PR/SD, and (iii) at disease progression. Second, we evaluated a novel “negative selection” CTCs capture-isolation platform, based on magnetic separation of pan-leukocyte marker CD45+ cells coupled with RBC lysis, to avoid potential bias of predefi...

e18017 Background: Recently, ethnic differences and genotypes such as EGFR mutation (EGFRm) or fusion gene (ALK translocation: ALKt) are important factors in non-small cell lung cancer (NSCLC) treatment. Pemetrexed (P)/cisplatin (C) is one of the standard care for advanced non-squamous (Nsq) NSCLC. However, the efficacy of the CP regimen has not been well examined in Japanese Nsq NSCLC patients (pts); furthermore, the difference in efficacy between genotypes was not thoroughly examined. Therefore, the present study was conducted to evaluate the efficacy of the CP regimen in Japanese Nsq NSCLC pts, and to determine whether EGFRm and ALKt impacted the treatment. Methods: This study was conducted from May 2009 to December 2010. Pts were eligible for this study if they had histologically or cytologically confirmed recurrent or metastatic Nsq NSCLC previously untreated with chemotherapy, an ECOG performance status of 0 or 1, life expectancy of more than 12 weeks, and adequate organ function. Pts received C (75 mg/m2) plus P (500 mg/m2) on day 1 every 3 weeks. Of the 50 pts initially enrolled, 49 were evaluated, and 43 tumor samples were available for analysis. Most pts were male (80%), and 80% of the pts had adenocarcinoma. The primary endpoint was the response rate that was evaluated according to RECIST. EGFRm was examined using PCR-based methods, and the ALK fusion protein was examined using a highly sensitive IHC method in the available tumor specimens. Although the CP regimen demonstrates consistent efficacy in Japanese Nsq NSCLC pts, EGFRm and ALKt may have impacted this treatment. Results: The objective response rate and disease control rate in all pts were 44.9% and 79.6%, respectively. The median progression-free survival was 4.4 months, and the 1-year survival was 73.5%. Toxicities were mild; no new toxicity profile was identified. Among the 43 samples, the following mutations were identified: 9 EGFRm (21%), 5 ALKt (12%), and 29 wild-type (67%). Objective response was observed in 6 (66.7%) EGFRm, 2 (40%) ALKt, and 13 (44.8%) wild-type. Conclusions: Although the CP regimen demonstrates consistent efficacy in Japanese Nsq NSCLC pts, EGFRm and ALKt may have impacted this treatment.

10598 Background: A small subset of human lung cancer harbors the fusion of the gene for echinoderm microtubule-associated protein-like 4 (EML4) and the gene for anaplastic lymphoma kinase (ALK), r...

7606 Background: The EML4-ALK fusion oncogene represents one of the newest molecular targets in NSCLC. In previous work, we have shown that patients with EML4-ALK-positive NSCLC have distinct clini...