Rearrangement-positive Non-small Cell Lung Cancer Research Articles

Registry of Genetic Alterations of Taiwan Non-Small Cell Lung Cancer by Comprehensive Next-Generation Sequencing: A Real-World Cohort Study-Taiwan Cooperative Oncology Group T1521.

Tissue-based next-generation sequencing (NGS) analysis is highly recommended for patients with advanced/metastatic non-small cell lung cancer (NSCLC). We investigated a specific patient population with NSCLC that required tissue-based NGS analysis. We enrolled 500 patients with advanced/metastatic (1) epidermal growth factor receptor (EGFR) mutations or anaplastic large-cell lymphoma kinase (ALK) rearrangement-positive NSCLC who had failed at minimum one line of tyrosine kinase inhibitor (TKI) therapy, (2) EGFR-/ALK-negative nonsquamous, and (3) non- or light-smoker patients with squamous NSCLC who were treatment-naïve or had failed at maximum two lines of systemic treatment. These patients were divided into five cohorts. Comprehensive tissue-based NGS testing (ACTOnco+) was conducted. Cohort 1: EGFR TKI-pretreated EGFR-mutated population (50.0%, n = 250), cohort 2: ALK inhibitor-pretreated ALK-positive population (1.6%, n = 8), cohort 3: treatment-naïve EGFR-/ALK-negative population (28.2%, n = 141), cohort 4: pretreated EGFR-/ALK-negative population (16.8%, n = 84), and cohort 5: squamous cell carcinoma (3.4%, n = 17). In cohort 1, 11.2% (28/250) of the patients had MET amplification, 32.4% (81/250) had been treated with osimertinib, and EGFR C797S was detected in 6.2% (5/81) of these patients. In cohort 2, resistance ALK mutation was detected in 37.5% (3/8) of the patients. In cohorts 3 and 4, targetable genetic alterations, including EGFR mutation (13.3%), ERBB2 mutation (9.3%), MET exon 14 skipping (5.3%), KRAS G12C mutation (4.4%), ROS1 fusion (2.7%), RET fusion (1.8%), and BRAF V600E mutation (1.3%), were detected. In cohort 5, MET exon 14 skipping was detected in 29.4% (5/17) of the patients. This multicenter registration study investigated tissue-based NGS for a specific patient population with NSCLC in Taiwan.

Efficacy and safety of anaplastic lymphoma kinase inhibitors for non-small cell lung cancer: A systematic review and network meta-analysis.

To assess the efficacy and safety of anaplastic lymphoma kinase inhibitors (ALKIs) for the treatment of advanced-stage ALK rearrangement-positive non-small cell lung cancer (NSCLC). We searched PubMed, EMBASE, and the Cochrane Library for randomized controlled trials (RCTs) that included patients with ALK-positive NSCLC receiving ALKIs. The outcomes of the study included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (TRAEs) of grade ≥3. A total of 12 RCTs consisting of 3169 patients with eight treatment options were included in this study. Our results showed that ALKIs have superior efficacy in OS, PFS, and ORR than chemotherapy or crizotinib (first-generation ALKI). Our study showed that only alectinib has a significant improvement in OS compared to chemotherapy (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.40-0.94). Alectinib appeared to have better OS than crizotinib (HR, 0.66; 95% CI, 0.45-0.95). Ensartinib has a significant PFS advantage over alectinib (HR, 0.62; 95% CI, 0.40-0.96). The surface under the ranking curve indicated that ensartinib (99.0%) was the highest rank regarding PFS. Moreover, both ensartinib and ceritinib showed significantly higher TRAEs of grade ≥3 compared with chemotherapy (risk ratios [RR], 2.74; 95% CI, 1.45-5.18; RR, 1.80; 95% CI, 1.26-2.57, respectively). These results indicated that alectinib could be associated with the best therapeutic efficacy and well-tolerance AEs in the treatment of ALK-positive NSCLC.

Molecular characterization of genomic breakpoints of ALK rearrangements in non-small cell lung cancer.

ALK rearrangement is called the 'diamond mutation' in non-small cell lung cancer (NSCLC). Accurately identifying patients who are candidates for ALK inhibitors is a key step in making clinical treatment decisions. In this study, a total of 783 ALK rearrangement-positive NSCLC cases were identified by DNA-based next-generation sequencing (NGS), including 731 patients with EML4-ALK and 52 patients with other ALK rearrangements. Diverse genomic breakpoints of ALK rearrangements were identified. Approximately 94.4% (739/783) of the cases carried ALK rearrangements with genomic breakpoints in the introns of ALK and its partner genes, and 2.8% (21/739) of these cases resulted in frameshift transcripts of ALK. Meanwhile, 5.6% (44/783) of the ALK rearrangement-positive cases had breakpoints in the exons that would be expected to result in abnormal transcripts. RNA-based NGS was performed to analyse the aberrant fusions at the transcript level. Some of these rearranged DNAs were not transcribed, and the others were fixed by some mechanisms so that the fusion kinase proteins could be expressed. Altogether, these findings emphasize that, when using DNA-based NGS, functional RNA fusions should be confirmed in cases with uncommon/frameshift rearrangement by RNA-based assays.

Outcomes of Gamma Knife Radiosurgery for Brain Metastases From Anaplastic Lymphoma Kinase Rearrangement-Positive and EGFR Mutation-Positive Non-Small Cell Lung Cancer.

IntroductionThe outcomes after gamma knife radiosurgery (GKRS) were retrospectively analysed in patients with brain metastases from anaplastic lymphoma kinase (ALK) rearrangement-positive and epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) to evaluate the efficacy, safety and difference for overall survival and local tumor control.MethodsThe medical records were retrospectively reviewed of 607 patients (25 ALK-positive, 171 EGFR-positive, and 411 wild type) with 2959 tumors who had undergone GKRS.ResultsThe median overall survival time after initial GKRS was 14 months. Driver gene mutation-positive patients had significantly longer overall survival than wild type patients (p < 0.0001), and ALK-positive patients survived significantly longer than EGFR-positive patients (p = 0.04). Multivariate analysis showed the unfavorable factors significantly affecting overall survival outcomes were older age, lower Karnofsky Performance Status score, multiple intracranial metastases, uncontrolled primary cancer, uncontrolled extracranial metastases, no administration of immune checkpoint inhibitors, and driver gene mutation-negative cases. Seventy-three patients died of uncontrolled brain metastases at a median of 12 months. Driver gene mutations had no influence (p = 0.33), and ALK-positive and EGFR-positive patients showed no significant difference in neurological survival (p = 0.83). A total of 174 patients demonstrated distant brain control failure at a median of 15 months. ALK-positive type was significant compared with EGFR-positive type (p = 0.047), but driver gene mutation-positive and -negative types showed no significant difference in the development of new brain metastases (p = 0.2). The median tumor volume was 1.06 cm3 in the driver gene mutation-positive type and 1.85 cm3 in wild type. The median marginal dose was 20 Gy in both types. The 6-, 12-, and 24-month local tumor control rates were 97.3%, 96.1%, and 95.9%, respectively. Driver gene mutations had a significantly positive impact on local tumor control (p = 0.001), and ALK-positive and EGFR-positive types showed no significant difference (p = 0.95). A total of 193 tumors had radiation injury at a median of 12 months after GKRS. The 6-, 12-, and 24-month GKRS-related complication rates were 3.3%, 8.1%, and 8.7%, respectively. Driver gene mutations significantly induced radiation damage (p = 0.021), and the ALK-positive type was affected more than the EGFR-positive type (p = 0.02).ConclusionsALK rearrangement-positive NSCLC patients tended to have significantly longer survival, but had higher incidence of new intracranial metastases due to long-term survival after GKRS, compared with EGFR mutation-negative and driver gene mutation-negative NSCLC patients. GKRS induced significantly satisfactory local tumor control in driver gene mutation-positive tumors but GKRS-related complication frequency was higher, especially in ALK-positive NSCLC patients. Therefore, more careful imaging follow-up is necessary after GKRS for patients with driver gene mutation-positive NSCLC.

Systematic Review and Network Meta-Analysis of Anaplastic Lymphoma Kinase (ALK) Inhibitors for Treatment-Naïve ALK-Positive Lung Cancer.

Simple SummaryThe prognosis of non-small cell lung cancer (NSCLC) is poor as more than half of the patients are diagnosed at an advanced stage. The outcomes have greatly improved in the recent two decades due to the introduction of target therapy. Anaplastic lymphoma kinase (ALK) rearrangement is the second most common driver mutation found in lung cancer, and several ALK inhibitors have shown excellent efficacy. However, head-to-head randomized controlled trials of these agents are lacking. We conducted this systematic review and network meta-analysis to indirectly compare the currently available ALK inhibitors. In summary, lorlatinib had the highest probability of the best progression-free survival in first-line treatment of ALK-positive NSCLC, followed by low-dose (300 mg twice daily) alectinib, high-dose (600 mg twice daily) alectinib, brigatinib, ensartinib, and ceritinib. Lorlatinib was associated with the best objective response rate and the highest probability of grade 3–5 adverse effects. Low-dose alectinib had the best safety profile.Several anaplastic lymphoma kinase inhibitors (ALKIs) have demonstrated excellent efficacy on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and also better adverse effect (AE) profiles compared to cytotoxic chemotherapy in advanced stage anaplastic lymphoma kinase (ALK) rearrangement-positive non-small cell lung cancer (NSCLC) in phase III randomized clinical trials (RCTs). We conducted this systematic review and network meta-analysis to provide a ranking of ALKIs for treatment-naïve ALK-positive patients in terms of PFS, ORR, and AEs. In addition, a sub-group analysis of treatment benefits in patients with baseline brain metastasis was also conducted. Contrast-based analysis was performed for multiple treatment comparisons with the restricted maximum likelihood approach. Treatment rank was estimated using the surface under the cumulative ranking curve (SUCRA), as well as the probability of being the best (Prbest) reference. All next-generation ALKIs were superior to crizotinib in PFS but lorlatinib and brigatinib had increased AEs. The probability of lorlatinib being ranked first among all treatment arms was highest (SUCRA = 93.3%, Prbest = 71.8%), although there were no significant differences in pairwise comparisons with high- (600 mg twice daily) and low- (300 mg twice daily) dose alectinib. In subgroup analysis of patients with baseline brain metastasis, low-dose alectinib had the best PFS (SUCRA = 87.3%, Prbest = 74.9%). Lorlatinib was associated with the best ranking for ORR (SUCRA = 90.3%, Prbest = 71.3%), although there were no significant differences in pairwise comparisons with the other ALKIs. In addition, low-dose alectinib had the best safety performance (SUCRA = 99.4%, Prbest = 97.9%). Lorlatinib and low-dose alectinib had the best PFS and ORR in the overall population and baseline brain metastasis subgroup, respectively. Low-dose alectinib had the lowest AE risk among the available ALKIs. Further head-to-head large-scale phase III RCTs are needed to verify our conclusions.

Pharmacology and Clinical Evaluation of Ensartinib Hydrochloride Capsule

肺癌是全世界发病率和致死率最高的恶性肿瘤，其中非小细胞肺癌（non-small cell lung cancer, NSCLC）约占肺癌的85%。间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）重排阳性的NSCLC仅占全部NSCLC的5%，但预后较差，因此积极的治疗非常迫切。盐酸恩沙替尼胶囊（ensartinib hydrochloride capsule，X-396，商品名贝美纳TM）是第二代ALK抑制剂，对ALK的抑制活性和肺癌中枢神经系统转移的有效性较克唑替尼更强，并且可抑制多个克唑替尼耐药突变位点，临床拟用于治疗克唑替尼耐药的ALK阳性NSCLC。文中对盐酸恩沙替尼胶囊在国内外开展的Ⅰ期-Ⅲ期临床试验进行了总结，并对其药理作用、药代动力学和药效学、临床疗效和安全性评价进行了综述。

Survival Analysis for Patients with ALK Rearrangement-Positive Non-Small Cell Lung Cancer and a Poor Performance Status Treated with Alectinib: Updated Results of Lung Oncology Group in Kyushu 1401.

Alectinib confers a pronounced survival benefit in patients with ALK rearrangement-positive non-small cell lung cancer and a poor performance status. Survival benefit of alectinib for patients with a poor performance status was consistent regardless of the presence of central nervous system metastases. We previously reported a marked objective response rate (ORR) and safety for alectinib treatment in patients with ALK rearrangement-positive non-small cell lung cancer (NSCLC) and a poor performance status (PS) in the Lung Oncology Group in Kyushu (LOGiK) 1401 study. It remained unclear, however, whether alectinib might also confer a long-term survival benefit in such patients. Eighteen patients with ALK rearrangement-positive advanced NSCLC and a PS of 2, 3, or 4 (n = 12, 5, and 1, respectively) were enrolled in LOGiK1401 between September 2014 and December 2015 and received alectinib. We have now updated the survival data for the study. The median follow-up time for all patients was 27.3 months. The median progression-free survival (PFS) was 16.2 months (95% confidence interval [CI], 7.1-30.8 months), and the median survival time (MST) and the 3-year overall survival rate were 30.3 months (95% CI, 11.5 months to not reached) and 43.8% (95% CI, 20.8-64.7%), respectively. This survival benefit was similarly manifest in patients with a PS of 2 (MST, 20.5 months) and those with a PS of ≥3 (MST, not reached). PFS did not differ between patients with or without central nervous system (CNS) metastases at baseline (median of 17.5 and 16.2 months, respectively, p = .886). Alectinib showed a pronounced survival benefit for patients with ALK rearrangement-positive NSCLC and a poor PS regardless of the presence of CNS metastases, a patient population for which chemotherapy is not indicated.

Administration of crizotinib via jejunostomy tube: A case report

Crizotinib is an orally available tyrosine kinase inhibitor, approved for treatment of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) rearrangement-positive non-small cell lung cancer (NSCLC). According to the product leaflet, crizotinib capsules should be swallowed whole, and should not be crushed, dissolved or opened. However, this manner of administration is not always possible. At present, literature is lacking regarding the absorption of crizotinib via percutaneous endoscopic jejunostomy (PEJ) tube. We report a case of a patient with ALK+ NSCLC who was administered crizotinib via PEJ tube. An adequate steady state crizotinib trough concentration was reached, resulting in a metabolic response. Safety for the caregiver was ensured since the administration of crizotinib was made without crushing or opening the capsule. This case supports the option for providing crizotinib via PEJ tube in patients who have ALK+ NSCLC and are unable to swallow whole capsules. This option might also apply to the administration of other ALK inhibitors. Keywords Crizotinib, ALK inhibitor, percutaneous endoscopic jejunostomy tube, pharmacokinetics, non-small cell lung cancer.

Administration of crizotinib via jejunostomy tube: A case report

Crizotinib is an orally available tyrosine kinase inhibitor, approved for treatment of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) rearrangement-positive non-small cell lung cancer (NSCLC). According to the product leaflet, crizotinib capsules should be swallowed whole, and should not be crushed, dissolved or opened. However, this manner of administration is not always possible. At present, literature is lacking regarding the absorption of crizotinib via percutaneous endoscopic jejunostomy (PEJ) tube. We report a case of a patient with ALK+ NSCLC who was administered crizotinib via PEJ tube. An adequate steady state crizotinib trough concentration was reached, resulting in a metabolic response. Safety for the caregiver was ensured since the administration of crizotinib was made without crushing or opening the capsule. This case supports the option for providing crizotinib via PEJ tube in patients who have ALK+ NSCLC and are unable to swallow whole capsules. This option might also apply to the administration of other ALK inhibitors. Keywords: Crizotinib, ALK inhibitor, percutaneous endoscopic jejunostomy tube, pharmacokinetics, non-small cell lung cancer.

Serum ProGRP and NSE levels predicting small cell lung cancer transformation in a patient with ALK rearrangement-positive non-small cell lung cancer: A case report.

The resistance mechanisms to anaplastic lymphoma kinase (ALK) inhibitors comprise ALK gene variations, such as ALK point mutations and copy-number gains, the activation of bypass signaling through the activation of other oncogenes and small cell lung cancer (SCLC) transformation. To date, few studies have investigated whether tumor markers for SCLC correlate with the SCLC transformation in EGFR-mutant NSCLC and ALK-positive non-SCLC (NSCLC). The present case study reported a patient with SCLC transformation after alectinib treatment. The patient exhibited elevation of pro-gastrin-releasing peptide precursor and neuron-specific enolase levels, which may be predictive of SCLC transformation during the resistance to ALK-tyrosine kinase inhibitors.

Detection of Anaplastic Lymphoma Kinase (ALK) gene in Non-Small Cell lung Cancer (NSCLC) By CISH Technique

Background/Aim: Anaplastic Lymphoma Kinase (ALK) rearrangement has evaluated activity of NSCLC compared with other molecular subtypes (EGFR, KRAS). Many studies demonstrated that patients with ALK rearrangement positive NSCLC have improved with a good response rates and progression (free survival) when treated with either monotherapy or by a combination therapy compared with EGFR-mutated, KRAS/EGFR/ALK wild type or KRAS-mutated. The aim of this study was to detect and study the signal pattern of normal ALK and compare it to that of mutated ALK with gene rearrangement in cases of non-small cell lung cancer and Inflammatory conditions by implementing the CISH technique. In addition to correlate ALK signal pattern with the histopathological type and grade as well as the age and sex of the patients.Materials &amp; Methods: Forty patients with NSCLC and Inflammatory diseases were enrolled in a comparative cross sectional study. The tissue blocks were sectioned on non-charged slides for the preparation of routine H&amp;E staining. Positively charged slides were used for tissue sections prepared for chromogenic in situ hybridization procedure to detect ALK gene.Results: ALK gene signal break apart was detected in (18/20, 90%) of malignant cases; (0/20, 0%) of non-neoplastic lung lesions. There was a significant statistical difference in their distribution, p &lt; 0.05. While There was no significant association between any disease status and sex P value = 1.000NS. The CISH test was 100% sensitive using negative score as a cutoff point and 90.9% specific. The score was divided into three levels that categorized the cases, so there were six cases in score one (1-32%), nine cases in score two (33-67%) and three cases in score three (68-100%).Conclusion: Detection of ALK rearrangement in the early diagnosis of NSCLC is highly sensitive and can save a lot of efforts in planning chemotherapy regimens. Results were very promising in identifying this mutation by a sensitive and highly specific test. The ALK gene rearrangement could be an early mutation and it is needed as an initiating step for the carcinogenesis process. The presence of a double gene mutation, however, could be the cause of a higher-grade cancer.

Radiotherapy and Tyrosine Kinase Inhibitors in Stage IV Non-small Cell Lung Cancer: Real-life Experience.

To investigate the role of conventional radiotherapy (RT) and stereotactic body radiotherapy (SBRT) in patients with epidermal growth factor (EGFR)-mutant or anaplastic lymphoma kinase (ALK) rearrangement-positive metastatic non-small cell lung cancer (NSCLC). Fifty patients with EGFR-mutated or ALK rearrangement-positive NSCLC were treated at our Institution. Radiotherapy was delivered before, after or concomitantly with tyrosine kinase inhibitors (TKIs). Acute toxicities and overall survival (OS) were assessed. Radiotherapy was performed within 30 days before TKI, concomitantly with TKI and within 30 days after TKI in eight (16%), 33 (66%) and 9 (18%) cases, respectively. The median duration of TKI therapy in the whole series was 11.9 months. The median OS was 19.3 months and 1- and 2-year OS was 71.5% and 36.5%, respectively. The group treated with SBRT had a significant benefit in terms of OS (p=0.043). Only two grade 3 toxicities were reported. RT concomitantly or close to TKI administration in stage IV NSCLC was shown to be feasible and safe. Intriguing data on OS were also reported.

Clinical Efficacy of Alectinib in Patients with ALK-Rearranged Non-small Cell Lung Cancer After Ceritinib Failure.

Several second-generation inhibitors of anaplastic lymphoma kinase (ALK) have demonstrated potent activity in ALK rearrangement-positive non-small cell lung cancer (NSCLC). Two of these agents, ceritinib, and alectinib, recently received approval for the treatment of ALK-rearranged NSCLC in Japan. The efficacy of treatment with a second-generation ALK inhibitor after failure with a different second-generation ALK inhibitor remains unclear. We present a series of eight patients with ALK-rearranged NSCLC treated with alectinib who experienced disease progression after ceritinib. Both crizotinib and ceritinib were administered to six patients, with four (29%) patients receiving crizotinib followed by ceritinib. Among the eight study patients, two (25%) had partial response, one (12%) stable disease, and five (63%) had progressive disease. The median progression-free survival was 3.6 months (95% confidence interval=0-7.1 months). The results of this study suggest that the second-generation ALK inhibitor alectinib has limited efficacy after initial treatment with the second-generation ALK inhibitor ceritinib.

Differential protein stability and clinical responses ofEML4-ALK fusion variants to various ALK inhibitors in advancedALK-rearranged non-small cell lung cancer

Anaplastic lymphoma kinase (ALK) inhibition using crizotinib has become the standard of care in advanced ALK-rearranged non-small cell lung cancer (NSCLC), but the treatment outcomes and duration of response vary widely. Echinoderm microtubule-associated protein-like 4 (EML4)-ALK is the most common translocation, and the fusion variants show different sensitivity to crizotinib in vitro. However, there are only limited data on the specific EML4-ALK variants and clinical responses of patients to various ALK inhibitors. By multiplex reverse-transcriptase PCR, which detects 12 variants of known EML4-ALK rearrangements, we retrospectively determined ALK fusion variants in 54 advanced ALK rearrangement-positive NSCLCs. We subdivided the patients into two groups (variants 1/2/others and variants 3a/b) by protein stability and evaluated correlations of the variant status with clinical responses to crizotinib, alectinib, or ceritinib. Moreover, we established the EML4-ALK variant-expressing system and analyzed patterns of sensitivity of the variants to ALK inhibitors. Of the 54 tumors analyzed, EML4-ALK variants 3a/b (44.4%) was the most common type, followed by variants 1 (33.3%) and 2 (11.1%). The 2-year progression-free survival (PFS) rate was 76.0% [95% confidence interval (CI) 56.8-100] in group EML4-ALK variants 1/2/others versus 26.4% (95% CI 10.5-66.6) in group variants 3a/b (P = 0.034) among crizotinib-treated patients. Meanwhile, the 2-year PFS rate was 69.0% (95% CI 49.9-95.4) in group variants 1/2/others versus 32.7% (95% CI 15.6-68.4) in group variants 3a/b (P = 0.108) among all crizotinib-, alectinib-, and ceritinib-treated patients. Variant 3a- or 5a-harboring cells were resistant to ALK inhibitors with >10-fold higher half maximal inhibitory concentration in vitro. Our findings show that group EML4-ALK variants 3a/b may be a major source of ALK inhibitor resistance in the clinic. The variant-specific genotype of the EML4-ALK fusion allows for more precise stratification of patients with advanced NSCLC.

Abstract IA15: Lung cancer genomics

Abstract Lung cancer remains the most common cause of cancer related deaths in the United States. The primary reason for the high mortality rate is the advanced stage of the disease at the time of diagnosis. Racial disparities in incidence and mortality have been observed in the United States, with higher rate among African-Americans, particularly males. In recent years genetic alterations that bestow a proliferative and survival advantage, so called ‘driver' genetic alterations, have been identified in a subset of cancers including Non-Small Cell Lung Cancer (NSCLC). Molecular changes resulting from these genetic alterations can be targeted for therapeutic benefit and such targeted therapy has become standard of care for the management of NSCLC patients. These data have generated an interested in assessing and understanding lung cancer genomics. Several studies have been conducted and results of these studies have allowed the characterization of lung cancer into genomically distinct categories that may have implications for tumor biology and possibly for cancer therapeutics. Racial and ethnic variations in the incidence of specific ‘driver' genetic alterations have been observed. Thus the incidence of EGFR (epidermal growth factor receptor) mutation positive NSCLC is higher in Asian population compared to North American population. Such differences have not been observed for ALK (anaplastic lymphoma kinase) gene rearrangement positive NSCLC. These observations have generated an interest in evaluating lung cancer genomics to explain the observed racial differences in both incidence and mortality. Ongoing efforts will attempt to define racial and ethnic differences, if any in lung cancer genomics and the implications of the same. Citation Format: Shirish M. Gadgeel. Lung cancer genomics. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr IA15.

Personalized Medicine Tackles Clinical Resistance: Alectinib in ALK-Positive Non-Small Cell Lung Cancer Progressing on First-Generation ALK Inhibitor.

Over the last 2 years, our therapeutic armamentarium against genomically defined subgroups of non-small cell lung cancer (NSCLC) has extended to patients with acquired resistance to front-line targeted therapy. Alectinib (Alecensa; Roche/Genentech), a second-generation, orally active, potent, and highly selective inhibitor of anaplastic lymphoma kinase (ALK), is indicated for patients with metastatic, ALK rearrangement-positive NSCLC whose disease has worsened after treatment with crizotinib or who became intolerant to the drug. Alectinib received orphan drug designation, breakthrough therapy designation, priority review status, and accelerated approval by the FDA. Clin Cancer Res; 22(21); 5177-82. ©2016 AACR.

Ovarian metastasis from non-small cell lung cancer with ALK and EGFR mutations: A report of two cases.

Ovarian metastasis from non-small cell lung cancer (NSCLC) is a rare condition. The current study presents the cases of 2 female patients aged 38 and 47 years old, respectively, who were initially diagnosed with NSCLC adenocarcinoma on histology. Both patients initially presented with chest pain and a cough, and subsequently developed ovarian metastases following multiple treatments. The 38-year old patient exhibited an epidermal growth factor receptor mutation, confirmed by scorpion/amplified refractory mutation system analysis from a lung biopsy. The 47-year old exhibited an anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangement, revealed by fluorescence in situ hybridization analysis of the breast tissue biopsy, confirming a diagnosis of ALK rearrangement-positive NSCLC. These patients developed ovarian metastasis in the course of the disease. The current study reports the diagnostic challenges and clinical management of the disease, and provides a review of the literature.

Development of anaplastic lymphoma kinase (ALK) inhibitors and molecular diagnosis in ALK rearrangement-positive lung cancer

The fusion of echinoderm microtubule-associated protein-like 4 with anaplastic lymphoma kinase (ALK) was identified as a transforming gene for lung cancer in 2007. This genetic rearrangement accounts for 2%–5% of non-small-cell lung cancer (NSCLC) cases, occurring predominantly in younger individuals with adenocarcinoma who are never- or light smokers. A small-molecule tyrosine-kinase inhibitor of ALK, crizotinib, was rapidly approved by the US Food and Drug Administration on the basis of its pronounced clinical activity in patients with ALK rearrangement-positive NSCLC. Next-generation ALK inhibitors, such as alectinib, LDK378, and AP26113, are also being developed in ongoing clinical trials. In addition, the improvement and validation of methods for the detection of ALK rearrangement in NSCLC patients will be key to the optimal clinical use of ALK inhibitors. We here summarize recent progress in the development of new ALK inhibitors and in the molecular diagnosis of ALK rearrangement-positive NSCLC.

Bilateral ovarian metastasis of non-small cell lung cancer with ALK rearrangement

The discovery of a distinct subtype of non-small cell lung cancer (NSCLC) positive for rearrangement of the anaplastic lymphoma kinase gene (ALK) has had a substantial impact on personalized therapy for this disease. The clinical features associated with metastasis in individuals with ALK rearrangement-positive NSCLC remain to be fully characterized, however. We now describe a case of ovarian metastasis from NSCLC with ALK rearrangement. A 39-year-old woman underwent a right middle lobectomy for acinar-type adenocarcinoma of the lung (pT2aN2M0, stage IIIA). Fluorescence in situ hybridization (FISH) analysis of the resected tumor tissue revealed the presence of an ALK rearrangement. Twenty months later, a large intrapelvic mass was detected in the patient at follow-up. She underwent both left salpingo-oophorectomy and right ovarian cystectomy. Histological examination of the ovarian tumors showed acinar adenocarcinoma, and FISH analysis revealed the presence of ALK rearrangement, confirming a diagnosis of ALK rearrangement-positive NSCLC with ovarian metastasis. Although the ovary is an uncommon site for metastasis from lung cancer, physicians should be aware of the possibility for such metastasis during follow-up for female patients with ALK rearrangement-positive NSCLC. Further investigation is warranted to clarify the incidence of ovarian metastasis in NSCLC patients with ALK rearrangement.

EL6 - Lung Cancer: Driver Oncogene and Molecular-Targeted Therapies

ABSTRACT Identification of oncogenic genomic alterations is expected to facilitate the development of new molecularly targeted therapies for cancer. The first identified ‘driver oncogene’ directly associated with molecular targeted therapies for non-small-cell lung cancer (NSCLC) is mutated epidermal growth factor receptor (EGFR) which is found in up to 30% of Asian NSCLC patients. Preclinical studies demonstrated that EGFR mutation-positive tumors are dependent on, or ‘addicted’ to, EGFR signaling for their growth and survival and exposure of those tumors to EGFR tyrosine kinase inhibitors (TKIs), thus results in EGFR-signaling pathways being turned off and the cancer cells undergoing apoptosis. These findings did quickly translate into clinical trials. Asian landmark phase III trials have now led to the new paradigm of using EGFR-TKIs such as gefitinib or elrotinib for first-line treatment of EGFR-mutation-positive advanced NSCLC. Such findings indicate that the use of molecularly targeted therapy in genetically defined subsets of NSCLC patients may prove to be an effective strategy. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase whose gene was initially identified as part of the NPM-ALK fusion gene that contributes to the pathogenesis of a subset of anaplastic large cell lymphoma cases. In 2007, a fusion of ALK with the echinoderm microtubule-associated protein-like 4 gene (EML4) was identified by a Japanese group led by Hiroyuki Mano. EML4-ALK undergoes constitutive oligomerization mediated by the coiled-coil domain of the EML4 portion of the fusion protein, and it manifests marked oncogenic activity both in vitro and in vivo. Crizotinib was the first ALK inhibitor to be tested in the clinical setting. On the basis of its dramatic clinical activity, crizotinib was approved by the FDA for treatment of ALK rearrangement-positive NSCLC in August 2011. The promise of molecular targeted drugs against these driver gene alterations brings us closer to personalized lung cancer therapy.