Lymphoma Kinase-positive Non-small Cell Lung Research Articles

Pharmacokinetically-guided dosing to improve the efficacy of brigatinib in non-small cell lung cancer patients.

Brigatinib was recently approved for the treatment of anaplastic lymphoma kinase‐positive non‐small cell lung cancer and is dosed according to a one‐dose‐fits‐all paradigm. We aimed to identify a pharmacokinetically‐guided precision dosing strategy to improve treatment response with brigatinib through simulations using a previously published pharmacokinetic‐pharmacodynamic model. Dosing strategies explored were the approved 180 mg QD; the highest tolerable dose tested in clinical trials: 240 mg QD; and two precision dosing strategies targeting the median trough concentrations following 180 mg QD, and 240 mg QD. We investigated the impact of alternative dosing regimens on progression‐free survival (PFS), overall survival (OS) and the probability of developing a grade ≥2 rash or grade ≥2 amylase increase. Median PFS and OS increased by 1.6 and 7.8 months, respectively between the currently approved dosing strategy and precision dosing to the median trough concentration of the 240 mg dosing strategy, with only a minor increase in the probability of developing toxicity.

1205P Treatment sequencing and duration of subsequent tyrosine kinase inhibitors in ALK+ non-small cell lung cancer patients treated with brigatinib in the US

Next-generation targeted therapies for anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer are associated with improved clinical outcomes, however, tumors develop resistance thus requiring subsequent therapies. Limited data are available on ALK TKI sequencing. The aim of our study was to understand duration of post-brigatinib ALK TKI therapy in the real-world setting.

Cost-Effectiveness of Lorlatinib as a First-Line Therapy for Untreated Advanced Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer.

IntroductionRecently, a phase III CROWN trial compared the efficacy of two anaplastic lymphoma kinase (ALK) inhibitors and demonstrated that lorlatinib displayed clinical improvement over crizotinib for advanced non-small cell lung cancer (NSCLC) patients. Therefore, the aim of this study was to estimate the cost-effectiveness of lorlatinib as a first-line therapy for patients with advanced ALK-positive (+) NSCLC.Materials and MethodsA cost-effectiveness analysis was performed using a microsimulation model from the US payer perspective and a lifetime horizon (30 years) in patients with previous untreated advanced ALK+ NSCLC. Based on the CROWN trial, patient characteristics were obtained, and the transition probabilities were estimated. All direct costs were derived from official sources and published literature. The main outcomes of the model were total costs, incremental cost-effectiveness ratio (ICER), quality-adjusted life years (QALYs), and life years (LYs). One-way and probabilistic sensitivity analyses and multiple scenario analyses were conducted to test the robustness of the model outcomes.ResultsIn the base case analysis, in which 1 million patients were simulated, treatment with lorlatinib or crizotinib as the first-line treatment was related to a mean cost of $909,758 and $616,230 (incremental cost: $293,528) and a mean survival of 4.81 QALYs and 4.09 QALYs (incremental QALY: 0.72) per patient, respectively. The main drivers of cost effectiveness were drug price and subsequent cost. PAS indicated that lorlatinib has 90% cost-effectiveness when compared to crizotinib when the willingness-to-pay (WTP) threshold in increased to $448,000/QALY. Scenario analysis demonstrated that lorlatinib has 100% cost-effectiveness at a WTP threshold of 200,000/QALY compared to crizotinib treatment when the price of lorlatinib is decreased to 75% ($424.5) of its original price.ConclusionsIn this study, lorlatinib was unlikely to be cost effective compared with crizotinib for patients with previously untreated advanced ALK+ NSCLC at a WTP threshold of 200,000/QALY.

Combining Radiation Therapy with ALK Inhibitors in Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer (NSCLC): A Clinical and Preclinical Overview.

Simple SummaryThe use of tyrosine kinase inhibitors has significantly improved the outcome of patients with ALK (anaplastic lymphoma kinase)-rearranged non-small cell lung cancer. Combining drugs with radiotherapy could increase its effectiveness on tumors or overcome resistance to ALK-targeted therapies. In this review, we provide a clinical and preclinical overview of combining radiation therapy with ALK inhibitors in anaplastic lymphoma kinase-positive non-small cell lung cancer, and we also propose several approaches to overcome resistance to ALK-targeted therapies with a combination of radiation and tyrosine kinase inhibitors.Over the past years, the identification of genetic alterations in oncogenic drivers in non-small cell lung cancer (NSCLC) has significantly and favorably transformed the outcome of patients who can benefit from targeted therapies such as tyrosine kinase inhibitors. Among these genetic alterations, anaplastic lymphoma kinase (ALK) rearrangements were discovered in 2007 and are present in 3–5% of patients with NSCLC. In addition, radiotherapy remains one of the cornerstones of NSCLC treatment. Moreover, improvements in the field of radiotherapy with the use of hypofractionated or ablative stereotactic radiotherapy have led to a better outcome for localized or oligometastatic NSCLC. To date, the effects of the combination of ALK inhibitors and radiotherapy are unclear in terms of safety and efficacy but could potently improve treatment. In this manuscript, we provide a clinical and preclinical overview of combining radiation therapy with ALK inhibitors in anaplastic lymphoma kinase-positive non-small cell lung cancer.

P84.08 First-line Brigatinib in Anaplastic Lymphoma Kinase-positive Non-small Cell Lung Cancer: A Network Meta-Analysis

Anaplastic Lymphoma Kinase (ALK)-targeted tyrosine kinase inhibitors have shown to be effective as first-line (1L) treatment of ALK-positive non-small cell lung cancer (NCSLC). However, head-to-head comparisons between most available ALK inhibitors are lacking. The objective of this study was to conduct a systematic literature review (SLR) and meta-analyses to estimate the relative efficacy of brigatinib compared to other approved ALK inhibitors or chemotherapy in patients with locally advanced or metastatic ALK inhibitor-naïve ALK-positive NSCLC (≤1 prior chemotherapy regimen was allowed).

Brigatinib and lorlatinib: their effect on ALK inhibitors in NSCLC focusing on resistant mutations and central nervous system metastases.

Major issues in anaplastic lymphoma kinase-positive non-small cell lung carcinoma are acquired resistance against anaplastic lymphoma kinase inhibitors and control of central nervous system metastasis. The development of these inhibitors has changed therapeutic strategy in patients with advanced anaplastic lymphoma kinase-positive non-small cell lung carcinoma. Brigatinib and lorlatinib were designed to penetrate the blood-brain barrier and to inhibit resistant mutations against anaplastic lymphoma kinase inhibitors. We review the clinical data supporting treatment of advanced anaplastic lymphoma kinase-positive non-small cell lung carcinoma with brigatinib and lorlatinib. Brigatinib has shown promising antitumour activity, including substantial activity against central nervous system metastases, in crizotinib-treated (ALTA trial) patients and crizotinib-naïve (ALTA-1L trial) patients with anaplastic lymphoma kinase-positive non-small cell lung carcinoma. In addition, brigatinib improved progression-free survival compared with crizotinib in anaplastic lymphoma kinase inhibitor-naïve patients with anaplastic lymphoma kinase-positive non-small cell lung carcinoma. Lorlatinib has demonstrated clinical antitumour activity against both intracranial and extracranial lesions in patients with anaplastic lymphoma kinase- or c-ros oncogene 1 (ROS1)-positive non-small cell lung carcinoma. Ongoing trials and further studies of these agents' biological and clinical properties would provide insight into the optimal therapeutic strategy for administering them to achieve the best survival benefit.

A framework for clinical and translational research in the era of rigor and reproducibility.

Rigor and reproducibility are two important cornerstones of medical and scientific advancement. Clinical and translational research (CTR) contains four phases (T1-T4), involving the translation of basic research to humans, then to clinical settings, practice, and the population, with the ultimate goal of improving public health. Here we provide a framework for rigorous and reproducible CTR. In this paper we define CTR, provide general and phase-specific recommendations for improving quality and reproducibility of CTR with emphases on study design, data collection and management, analyses and reporting. We present and discuss aspects of rigor and reproducibility following published examples of CTR from the literature, including one example that shows the development path of different treatments that address anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC). It is particularly important to consider robust and unbiased experimental design and methodology for analysis and interpretation for clinical translation studies to ensure reproducibility before taking the next translational step. There are both commonality and differences along the clinical translation research phases in terms of research focuses and considerations regarding study design, implementation, and data analysis approaches. Sound scientific practices, starting with rigorous study design, transparency, and team efforts can greatly enhance CTR. Investigators from multidisciplinary teams should work along the spectrum of CTR phases, and identify optimal practices for study design, data collection, data analysis, and results reporting to allow timely advances in the relevant field of research.

Treatment Sequencing in Patients with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer in Japan: A Real-World Observational Study.

The anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) alectinib was approved in Japan in 2014 for the treatment of ALK fusion gene-positive advanced non-small cell lung cancer (NSCLC). With the approvals of crizotinib in 2012 and ceritinib in 2017, Japan became the first country with multiple ALK TKIs available for first-line or later use in patients with ALK-positive advanced NSCLC. Here, we collected and evaluated real-world data on ALK TKI clinical usage patterns and sequencing in patients with ALK-positive NSCLC in Japan. This retrospective observational study used the Japanese Medical Data Vision database to analyze data from patients with a confirmed diagnosis of lung cancer who visited a healthcare facility in the database between April 2010 and March 2017, underwent an ALK test, received a prescription for an ALK TKI, and were at least 18years old as of the date of the first ALK TKI prescription. There were no exclusion criteria. Descriptive analyses of demographics, baseline characteristics, ALK TKI treatment patterns and sequences, non-ALK TKI treatments received before, during, and after ALK TKI treatment, and treatment durations were reported. A total of 378 patients met the inclusion criteria and were evaluated in mutually exclusive groups of patients receiving one, two, or three ALK TKIs. The initial ALK TKI prescribed was crizotinib for 52.1% of patients and alectinib for 47.9% of patients; however, the proportion of patients receiving alectinib as the initial ALK TKI increased over time following the Japanese approval of alectinib in 2014. Of the 117 patients who received two or three ALK TKIs, 106 received crizotinib as the first ALK TKI and 11 received alectinib. Before the date of the patient's first ALK TKI prescription, 153 of 378 patients (40.5%) had received chemotherapy. Of 104 patients who discontinued ALK therapy, 46.2% received chemotherapy and 5.8% received immunotherapy as their next treatment. At the time of this analysis, most patients who received more than one ALK TKI received crizotinib as the initial ALK TKI. Additional ALK TKIs have since been approved in Japan as first-line or later therapeutic options for patients with ALK-positive NSCLC, but the optimal sequence of ALK TKI usage remains undetermined. As new data continue to emerge, additional research will be warranted to evaluate ALK TKI sequences that do not include crizotinib as the first therapy in this patient population.

Economic burden in patients with ALK + non-small cell lung cancer, with or without brain metastases, receiving second-line anaplastic lymphoma kinase (ALK) inhibitors

Aims: To describe the real-world economic burden of patients with anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC) treated with post-crizotinib, second-line ALK inhibitor therapy.Materials and methods: Retrospective analysis using data from US Optum: Clinformatics Data Mart administrative claims database. Adult patients with ALK + NSCLC treated with ceritinib or alectinib as second-line ALK inhibitors between 1 January 2011 and 30 September 2017 were included. Healthcare costs and resource utilization for up to 1 year of therapy were calculated on a per-patient-per-month (PPPM) basis and stratified by presence or absence of brain metastases (BM). Multivariate regression analysis was performed to identify factors associated with costs. Top ten cost drivers of non-inpatient procedure costs were recorded.Results: One hundred and twelve patients received second-line ALK inhibitors. Total mean PPPM healthcare costs were $23,984 for all patients receiving up to 1 year of post-crizotinib, second-line ALK inhibitor therapy. Total mean PPPM costs for patients with BM on or prior to post-crizotinib, second-line ALK inhibitor therapy were 1.37-times as high as those for patients without BM (p = 0.0406). Mean PPPM outpatient visits and inpatient hospitalization stays were higher for patients with BM versus no BM. The main cost drivers for non-inpatient procedures were radiation therapy, medications, and diagnostic radiology.Limitations: Analyses did not include newer ALK-directed therapies. BM development after the index date (defined as the date of the first claim for a second-line ALK inhibitor) may have been misclassified as non-BM. Findings may not be generalizable to patients with no health insurance coverage.Conclusions: Treatment of patients with ALK + NSCLC with ceritinib or alectinib as post-crizotinib, second-line ALK inhibitor therapy represents a high economic burden. Healthcare costs and resource utilization were significantly higher for patients with ALK + NSCLC with BM versus no BM.

Effect of the patient information brochure in communicating the risks associated with crizotinib treatment to patients with non-small cell lung cancer (NSCLC) in Europe.

Crizotinib (XALKORI®) is indicated for anaplastic lymphoma kinase‐positive and ROS1‐positive advanced non‐small cell lung cancer. This study evaluated the distribution of the crizotinib patient information brochure (PIB) in Europe and patient knowledge of the key messages in the PIB. A cross‐sectional survey was conducted in 10 European countries among patients who received crizotinib to ascertain whether each patient received and read the PIB, and his/her knowledge of its key messages on hepatotoxicity, interstitial lung disease/pneumonitis, QTc prolongation, bradycardia, and vision disorders. Of the 341 patients contacted, 40 responded (11.7%), and 39 patients were eligible. A total of 77% of respondents acknowledged receiving the PIB, of which, 93% reported reading it. Knowledge of the individual side effects ranged from 36% to 85%, and precautions for use ranged from 56% to 67%. Understanding the reasons for calling a physician ranged from 54% to 85%. Knowledge of each of the 6 key side effects was greater among readers of the PIB compared to non‐readers or respondents who did not recall receiving the PIB. Approximately three‐quarters of survey respondents recalled receiving the crizotinib PIB and respondents who read the PIB were more knowledgeable of the key side effects of crizotinib than those who did not read or receive. Caution should be taken in generalizing these results because of the potential for selection bias and small sample size. These survey results suggest that the crizotinib PIB may be an effective risk communication tool for crizotinib‐treated patients in Europe.

Lorlatinib in anaplastic lymphoma kinase-positive non-small cell lung cancer: Indian experience.

Lorlatinib in anaplastic lymphoma kinase-positive non-small cell lung cancer: Indian experience.

Use of lorlatinib subsequent to crizotinib in anaplastic lymphoma kinase-positive non-small cell lung cancer: Indian experience.

Use of lorlatinib subsequent to crizotinib in anaplastic lymphoma kinase-positive non-small cell lung cancer: Indian experience.

ES02.03 Management of Other Non EGFR Oncogene Addicted Tumors

Stage III non-small cell lung cancer accounts for heterogeneous group of diseases, due to differences in tumor size, location number of nodes involved, and lymph node station involved. Stage III non-small cell lung cancer comprises 2 distinct stages, stage IIIA and IIIB disease that have different prognosis, and are usually treated differently. Approximately 15% of all patients with newly diagnosed non-small cell lung cancer present with stage III disease. Options for stage III non-small cell lung cancer include surgery, with lobectomy or pneumonectomy depending on the tumor stage, and lymph node involvement. Chemotherapy may be administered in the neoadjuvant, concurrent or adjuvant setting. Radiation therapy can be given in a concurrent, sequential approach, or may be administered in the postoperative fashion. Combination approaches are often used, and due to the significant need of multi-modality therapy, treatment decisions are usually made in a multidisciplinary setting. The optimal therapeutic approach for patients with stage IIIA non-small cell lung cancer remains controversial. For subset of patients with T3 to T4 N0-1 disease, and superior sulcus location, surgery remains a viable and preferred option. However, the optimal treatment for patients with stage III A, with bulky lymph node involvement, or multi station lymph node involvement including N2 disease, remains an area of ongoing controversy. Tri-modality approaches using preoperative chemotherapy, or upfront chemoradiation therapy followed by surgery have been evaluated (1). For patients with surgically unresectable, or medically inoperable disease, concurrent chemoradiation therapy has been established as the standard of care for patients spanning the spectrum of stage IIIA and IIIB disease. Recently, the PACIFIC trial demonstrated an improvement in progression free survival and overall survival with the administration of durvalumab as consolidation therapy (regardless of PDL-1 status) for patients who had not progressed after 2 or more cycles of definitive concurrent platinum-based chemoradiation therapy (2, 3). This approach represents a new paradigm in the management of unresectable NSCLC, and has now been adopted as standard of care. Management of Stage III patients with non EGFR oncogene addicted tumors is an area of active research. ALK or ROS directed oral tyrosine kinase inhibitors (TKIs) are not typically administered in the adjuvant setting outside of a clinical trial. There are several trials evaluating the use of targeted therapies. ALINA, is one such trial, that is a phase III study of alectinib versus chemotherapy as adjuvant therapy in patients with stage IB–IIIA anaplastic lymphoma kinase-positive ALK positive NSCLC (4). Another study is comparing adjuvant alectinib versus adjuvant platinum-based chemotherapy in patients with ALK positive NSCLC, here the alectinib is administered for 2 years (NCT 03456076). The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing (ALCHEMIST) trial is actively enrolling patients with operable NSCLC and will perform genetic screening of their tumors. Patients with EGFR mutation or ALK gene rearrangement in their tumor will be randomized to placebo versus erlotinib or crizotinib, respectively (NCT02194738). We await the results of these trials prior to routine incorporation of molecularly directed therapy in the management of locally advanced disease. 1. Albain KS, Swann RS, Rusch VW, Turrisi AT, 3rd, Shepherd FA, Smith C, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet. 2009;374(9687):379-86. Epub 2009/07/28. https://doi.org/10.1016/S0140-6736(0960737-6). PubMed PMID: 19632716; PubMed Central PMCID: PMC4407808. 2. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. The New England journal of medicine. 2017;377(20):1919-29. 3. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. 2018; 379:2342-2350 4. Solomon BJ, Ahn JS, Barlesi F et al. ALINA: A phase III study of alectinib versus chemotherapy as adjuvant therapy in patients with stage IB–IIIA anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC). J Clin Oncol 37, 2019 (suppl; abstr TPS8569)

The efficacy of immune checkpoint inhibitors in anaplastic lymphoma kinase-positive non-small cell lung cancer.

BackgroundDespite recent advances in treating non‐small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs), their role in ALK‐positive NSCLC patients is unclear. We investigated the efficacy of ICIs in patients with ALK‐positive NSCLC.MethodsBetween 2011 and 2018, a total of 14 ALK‐positive NSCLC patients treated with ICIs were evaluated retrospectively. Clinicopathologic features including age, PD‐L1 expression, and treatment outcomes were analyzed. RNA expression level and cytolytic activity by ALK positivity were analyzed using The Cancer Genome Atlas (TCGA) and National Cancer Center Research Institute (NCCRI) data sets.ResultsA total of 13 patients (92.9%) received ALK inhibitors. Patients received a median of three (range 2–8) courses of therapy. The study included nine patients (64.3%) who were PD‐L1‐high (>50%) and four (28.6%) who were PD‐L1‐low (<50%). The objective response rate was 14.3% (2/14). The median progression‐free survival time was 2.18 months (95% confidence interval [CI] 1.13 months‐not reached [NR]). The median overall survival time was 5.67 months (95% CI 3.00 months‐NR). RNA expression levels of CD274 were similar between the ALK‐positive and negative groups in both TCGA and NCCRI datasets. RNA levels of CD8A in both TCGA and NCCRI data sets were nonsignificantly lower in the ALK‐positive group. Cytolytic activity scores including interferon‐γ‐related response were lower in the ALK‐positive group in the NCCRI but not TCGA dataset.ConclusionsDespite high PD‐L1‐positive rates, ICIs show limited efficacy in ALK‐positive NSCLC. Decreased interferon‐γ‐related response may underlie these findings.

ALINA: A phase III study of alectinib versus chemotherapy as adjuvant therapy in patients with stage IB–IIIA anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC).

TPS8569 Background: Patients with early-stage NSCLC (stage IA–IIIA) account for ~40% of cases at diagnosis; despite surgery, 5-year survival rates are low. Platinum-based adjuvant chemotherapy is the standard of care (SoC) for stage II–IIIA disease. Although patients with stage IA NSCLC do not benefit from adjuvant chemotherapy, patients with stage IB disease and large tumors (≥4cm) do. Adjuvant chemotherapy produces a 4–5% increase in 5-year survival rates, leaving significant unmet need for improved treatments. Approximately 5% of patients with NSCLC harbor an oncogenic fusion of the ALK gene. Treatment of advanced ALK+ NSCLC with ALK inhibitors improves efficacy and safety compared with chemotherapy. Alectinib, a potent ALK inhibitor, is the SoC first-line treatment for advanced ALK+ NSCLC. The ongoing ALINA trial will compare alectinib versus chemotherapy as adjuvant treatment for patients with stage IB–IIIA ALK+ NSCLC. Methods: ALINA is a randomized, multicenter, open-label phase III study investigating the efficacy and safety of adjuvant alectinib versus chemotherapy in ALK+ NSCLC (confirmed by an FDA-approved and CE-marked test). Adult patients (≥18 years) with completely resected stage IB (tumors ≥4cm) to IIIA disease and ECOG PS 0–1 are eligible for inclusion. Patients (N=255) from ~170 centers across ~30 countries will be randomized 1:1 to receive twice-daily alectinib 600mg for 24 months or four 21-day cycles of platinum-based chemotherapy (cisplatin 75mg/m2 [day 1] plus vinorelbine 25mg/m2 [days 1 and 8] or gemcitabine 1250mg/m2 [days 1 and 8] or pemetrexed 500mg/m2 [day 1]) according to local prescribing information. Stratification factors are disease stage (stage IB [≥4cm] vs stage II vs stage IIIA) and race (Asian vs non-Asian). Treatment will continue until planned completion, disease recurrence, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first. The primary endpoint is disease-free survival per investigator; secondary endpoints are overall survival, safety, and pharmacokinetics. Clinical trial information: NCT03456076.

Lorlatinib for the treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer

ABSTRACT Introduction Approximately 3–5% of patients with non-small cell lung cancer （NSCLC）belonged to anaplastic lymphoma kinase (ALK)-positive NSCLC. The treatment drugs of ALK-positive NSCLC mainly included crizotinib, ceritinib, alectinib, and brigatinib. Although these drugs had some effects, most of them were usually easy to develop drug resistance. Lorlatinib is a new inhibitor of ALK for treating ALK-positive NSCLC,the effect is obvious, and not easy to develop resistance. Areas covered The main mechanism of action, pharmacokinetics, clinical efficacy and safety of lorlatinib were introduced in this paper. Expert commentary Lorlatinib is a new, reversible, ATP-competitive small molecule inhibitor of ALK and c-ros oncogene 1 (ROS1). It can inhibit tumor cell growth in ALK- and ROS1-overexpressing tumor cells. Clinical trial indicated that lorlatinib had obvious therapeutic effect for patients with ALK-positive NSCLC. Lorlatinib could also pass through the blood-brain barrier, which had a good effect on patients with brain metastasis. Adverse events of lorlatinib were mostly mild and moderate in severity, and patients were easily tolerated. Most common adverse events were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea.

Treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer: update and perspectives.

We describe recent developments in the rapidly evolving field of anaplastic lymphoma kinase-targeting agents. Five targeted drugs are currently available in the clinic via regular approval or named patient programs, including crizotinib, ceritinib, alectinib, brigatinib and lorlatinib. Further drugs are tested in clinical trials. This review summarizes published data, together with drug-specific information on dosing and toxicity. Moreover, we discuss different clinical scenarios and potential treatment options in patients with tumor progression, based on current literature and our own experience. Patients with metastatic, anaplastic lymphoma kinase-rearranged nonsmall cell lung cancer should be managed by interdisciplinary expert teams. New drugs with enhanced brain activity are available, and some patients may benefit from local therapies.

Фармакоэкономический анализ применения ингибиторов киназы анапластической лимфомы для лечения пациентов с местно-распространенной или метастатической формой немелкоклеточного рака легкого с транслокацией гена киназы анапластической лимфомы (ALK)

Фармакоэкономический анализ применения ингибиторов киназы анапластической лимфомы для лечения пациентов с местно-распространенной или метастатической формой немелкоклеточного рака легкого с транслокацией гена киназы анапластической лимфомы (ALK)

ASCEND-8 pharmacokinetic, safety, and efficacy data for ceritinib 450 mg with food in patients with anaplastic lymphoma kinase–positive non-small cell lung Cancer: A clinical perspective

Anaplastic lymphoma kinase–positive (ALK+) non-small cell lung cancer (NSCLC) is diagnosed in up to 126,000 patients worldwide annually. Ceritinib is a next-generation ALK-targeted tyrosine kinase inhibitor that is approved for the treatment of patients with metastatic ALK+ NSCLC. In December 2017, the US Food and Drug Administration–approved dose of ceritinib was changed from 750 mg/day under fasting conditions to 450 mg/day taken with food for the treatment of patients with ALK+ NSCLC. This change was implemented on the basis of data from studies designed to investigate ways to reduce the frequency of gastrointestinal adverse events noted in patients enrolled in several ASCEND clinical trials that evaluated a ceritinib 750-mg fasted dose as either first- or second/third-line treatment. This review highlights and discusses published findings from the ASCEND-8 food-effect trial and includes commentary from physicians regarding their own clinical cases of patients who were enrolled in the trial and treated with either the 750-mg fasted or 450-mg fed dose of ceritinib. The review also discusses the implications of using the recently approved ceritinib 450-mg dose in the clinical setting.

Exploration of germline variants responsible for adverse events of crizotinib in anaplastic lymphoma kinase-positive non-small cell lung cancer by target-gene panel sequencing

ObjectivesCrizotinib is a standard treatment for advanced anaplastic lymphoma kinase (ALK)- or ROS1-fusion-gene-positive non-small cell lung cancer; however, serious adverse events (AEs), including elevated alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and interstitial lung disease (ILD), develop occasionally. Here, we evaluated relationships between clinically significant crizotinib-associated AEs and germline variations. Materials and MethodsDNA obtained from 75 patients allowed selection of 147 genes according to function, exon identification and sequencing, and determination of germline single nucleotide variants (SNVs). Correlations between clinically significant AEs and presence of germline variants were estimated by Fisher’s exact test. ResultsWe defined clinically significant AEs as grade 4 hematological toxicity, grade ≥3 non-hematological toxicity, and any grade of ILD. These AEs were observed in 26 patients (35%), with elevated AST/ALT (15%) the most common, followed by neutropenia (5%), ILD (4%), and thromboembolic events (4%). Nonsynonymous SNVs in epoxide hydrolase 1 (EPHX1) [odds ratio (OR): 3.86; p = 0.0009) and transcription factor 7-like 2 (TCF7L2) (OR: 2.51; p = 0.025) were associated with the presence of clinically significant AEs. ConclusionNonsynonymous EPHX1 and TCF7L2 SNVs might be associated with clinically significant crizotinib-associated AEs. These data indicated that target-gene sequencing could be feasible for predicting anticancer-agent toxicity, and that germline multi-gene information might be useful for predicting patient-specific AEs to promote precision medicine.