Lorlatinib: an additional option for ALK-positive non-small cell lung cancer?
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ABSTRACT:
SUBMITTER: Mogenet A
PROVIDER: S-EPMC6987344 | biostudies-literature | 2019 Dec
REPOSITORIES: biostudies-literature
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Lorlatinib: an additional option for ALK-positive non-small cell lung cancer?
Mogenet Alice A Tomasini Pascale P Greillier Laurent L Barlesi Fabrice F
Translational lung cancer research 20191201 Suppl 4
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Project description: Not available
| S-EPMC6735665 | biostudies-literature
Project description:Targeting genomic alterations, such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements, have radically changed the treatment of patients with non-small cell lung cancer (NSCLC). In the case of ALK-rearranged gene, subsequent rapid development of effective genotype-directed therapies with ALK tyrosine kinase inhibitors (TKIs) triggered major advances in the personalized molecularly based approach of NSCLC. Crizotinib was the first-in-class ALK TKI with proven superiority over standard platinum-based chemotherapy for the 1st-line therapy of ALK-rearranged NSCLC patients. However, the acquired resistance to crizotinib and its diminished efficacy to the central nervous system (CNS) relapse led to the development of several novel ALK inhibitors, more potent and with different selectivity compared to crizotinib. To date, four ALK TKIs, crizotinib, ceritinib, alectinib and brigatinib have received approval from the Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA) and even more agents are currently under investigation for the treatment of ALK-rearranged NSCLC. However, the optimal frontline approach and the exact sequence of ALK inhibitors are still under consideration. Recently announced results of phase III trials recognized higher efficacy of alectinib compared to crizotinib in first-line setting, even in patients with CNS involvement. In this review, we will discuss the current knowledge regarding the biology of the ALK-positive NSCLC, the available therapeutic inhibitors and we will focus on the raised issues from their use in clinical practise.
| S-EPMC5952030 | biostudies-literature
Project description:Alectinib, an anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is the recommended first-line treatment for ALK-positive non-small-cell lung cancer (NSCLC) in Japan. Lorlatinib was approved as a subsequent therapeutic option after progression while receiving ALK TKI treatment. However, data on the use of lorlatinib in the second- or third-line setting after alectinib failure are limited in Japanese patients. This retrospective real-world observational study investigated the clinical effectiveness of lorlatinib in second- or later-line settings after alectinib failure in Japanese patients. Clinical and demographic data collected in the Japan Medical Data Vision (MDV) database between December 2015 and March 2021 were used. Patients diagnosed with lung cancer who received lorlatinib following alectinib failure after the November 2018 marketing approval of lorlatinib in Japan were included. Of 1954 patients treated with alectinib, 221 were identified from the MDV database as receiving lorlatinib after November 2018. The median age of these patients was 62 years. Second-line lorlatinib treatment was reported for 154 patients (70%); third- or later-line lorlatinib treatment was reported for 67 patients (30%). The median duration of treatment (DOT) for all lorlatinib-treated patients was 161 days (95% confidence interval [CI], 126-248), and 83 patients (37.6%) continued treatment after data cut-off (March 31, 2021). Median DOTs of 147 days (95% CI, 113-242) and 244 days (95% CI, 109 to not reached) were reported with second-line and third- or later-line treatment, respectively. Consistent with clinical trial data, this real-world observational study supports data suggesting the effectiveness of lorlatinib after alectinib failure in Japanese patients.
| S-EPMC10236600 | biostudies-literature
Project description:BACKGROUND:Lorlatinib is a potent, third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI) designed to penetrate the blood-brain barrier. OBJECTIVE:We report the cumulative incidence of central nervous system (CNS) and non-CNS progression with lorlatinib in patients with ALK-positive non-small-cell lung cancer (NSCLC) previously treated with ALK TKIs. PATIENTS AND METHODS:In an ongoing phase II study (NCT01970865), 198 patients with ALK-positive NSCLC with ??1 prior ALK TKI were enrolled into expansion cohorts (EXP) based on treatment history. Patients received lorlatinib 100 mg once daily. Patients were analyzed for progressive disease, categorized as CNS or non-CNS progression, by independent central review. Cumulative incidence probabilities were calculated adopting a competing risks approach. RESULTS:Fifty-nine patients received crizotinib as their only prior ALK TKI (EXP2-3A); cumulative incidence rates (CIRs) of CNS and non-CNS progression were both 22% at 12 months in patients with baseline CNS metastases (n?=?37), and CIR of non-CNS progression at 12 months was higher versus that for CNS progression in patients without baseline CNS metastases [43% vs. 9% (n?=?22)]. In patients who received ??1 prior second-generation ALK TKI [EXP3B-5 (n?=?139)], CIR of non-CNS progression at 12 months was higher versus that for CNS progression in patients both with and without baseline CNS metastases (35% vs. 23% (n?=?94) and 55% vs. 12% (n?=?45), respectively). CONCLUSIONS:Lorlatinib showed substantial intracranial activity in patients with pretreated ALK-positive NSCLC, with or without baseline CNS metastases, whose disease progressed on crizotinib or second-generation ALK TKIs. CLINICALTRIALS. GOV IDENTIFIER:NCT01970865.
| S-EPMC7028836 | biostudies-literature
Project description:Anaplastic lymphoma kinase (ALK) fusion is found in ~3%-5% of patients with non-small-cell lung cancers (NSCLCs). Although the third-generation ALK tyrosine kinase inhibitor (TKI) lorlatinib shows high clinical efficacy in ALK-positive NSCLC, most of the patients eventually relapse with acquired resistance. Recently, drug-tolerant persister (DTP) cells have been considered an important seed of acquired resistance cells. In this study, we established lorlatinib intermediate resistant cells from a patient-derived cell model. Glycogen synthase kinase 3 (GSK3) inhibitions significantly suppressed lorlatinib intermediate resistant cell growth. GSK3 inhibition also sensitized acquired resistance cells derived from alectinib-treated patients with or without secondary mutations to lorlatinib. Therefore, GSK3 plays a crucial role in developing acquired resistance against lorlatinib in ALK-positive NSCLC mediated by lorlatinib intermediate resistant cells and could be a potential molecular target to prevent acquired lorlatinib resistance and overcome ALK-TKI resistance.
| S-EPMC8931094 | biostudies-literature
Project description:ObjectivesA drug that improves survival and/or disease progression can create real option value (ROV)-the additional health gain from future innovations enabled by a longer survival. ROV can be a relevant consideration for both clinical and payer decision-makers. We aimed to estimate the ex ante ROV for first-line (1L) alectinib in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC).MethodsWe developed a Markov model to estimate life-years (LYs) and quality-adjusted life-years (QALYs) gained with 1L alectinib versus 1L crizotinib due to potential future second-line (2L) drugs. Transition probabilities were derived from the phase 3 trial of 1L alectinib and phase 2 trial of 2L brigatinib. We identified drugs being studied in phase 2 and 3 trials in ALK-positive NSCLC at the time of alectinib's 1L approval and projected the likelihood and timing of their arrival and their potential efficacy based on publicly available data.ResultsThe discounted incremental LYs and QALYs for alectinib increased by 12.9% (95% CR - 2.96%, 34.82%; 1.25 vs. 1.11) and 11.2% (95% CR - 2.14%, 29.29%; 1.03 vs. 0.92), respectively, after accounting for ROV. The incremental ROV of alectinib was sensitive to the projected efficacy of future drugs, uptake level, and the hazard ratio of progression-free survival of alectinib (vs. crizotinib).ConclusionsEx ante ROV can be a significant value consideration in therapeutic areas with high levels of expected innovation. The potential efficacy of future drugs and incremental survival with alectinib at the projected time of arrival are important considerations in assessing ROV.
| S-EPMC9130184 | biostudies-literature
Project description:Non-small-cell lung cancer (NSCLC) is one of the leading causes of cancer deaths, both within the US and worldwide. There have been major treatment advances in NSCLC over the past decade with the discovery of molecular drivers of NSCLC, which has ushered in an era of personalized medicine. There are several actionable genetic aberrations in NSCLC, such as epidermal growth factor receptor and anaplastic lymphoma kinase (ALK). In 3%-7% of NSCLC, a chromosomal inversion event in chromosome 2 leads to fusion of a portion of the ALK gene with the echinoderm microtubule-associated protein-like 4 (EML4) gene. The constitutive activation of the ALK fusion oncogene renders it vulnerable to therapeutic intervention. This review focuses on the first-line treatment of advanced ALK-positive NSCLC using ALK inhibitors. Crizotinib was the first agent proven to be efficacious as first-line treatment for ALK-positive NSCLC. However, acquired resistance inevitably develops. The central nervous system is a sanctuary site that represents a common site for disease progression as well. Hence, more potent, selective next-generation ALK inhibitors that are able to cross the blood-brain barrier have been developed for treatment against crizotinib-resistant ALK-positive NSCLC and are also currently being evaluated for first-line therapy as well. In this review, we provide summary of the clinical experience with these drugs in the treatment of ALK-positive NSCLC.
| S-EPMC5217519 | biostudies-literature
Project description:EML4-ALK fusion transcripts have been found in a subset of non-small cell lung carcinomas (NSCLCs); however, their protein expression status has not yet been fully elucidated. In this study we investigated ALK protein expression in 302 NSCLCs and 291 gastric carcinomas by means of immunohistochemical analysis. Twelve (4.0%) NSCLCs, but none of the gastric carcinomas, were found to be positive for ALK. The ALK signal was detected in the cytoplasm of cancer cells. Subsequent RNA analysis of 10 RNA-available, immunohistochemically ALK-positive tumors revealed that three tumors had EML4-ALK variant 1, three tumors had variant 2, three tumors had variants 3a and 3b, and one tumor had a novel variant in which exon 14 of EML4 is connected to the nucleotide at position 53 of exon 20 of ALK by a 2-bp insertion. These results suggest that immunohistochemical ALK detection is a useful way to screen NSCLCs for tumors containing ALK fusions.
| S-EPMC3445876 | biostudies-literature
Project description:The cornerstone of treatment for advanced ALK-positive lung cancer is sequential therapy with increasingly potent and selective ALK inhibitors. The third-generation ALK inhibitor lorlatinib has demonstrated clinical activity in patients who failed previous ALK inhibitors. To define the spectrum of ALK mutations that confer lorlatinib resistance, we performed accelerated mutagenesis screening of Ba/F3 cells expressing EML4-ALK. Under comparable conditions, N-ethyl-N-nitrosourea (ENU) mutagenesis generated numerous crizotinib-resistant but no lorlatinib-resistant clones harboring single ALK mutations. In similar screens with EML4-ALK containing single ALK resistance mutations, numerous lorlatinib-resistant clones emerged harboring compound ALK mutations. To determine the clinical relevance of these mutations, we analyzed repeat biopsies from lorlatinib-resistant patients. Seven of 20 samples (35%) harbored compound ALK mutations, including two identified in the ENU screen. Whole-exome sequencing in three cases confirmed the stepwise accumulation of ALK mutations during sequential treatment. These results suggest that sequential ALK inhibitors can foster the emergence of compound ALK mutations, identification of which is critical to informing drug design and developing effective therapeutic strategies.Significance: Treatment with sequential first-, second-, and third-generation ALK inhibitors can select for compound ALK mutations that confer high-level resistance to ALK-targeted therapies. A more efficacious long-term strategy may be up-front treatment with a third-generation ALK inhibitor to prevent the emergence of on-target resistance. Cancer Discov; 8(6); 714-29. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 663.
| S-EPMC5984716 | biostudies-literature
Project description:The objective of this study was to understand outcomes of patients treated with ALK inhibitors, especially when ALK inhibitors are followed by other ALK inhibitors. A systematic literature review was conducted in PubMed, Embase, and Cochrane through July 17, 2017. Conference abstracts (three meetings in past 2 years) also were searched. Of 504 unique publications, 80 met inclusion criteria (47 clinical trials, 33 observational studies). Observational studies have the potential to provide information for ALK inhibitors used sequentially. Ten observational studies reported median overall survival of crizotinib-led sequences ranging from 30.3 to 63.75 months from initiation of crizotinib; 49.4-89.6 months from metastatic non-small-cell lung cancer diagnosis; and 15.5-22.0 months from initiation of the second-generation ALK inhibitor after initial crizotinib. Sequencing of ALK inhibitors may benefit patients progressing on initial ALK inhibitors.
| S-EPMC6372008 | biostudies-literature