Anaplastic Lymphoma Kinase Positive Non-small Cell Lung Cancer Research Articles

Early Onset Pulmonary Events and Management Strategies during the Treatment of ALK Positive NSCLC Patients with Brigatinib

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase and its rearrangements occur in non-small cell lung cancer (NSCLC), resulting in signal dysregulation in kinase domain. As a new generation of potent ALK tyrosine kinase inhibitors (TKIs), Brigatinib was approved in China in March 2022 as a treatment for locally advanced or metastatic NSCLC patients with ALK rearrangement positive. Brigatinib significantly improved the survival, cranial efficacy and quality of life compared to Crizotinib in clinical trials. Brigatinib is generally well tolerated. Brigatinib has been one of the preferred treatments and an addition of options in ALK-rearranged NSCLC. Pulmonary toxicity is one of the adverse effects observed during the treatment of TKIs and deserves the intense attention of clinicians, despite of its low incidence rate. Pulmonary toxicity reported during the treatment of Brigatinib has shown distinct clinical presentations, such as early-onset (median time to onset, 2 days) and rapid tolerance and reversibility of symptoms. In view of this, the concept of early-onset pulmonary events (EOPEs) was proposed and established during the submission for regulatory review and approval. We focused on clinical characteristics, potential mechanism of etiology, and management strategies of EOPEs to provide clinicians evidence for better clinical decision support. .

Abstract 5592: Expansion and characterization on ALK positive NSCLC circulating tumor cells isolated using a size based inertial microfluidic Labyrinth device

Abstract Introduction Lung cancer (LC) is the leading cause of cancer deaths. 85% of LC are non-small cell lung cancer (NSCLC). Fusions involving anaplastic lymphoma kinase (ALK) are oncogenic drivers in ~ 7% of NSCLC. Previous studies have shown that drug resistance develops within ~2 years after ALK tyrosine kinase inhibitor targeted therapy. Due to resistance mechanisms and the biological heterogeneity that evolves over the treatment of ALK+ NSCLC, it is important to monitor and study those dynamic changes through the clinical treatment course to understand cancer progression. Circulating tumor cells (CTCs) are rare cells, shed from cancer lesions into the bloodstream. They can be isolated from a patient's peripheral blood sample (~20ml) to enable study of tumor characteristics at multiple time points. They are promising biomarkers that not only offer phenotypic and genotypic information, but also present a potential to expand into patient derived ex vivo tumor models. In this study, we use a high throughput label-free microfluidic device, Labyrinth, developed in the Nagrath lab for cell size based CTC enrichment, followed by expansion of CTCs in organoid models, further molecular characterization, and growth in patient-derived xenograft (PDX) models. Methods Blood samples were collected from patients (n=22), three with known ALK status. CTC isolation was performed using Labyrinth at 2.0 mL/min. A part of the isolated CTCs were immunofluorescently stained for pan cytokeratin (pan CK), CD45, DAPI, epithelial cell adhesion molecule (EpCAM), and vimentin markers for enumeration. Others were processed for expansion in ultralow attachment plates with three types of organoid culture media. The rest of the CTCs were used for molecular characterizations. Growth curves were produced on expanded samples on Day 0, 7, 14, and 21 in different culture conditions. A live/dead assay and in situ hybridization (FISH) were also performed. On Day 7, selected samples were injected into NSG™ mice. Bulk RNA sequencing was conducted on the original tumor, Day 0 and 7 CTCs, and PDX samples. Results The median CTC concentration in this cohort (n=22) was 316.2 CTCs/ml of blood. Isolated CTCs from ALK+ NSCLC patients showed ALK fusions by FISH. We observed that the number of ALK CTCs was reduced over time consistent with decreased tumor size in CT scans. There were significant differences (p<0.05) for vimentin positive CTCs compared to the other three types of CTCs, which indicated a higher prevalence of a mesenchymal state of NSCLC CTCs. One of the two samples successfully developed into PDX after two months. In summary, we demonstrated a successful workflow to enrich and expand CTCs from ALK+ NSCLC patients. The expanded CTCs can be further characterized and can generate tumors in PDX models. Citation Format: Yuru Chen, Shamileh Fouladdel, Harrison Ball, Xu Cheng, Liwei Bao, Habib Serhan, Albert Liu, Bryce Vandenburg, Laura Goo, Nathan Merrill, Aaron Udager, Angel Qin, Sofia D. Merajver, Sunitha Nagrath. Expansion and characterization on ALK positive NSCLC circulating tumor cells isolated using a size based inertial microfluidic Labyrinth device. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5592.

FAT4 activation inhibits epithelial-mesenchymal transition (EMT) by promoting autophagy in H2228/Cer cells.

As a tumor suppressor in lung cancer, FAT atypical cadherin 4 (FAT4) has a critical role in epithelial-mesenchymal transition (EMT). However, the role of FAT4 in ceritinib-resistant anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) EMT has not been reported. It is necessary to discuss the role of FAT4 in this process and its potential mechanism of interaction. We found that the expression level of FAT4 was downregulated markedly in ceritinib-resistant NCI-H2228 (H2228/Cer) cells. Jujuboside A, a FAT4 activator, diminished EMT and metastasis of H2228/Cer cells. Importantly, autophagy inhibition inverted the inhibitory effect of FAT4 activation on EMT. Furthermore, we found the regulatory action of FAT4 on autophagy was related to proteasome 26S subunit ubiquitin receptor and non-ATPase 4 (PSMD4) and proteasome 20S subunit beta 4 (PSMB4), and the inhibitory effect of autophagy on EMT might be related to ROS/NF-κB/IκB-α and Wnt/β-catenin pathways. In conclusion, FAT4 activation can inhibit the process of EMT in H2228/Cer cells by promoting autophagy, which provides a potential target for ceritinib-resistant ALK positive NSCLC therapy.

Short communication: The activity of brigatinib in patients with disease progression after next generation anaplastic lymphoma tyrosine kinase inhibitors and an exploratory analysis of circulating tumor DNA

BackgroundBrigatinib, a second generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is central nervous system (CNS) penetrant and active against anaplastic lymphoma kinase (ALK) resistance mutations. We prospectively studied the activity of brigatinib in patients with disease progression after second generation ALK TKIs. MethodsPatients with stage IIIB/IV ALK + non-small cell lung cancer (NSCLC), and progressive disease after second ALK TKIs were eligible. Cohort A enrolled patients with disease progression on any second ALK TKI, cohort B enrolled patients with disease progression after first-line therapy with alectinib, and cohort C enrolled patients who experienced disease progression on standard dose brigatinib. Brigatinib treatment was 90 mg daily for seven days and then escalated to 180 mg daily in cohorts A and B, and 240 mg daily in cohort C. The primary endpoint was objective response rate (ORR), and a 2-stage design was used. The intended enrollment was 20 patients in stage 1, and 20 patients in stage 2. ResultsThe study was closed due to slow accrual. Between March 2017 and June 2020, 32 patients received study therapy; three patients in cohort A moved to cohort C after initial progression for a total of 35 study subjects. Of the 32 patients, 16 (50%) were male, the median age was 55 years (range 32–76), and patients received a median number of 2 prior ALK TKI’s (range 1–3). Cohort A enrolled 27 patients, cohort B enrolled four patients, and cohort C enrolled four patients. The ORR in cohorts A, B, and C was 33% (95% confidence interval (CI: 16% to 54%), 25% (95% CI: 0.63% to 81%), and 0%, respectively. ConclusionBrigatinib has activity in ALK positive NSCLC patients with disease progression after second generation ALK TKIs.

The Genomic Characteristics of ALK Fusion Positive Tumors in Chinese NSCLC Patients.

Anaplastic lymphoma kinase (ALK) fusion events account for ~3–7% genetic alterations in patients with non-small cell lung cancer (NSCLC). In this study, we identified the ALK fusion patterns and a novel ALK fusion partner in 44 ALK positive NSCLC patients using a customized HapOncoCDx panel, and identified ALK fusion partners. The most common partner is EML4, forming the variant 1 (v1, E13:A20, 18/44), variant 2 (v2, E20:A20, 5/44), and variant 3 (v3, E6:A20, 13/44). Moreover, we detected a new ALK fusion partner HMBOX1. At the mutation level, TP53 is the most frequently mutated gene (24%), followed by ALK (12%) and STED2 (12%). The median tumor mutation burden (TMB) of these samples is 2.29 mutations/Mb, ranging from 0.76 mut/Mb to 16.79 muts/Mb. We further elaborately portrayed the TP53 mutation sites on the peptide sequence of the encoded protein by lollipop. The mutational signature and copy number alterations (CNAs) of the samples were also analyzed. The CNA events were found in 13 (13/44) patients, and the most commonly amplified genes were MDM2 (n = 4/13) and TERT (n = 4/13). Together, these results may guide personalized clinical management of patients with ALK fusion in the era of precision medicine.

Clinical utility of liquid biopsy for the diagnosis and monitoring of EML4-ALK NSCLC patients.

Genomic rearrangement in anaplastic lymphoma kinase (ALK) gene occurs in 3-7% of patients with non-small-cell lung cancer (NSCLC). The detection of this alteration is crucial as ALK positive NSCLC patients benefit from ALK inhibitors, which improve both the patient's quality of life and overall survival (OS) compared to traditional chemotherapy. In routine clinical practice, ALK rearrangements are detected using tissue biopsy. Nevertheless, the availability of tumor tissue is compromised in NSCLC patients due to surgical complications or difficult access to the cancer lesion. In addition, DNA quality and heterogeneity may impair tumor biopsies testing. These limitations can be overcome by liquid biopsy, which refers to non-invasive approaches for tumor molecular profiling. In this paper we review currently available technology for non-invasive ALK testing, in NSCLC patients, based on the analysis of circulating tumor DNA (ctDNA), circulating tumor RNA (ctRNA), circulating tumor cells (CTCs), tumor-educated platelets (TEPs) and extracellular vesicles (EVs) such as exosomes. Non-invasive tumor molecular profiling is crucial to improve outcomes and quality of life of NSCLC patients whose tumors harbor a translocation involving ALK locus.

Crizotinib versus chemotherapy: a real-world cost-effectiveness study in China.

Aim: To assess the cost-effectiveness of crizotinib verses platinum-based doublet chemotherapy as the first-line treatment for anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) in the real-world setting. Methods: Data from 163 advanced ALK positive NSCLC patients were collected from West China Hospital, Sichuan University (Chengdu, China). They were categorized into two groups as treated with crizotinib (n=83) or chemotherapy (n=80) as a first-line therapy. The progression-free survival (PFS) as the primary clinical outcome, and the direct medical costs were collected from hospital information systems. Incremental cost-effectiveness ratio (ICER) was calculated with costs, quality-adjusted life-years, as well as the costs discounted at 3% annually. Additionally, two different kinds of medical insurance (MI) for pharma-economic assessment were considered. Results: Crizotinib improved PFS versus chemotherapy in ALK positive patients (median PFS 19.67m vs 5.47m; p < 0.001). Moreover, crizotinib obtained an ICER of US$36,285.39 before the end of 2016, when crizotinib, pemetrexed and anti-angiogenesis drugs were not MI covered. This is more than the willingness to pay threshold (three-times of gross domestic product per capita in mainland China or Sichuan Province). However, ICER was US$7321.16, which is less than willingness to pay, when crizotinib and all chemotherapy drugs were covered by MI from the end of 2016. Sensitivity analysis demonstrated a 99.7% probability for crizotinib to be more cost-effective than chemotherapy, when crizotinib and all anticancer drugs were MI covered. One-way sensitivity analysis for the reimbursement ratio of crizotinib indicated that cost-effective tendency for crizotinib increased as reimbursement ratio increased. Conclusion: Crizotinib could be an effective, and cost-effective first-line treatment for ALK positive advanced NSCLC with the MI coverage currently available in Chengdu, Sichuan Province, China.

Alectinib versus crizotinib in untreated Asian patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer (ALESIA): a randomised phase 3 study

Anaplastic lymphoma kinase-positive (ALK-positive) disease occurs in approximately 5% of all patients with non-small-cell lung cancer, with a similar incidence reported in Asian patients. This study is the first phase 3 randomised trial recruiting only Asian patients to compare alectinib with crizotinib as a first-line treatment for ALK-positive non-small-cell lung cancer with 600 mg of alectinib twice per day. This study assessed consistency of the progression-free survival benefit with the global phase 3 ALEX study. In this randomised, open-label, phase 3 study done at 21 investigational sites in China, South Korea, and Thailand, Asian patients, aged 18 years or older, with ALK-positive non-small-cell lung cancer were randomly assigned (2:1) to twice-daily oral alectinib (600 mg) or crizotinib (250 mg). Patients were randomly assigned via a block-stratified (block size three) randomisation procedure, done centrally via an interactive voice or web response system, with stratification by Eastern Cooperative Oncology Group performance status and baseline CNS metastases. Clinical staff and the funder's drug safety and medical monitoring staff had access to treatment assignments. The independent review committee was masked to treatment assignment, and funder personnel did not have access to efficacy and safety summaries by treatment group, before the formal reporting of study results. Patients with asymptomatic CNS metastases were permitted. The primary endpoint was investigator-assessed progression-free survival. The primary analysis population for efficacy was the intention-to-treat population, defined as all randomly assigned patients. The primary analysis population for safety was defined as all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02838420. Between Aug 3, 2016, and May 16, 2017, 187 patients were randomly assigned to treatment: 125 to alectinib and 62 to crizotinib. Median follow-up was 16·2 months (IQR 13·7-17·6) in the alectinib group, and 15·0 months (12·5-17·3) in the crizotinib group. Investigator-assessed progression-free survival was significantly prolonged with alectinib versus crizotinib (hazard ratio [HR] 0·22, 95% CI 0·13-0·38; p<0·0001; median progression-free survival not estimable vs 11·1 months). Independent review committee-assessed progression-free survival was also significantly longer in the alectinib group compared with the crizotinib group (HR 0·37, 0·22-0·61; p<0·0001). The proportion of patients who achieved an objective response was 114 (91%) of 125 with alectinib, and 48 (77%) of 62 with crizotinib, with a longer duration of response for alectinib than crizotinib (HR 0·22, 95% CI 0·12-0·40; p<0·0001). Time to CNS progression (cause-specific HR 0·14) and the percentage of patients who achieved a CNS objective response with measurable or non-measurable baseline CNS lesions were improved (32 [73%] of 44 patients treated with alectinib vs five [22%] of 23 patients treated with crizotinib). Despite longer treatment duration with alectinib than crizotinib (14·7 months vs 12·6 months, respectively), fewer patients had grade 3-5 adverse events (36 [29%] of 125 vs 30 [48%] of 62, respectively) or serious adverse events (19 [15%] of 125 vs 16 [26%] of 62, respectively). Our results align with ALEX, confirming the clinical benefit of 600 mg of alectinib twice per day as a first-line treatment for ALK-positive non-small-cell lung cancer. F Hoffmann-La Roche.

P2.13-04 Outcomes of ALK-Positive Non-Small-Cell Lung Cancer (NSCLC) Patients Treated with Crizotinib: A Multicenter Cohort Retrospective Study.

Crizotinib has demonstrated promising efficacy in patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) in clinical trials. However, there is lack of multicenter real-world data summary with large cohort of patients, especially in China. We conducted this multicenter and retrospective study to assess the outcomes of crizotinib in, to our knowledge, the largest cohort of patients with ALK-positive advanced NSCLC. We reviewed medical records of 484 unselected ALK-positive NSCLC patients treated with crizotinib at five cancer centers in China from January 2013 to November 2017. Clinical data were collected from crizotinib initiation to RECIST-defined progressive disease (PD), and post-PD systemic treatment outcomes were also analyzed. A total of 428 eligible ALK-positive NSCLC patients were enrolled. Among them, 273 (63.8%) patients received crizotinib as first-line treatment. The median progression-free survival (PFS) and overall survival (OS) from crizotinib initiation were 14.4 months (95%CI: 12.4-16.4) and 53.4 months (95% CI: 33.7-73.1) respectively. In the subgroup analysis, patients received crizotinib as first-line treatment showed a higher disease control rate (DCR) and longer median OS with statistical significance compared with second-/ further line crizotinib treatment (94.8%, not estimated vs. 89.0%, 40.5 months, respectively). For 261 patients with RECIST-defined PD, multivariate COX analysis revealed that patients who received first-line crizotinib (P=0.013), continued crizotinib beyond progressive disease (CBPD) (P=0.011) and received next-generation ALKis after crizotinib failure (P<0.001) were associated with improved survival both from crizotinib progression and from the first crizotinib dose. This study demonstrated the clinically meaningful benefit of crizotinib treatment in the largest cohort of Chinese ALK positive NSCLC patients. CBPD and next-generation ALK TKI treatment may provide survival improvement after RECIST-defined progression on crizotinib.

Imaging on Lung Cancer and Treatment with Targeted Therapy

The identification of genetic mutations known as oncogenic driver mutations that lead to the growth and survival of cancer cells has been an important advance in the field of oncology. Treatment in advanced non-small-cell lung cancer (NSCLC) has transitioned from a more general approach to a more personalized approach based on genetic mutations of the cancer itself. Common mutations detected in patients with advanced NSCLC include mutations of epidermal growth factor receptor and anaplastic lymphoma kinase (ALK). Targeted therapies are aimed at the products of these gene mutations and include erlotinib (used in epidermal growth factor receptor mutant NSCLC) and crizotinib (used in anaplastic lymphoma kinase positive NSCLC). In this review, we discuss common genetic mutations in advanced NSCLC, the role of targeted therapies, and imaging findings that can be associated with various genetic mutations.

Outcomes of ALK positive lung cancer patients treated with crizotinib or second-generation ALK inhibitor: a monoinstitutional experience

Rearrangement in the anaplastic lymphoma kinase (ALK) gene is one of the oncogenic drivers in non-small cell lung cancer (NSCLC) patients.Several ALK inhibitors (ALKis) have been developed and have demonstrated their efficacy, however the best treatment strategy for ALK positive NSCLC patients has yet to be determined. Our retrospective study has investigated the outcome of 40 ALK-rearranged NSCLC patients treated with two different sequential strategies in our Institute; a “classical group”, treated with crizotinib followed by second or third generation ALKis, and the “experimental group”, treated upfront with a second generation ALK inhibitor. The primary endpoints investigated were Progression-free survival (PFS) and intracranial activity. The analysis has revealed a significant improvement in PFS (p = 0.050) in the experimental group, furthermore none of these patients developed brain metastasis. There was no statistically significant difference in OS, but all patients in the experimental group were still alive after a median follow up of 15 months. Our retrospective analysis suggests that systemic and intracranial efficacy tends to be better in the experimental group; randomized prospective studies could confirm our observations.

Benefit of crizotinib in a lung cancer patient with discordant ALK testing results

Crizotinib is a first line treatment for patients with non-small cell lung cancer (NSCLC) harboring translocations in anaplastic lymphoma kinase (ALK). The current gold standard for determining ALK status is fluorescence in-situ hybridisation (FISH), but immunohistochemistry (IHC) is becoming increasingly popular due to lower cost. There are currently few reports on clinical outcomes with crizotinib therapy in patients who have tested negative by FISH and positive by IHC. A 53 year old lifelong non-smoking, physically active male with newly diagnosed Stage IV NSCLC presented with shortness of breath on exertion one month prior to referral. Staging CT scan failed to show a discreet lung lesion, but the left lower lobe was collapsed due to pleural effusion. Pleural fluid showed adenocarcinoma and IHC was positive for an ALK mutation, while FISH was negative. Pre-treatment PET-CT showed hypermetabolic, enlarged lymph nodes in the mediastinum and retroperitoneum. Partially due to patient concerns about cytotoxic chemotherapy toxicity, crizotinib therapy was instituted. Repeat CT conducted two months after crizotinib initiation showed a decrease in lymphadenopathy at all sites compared to the PET-CT. Furthermore, the patient showed clinical improvement, with less drainage through his PleurX catheter and stability of his excellent performance status. After 12 months on crizotinib CT showed ongoing improvement in lymphadenopathy. His bloodwork has been stable, and he denies significant drug toxicity. This case illustrates a sustained response to crizotinib therapy in a patient with an ALK translocation identified by IHC, but with negative FISH testing. The literature suggests that the population with these discordant results could be up to 19% of ALK positive NSCLC. Patients in this subgroup who are receiving crizotinib should be identified and outcome data pooled. However, in the interim, oncologists may wish to consider targeted therapy for these discordant patients.

Meta-analysis of incidence and risk of severe adverse events and fatal adverse events with crizotinib monotherapy in patients with ALK-positive NSCLC.

BackgroundNumerous clinical trials show crizotinib has promising efficacy for anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) patients which trigger the substitution of traditional chemotherapy to be the current standard first-line treatment for these patients. Conversely, few reports systematically analyze toxicity of crizotinib. Hence, we performed a first meta-analysis to determine the risk of crizotinib-related severe adverse events (SAEs) and fatal adverse events (FAEs) in ALK positive NSCLC patients.Materials and MethodsA systematic literature search was conducted through December 2016 to identify clinical trials that reported crizotinib monotherapy in ALK-positive NSCLC patients. Data on crizotinib-related SAEs and FAEs were extracted from each study and pooled to determine the overall incidence and risk. Random-effects or fixed-effects models were conducted to calculate the summary incidence, relative risk (RR), and 95% CIs on basis of the heterogeneity of included studies.Results1,924 patients from 11 clinical trials were included. The overall incidence of SAEs and FAEs with crizotinib was 19.9% (95% CI, 14.1% to 23.7%; P < 0.001) and 1.4% (95% CI, 0.9% to 2.1%; P < 0.001), respectively. Meanwhile, Asian patients have lower incidence of SAEs (11.5%, 95% CI: 7.9% to 16.5%). However, significant differences of SAEs (RR: 0.97, 95% CI, 0.79 to 1.18; P = 0.76) and FAEs (RR: 2.24, 95% CI, 0.49 to 10.30; P = 0.30) were not detected between crizotinib monotherapy and chemotherapy.ConclusionsCrizotinib may not increase the risk of SAEs and FAEs in patients with ALK positive NSCLC compared with chemotherapy.

Molecular Dynamics Validation of Crizotinib Resistance to ALK Mutations (L1196M and G1269A) and Identification of Specific Inhibitors.

Anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) patients are mostly treated with ALK tyrosine kinase inhibitors (TKIs). Crizotinib is the first generation ALK inhibitor practiced as a primary chemo to combat cancer cells followed by second generation inhibitor ceritinib which are effective against crizotinib resistant ALK mutations. However, patients treated with these drugs invariably relapsed because of the development of new drug resistance mutations. In this study we explored the crizotinib resistance in the presence of ALK mutations L1196M and G1269A through molecular dynamics simulation studies. Further mutation specific inhibitors CID 71748211 and CID 71728095 were identified to potentially inhibit ALK with mutations L1196M and G1269A, respectively. This computational investigation in-sighted the molecular factors involved in crizotinib resistance which enhanced in the identification of new ALK drugs that brings individualized medicine to treat ALK positive NSCLC patients with specific mutations. J. Cell. Biochem. 118: 3462-3471, 2017. © 2017 Wiley Periodicals, Inc.

P3.02a-018 Efficacy of Pemetrexed Based Chemotherapy Compared with Non-Pemetrexed Based Chemotherapy in Advanced, ALK-Positive NSCLC: Topic: ALK Clinical

Previous retrospective studies suggested that lung cancer patients with anaplastic lymphoma kinase (ALK) gene rearrangements are associated with sensitivity to pemetrexed chemotherapy. To determine the efficacy of pemetrexed based chemotherapy compared with non-pemetrexed based chemotherapy, we retrospectively evaluated clinical outcome in ALK positive non-small cell lung cancer (NSCLC) patients. We identified 126 patients with advanced, ALK-positive NSCLC who received 1st line cytotoxic chemotherapy from Seoul National University Hospital and Seoul National University Bundang Hospital. We compared response rate, progression-free survival, and overall survival according to chemotherapy regimens. We also analyzed the intra-cranial time to progression and proportion of ALK-positive cells as a predictive factor of pemetrexed efficacy. Forty eight patients received pemetrexed based chemotherapy and Seventy eight patients received non-pemetrexed based chemotherapy as first line systemic treatment. One hundred eighteen patients received platinum double combination chemotherapy. The pemetrexed based chemotherapy group shows superior overall response rate (44.7% versus 14.3%, p<0.001) and disease control rate (85.1% versus 62.3%, p=0.008). Pemetrexed based chemotherapy group had longer progression free survival (6.6 months versus 3.8 months, p<0.001). Exposure to pemetrexed and exposure to second generation ALK inhibitor were independent prognostic factors of overall survival (p=0.016 and p=0.011, respectively). Intra-cranial time to progression (TTP) was similar among treatment group (32.7 months versus 35.7 months, p= 0.733). Proportion of ALK positive cells was not statistically significant predictive factor of survival in pemetrexed based chemotherapy. Pemetrexed based regimen may prolong progression free survival compared with other regimens in ALK positive NSCLC in the first line setting. Exposure to pemetrexed is associated with improved survival compared with that of premetrexed-naive controls in ALK positive NSCLC.

Achievements and future developments of ALK-TKIs in the management of CNS metastases from ALK-positive NSCLC

Non-small cell lung cancer (NSCLC) represents the paradigm of personalized treatment of human cancer. Several oncogenic druggable alterations have been so far identified, with anaplastic lymphoma kinase (ALK) gene rearrangements being one of the newest and most appealing. Presence of ALK fusions is associated with some particular clinical and pathological features, including a preferential seeding into the central nervous system (CNS). In addition, ALK rearrangements are recognized as the strongest predictor for benefit of anti-ALK therapy. Crizotinib, the first ALK inhibitor (ALK-I) licensed in clinical practice, is the standard of care for newly diagnosed patients. Unfortunately, within the first year of treatment the majority of patients become insensitive to crizotinib, with approximately one third of them developing brain metastases (BMs). Optimal management of BMs is one of the major challenges in treating ALK positive NSCLC. Several novel and highly CNS penetrant ALK-Is are currently under investigation and available data clearly indicated their ability in controlling intracranial disease.

Uterine Cervix Metastasis in Lung Adenocarcinoma with Anaplastic Lymphoma Kinase Rearrangement

The importance of anaplastic lymphoma kinase (ALK) as an oncogene in non-small cell lung cancer (NSCLC) has emerged as a major concern due to a dramatic clinical effect of targeted therapy. As compared with the research for targeted therapy, the study about clinicopathological characteristics for ALK positive NSCLC hasn’t been worked enough. Here, we describe a 35-year-old woman diagnosed with stage IVb NSCLC with ALK rearrangement. During evaluating her disease, a metastatic lesion to uterine cervix was found. Although lung cancer metastasis to female genital tract is rare, we also present case series that show a metastasis to the female genital tract in NSCLC with ALK rearrangement. These case series could suggest that ALK positive NSCLC has distinct metastatic pattern.

Crizotinib as first line therapy for advanced ALK-positive non-small cell lung cancers.

The field of targeted therapeutic development has been propelled forward by remarkable advances in the understanding of driver mutations, particularly in non-small cell lung cancer (NSCLC). Our initial understanding of the importance of driver mutations developed from the discovery of somatic oncogenic epidermal growth factor receptor (EGFR) mutations, which sensitize tumors to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib (1), erlotinib (2), and afatinib (3). Anaplastic lymphoma kinase (ALK) gene rearrangements act as a distinct oncogenic driver in about 4% of NSCLC tumors (4). Testing of metastatic NSCLC adenocarcinomas to determine if they are “ALK-positive” has become the standard of care, because these tumors respond well to ALK inhibitors such as crizotinib, an orally available TKI. Crizotinib induced remarkable responses in patients with ALK positive NSCLCs in phase I and II trials (5), and appeared to improve survival of these patients in a retrospective analysis (6). A second line phase III study subsequently showed that crizotinib was superior to both pemetrexed and docetaxel as standard chemotherapy (7).

Anaplastic lymphoma kinase-positive lung adenocarcinoma patient with development of sick sinus syndrome while on targeted treatment with crizotinib.

The anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) patients are younger and have never smoked, while pathologically are predominately adenocarcinomas. Crizotinib as an ALK inhibitor has been used in treating ALK positive NSCLC patients for several years and some adverse effects should be paid attention to. We now describe a case of ALK positive NSCLC patient with development of sick sinus syndrome (SSS) while on targeted treatment with crizotinib. A 46-year-old non-smoking woman with right hilar mass and underwent transesophageal endoscopic ultrasonography lymph node biopsy showed low differentiation adenocarcinoma, immunohistochemistry (IHC) of tumor samples revealed the ALK overexpression. The severe sinus bradycardia and RR interval prolongation were detected 3 months after crizotinib treatment, she underwent pacemaker implantation. Although the severe sinus bradycardia and RR interval prolongation were unusual adverse effects, physicians should be aware of these side effects when using crizotinib.

Treatment of patients with ALK gene rearranged non-small cell lung cancer after resistance to crizotinib

肺癌是全球发病率和致死率最高的疾病之一。非小细胞肺癌（non-small cell lung cancer, NSCLC）是肺癌最为常见的组织学类型。近些年，分子生物学的发展让我们对NSCLC的认识从组织水平深入到分子水平。表皮生长因子受体（epidermal growth factor receptor, EGFR）基因突变和间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）融合基因是NSCLC患者最为重要的两个肿瘤驱动基因。针对它们的酪氨酸激酶抑制剂（tyrosine kinase inhibitors, TKIs）显著改善了带有这类分子特征的NSCLC患者的生存。不幸的是，目前几乎所有针对这两种突变的初始靶向治疗都会不可避免地出现耐药问题。有关EGFR-TKIs的耐药机制及其应对策略已经有很多文章进行阐述，而对于ALK TKIs治疗后出现耐药问题的机制和相应的治疗策略还未曾有过详细的综述。因此，本文针对一代ALK TKI（克唑替尼）治疗ALK融合基因阳性的NSCLC患者（ALK+ NSCLC）后引起耐药问题的机制和有关后续治疗策略做一综述。