ALK-rearranged Non-small Cell Lung Cancer Research Articles

Efficacy of gilteritinib in comparison with alectinib for the treatment of ALK-rearranged non-small cell lung cancer.

Gilteritinib is a multitarget tyrosine kinase inhibitor (TKI), approved for the treatment of FLT3-mutant acute myeloid leukemia, with a broad range of activity against several tyrosine kinases including anaplastic lymphoma kinase (ALK). This study investigated the efficacy of gilteritinib against ALK-rearranged non-small cell lung cancers (NSCLC). To this end, we assessed the effects of gilteritinib on cell proliferation, apoptosis, and acquired resistance responses in several ALK-rearranged NSCLC cell lines and mouse xenograft tumor models and compared its efficacy to alectinib, a standard ALK inhibitor. Gilteritinib was significantly more potent than alectinib, as it inhibited cell proliferation at a lower dose, with complete attenuation of growth observed in several ALK-rearranged NSCLC cell lines and no development of drug tolerance. Immunoblotting showed that gilteritinib strongly suppressed phosphorylated ALK and its downstream effectors, as well as mesenchymal-epithelial transition factor (MET) signaling. By comparison, MET signaling was enhanced in alectinib-treated cells. Furthermore, gilteritinib was found to more effectively abolish growth of ALK-rearranged NSCLC xenograft tumors, many of which completely receded. Interleukin-15 (IL-15) mRNA levels were elevated in gilteritinib-treated cells, together with a concomitant increase in the infiltration of tumors by natural killer (NK) cells, as assessed by immunohistochemistry. This suggests that IL-15 production along with NK cell infiltration may constitute components of the gilteritinib-mediated antitumor responses in ALK-rearranged NSCLCs. In conclusion, gilteritinib demonstrated significantly improved antitumor efficacy compared with alectinib against ALK-rearranged NSCLC cells, which can warrant its candidacy for use in anticancer regimens, after further examination in clinical trial settings.

Superior clinical outcomes in patients with non-small cell lung cancer harboring multiple ALK fusions treated with tyrosine kinase inhibitors.

Patients with non-small cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) fusions may benefit from ALK-tyrosine kinase inhibitors (ALK-TKIs). However, few studies have analyzed the clinical outcome in patients harboring multiple ALK fusions, including double or triple ALK fusions. Here, our study aimed to analyze the impact of harboring multiple ALK fusions on the efficacy of receiving ALK-TKIs in NSCLC patients. A total of 125 patients with ALK-rearranged NSCLC detected by targeted capture DNA-based next-generation sequencing (NGS) at West China Hospital were enrolled. The literature on patients harboring multiple ALK fusions was systematically reviewed. The clinical response to ALK-TKIs was evaluated according to ALK fusion patterns in 62 patients: 56 from our center and 6 from the literature. Among the 125 patients, a single canonical echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion was detected in 65.6% (82/125), a single non-EML4-ALK fusion was detected in 13.6% (17/125), and multiple ALK fusions were detected in 20.8% (26/125). Among the 62 patients with ALK fusion treated with ALK-TKIs, the median progression-free survival (PFS) was significantly longer in patients with multiple ALK fusions than in those with a single ALK fusion (26.9 vs. 11.2 months, P=0.009), irrespective of brain metastasis, type of TKI drug, and treatment lines. The multiple ALK fusion group also tended to have a longer overall survival (OS) (P=0.26). Multivariate Cox regression analysis revealed that harboring multiple ALK fusions had the potential to be an independent predictor of better PFS for ALK-positive NSCLC [hazard ratio (HR) =0.490; 95% confidence interval (CI): 0.229-1.049]. Harboring multiple ALK fusions could serve as an independent predictive marker of better clinical outcome for patients with NSCLC and ALK rearrangement who have received ALK-TKIs treatment.

Cardiac arrhythmias associated with anaplastic lymphoma kinase (ALK) inhibitors: an analysis of the FDA Adverse Event Reporting System (FAERS)

ABSTRACT Background Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) may provoke cardiac arrhythmias. We conducted this pharmacovigilance analysis to research cardiac arrhythmias associated with ALK-TKIs using the Food and Drug Administration Adverse Event Reporting System (FAERS). Research design and methods The first ALK-TKI, named crizotinib, was approved by the Food and Drug Administration (FDA) on 26 August 2011 for the treatment of ALK-rearranged non-small cell lung cancer (NSCLC). We evaluated ALK-TKIs-induced cardiac arrhythmias, by using the reporting odds ratio (ROR) and information component (IC) for mining the adverse event report signals in the FAERS database between January 2016 and June 2022. Results We identified a total of 362 ALK-TKIs-related cardiac arrhythmia reports which appeared to influence more men (64.44%) than women (30.76%), with a median age of 68 (interquartile range [IQR] 7–74) years. Compared with the full database, ALK-TKIs were detected with pharmacovigilance of cardiac arrhythmias (ROR025 = 1.26, IC025 = 0.26). Crizotinib and alectinib were found to be related to higher reporting of arrhythmias. The median time to onset (TTO) among five ALK-TKI therapies was significantly different (p = 0.044). Conclusion ALK-TKIs present different frequencies of cardiac arrhythmias reporting, with only crizotinib and alectinib producing positive signals in high-level group term (HLGT) level arrhythmia. The time interval between the initial of drug treatment to the onset of arrhythmia varies greatly and cannot be predicted.

ALK peptide vaccination restores the immunogenicity of ALK-rearranged non-small cell lung cancer.

Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) is treated with ALK tyrosine kinase inhibitors (TKIs), but the lack of activity of immune checkpoint inhibitors (ICIs) is poorly understood. Here, we identified immunogenic ALK peptides to show that ICIs induced rejection of ALK+ tumors in the flank but not in the lung. A single-peptide vaccination restored priming of ALK-specific CD8+ T cells, eradicated lung tumors in combination with ALK TKIs and prevented metastatic dissemination of tumors to the brain. The poor response of ALK+ NSCLC to ICIs was due to ineffective CD8+ T cell priming against ALK antigens and is circumvented through specific vaccination. Finally, we identified human ALK peptides displayed by HLA-A*02:01 and HLA-B*07:02 molecules. These peptides were immunogenic in HLA-transgenic mice and were recognized by CD8+ T cells from individuals with NSCLC, paving the way for the development of a clinical vaccine to treat ALK+ NSCLC.

Distinct metastatic spread and progression patterns in patients treated with crizotinib for ROS1- and ALK-rearranged non-small cell lung cancer: a single-center retrospective study.

Crizotinib has been approved for C-ros oncogene 1 (ROS1)- and anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) patients. Few studies have examined the differences in crizotinib treatment outcomes between these patients and the progression sites during treatment. We investigated the metastatic spread, crizotinib efficacy, and progression patterns during crizotinib treatment in ROS1- and ALK-rearranged NSCLC patients. We retrospectively reviewed crizotinib-treated ROS1- and ALK-rearranged NSCLC patients between January 2011 and March 2021. Patient characteristics, clinical outcomes, and progression patterns during treatment were collected from medical records. The metastasis extent, crizotinib response, and progression patterns between the groups were compared. We identified 26 patients with ROS1- and 42 with ALK-positive NSCLC. The baseline proportion of central nervous system (CNS) metastases did not differ between the groups (12% vs. 29%, P=0.10), but the proportion of extrathoracic metastases, including CNS metastases, was significantly higher in ALK-positive than in ROS1-positive NSCLC patients (35% vs. 71%, P=0.003). Regarding the response to crizotinib, the objective response rate (ORR), progression-free survival (PFS), or overall survival (OS) did not significantly differ between the groups (ROS1 vs. ALK, ORR: 69% vs. 69%, P=0.987; PFS: median 10.9 vs. 10.7 months, P=0.232; median OS: not reached vs. 67.7 months, P=0.495). The CNS was the most common metastasis site in both groups [ROS1 vs. ALK, 69% (11/16) vs. 46% (17/37), P=0.127], and the cumulative incidence of CNS metastasis did not differ between the groups (P=0.914). Crizotinib treatment outcomes, including progression patterns, were similar between ROS1- and ALK-positive NSCLC patients.

Evaluation of Efficacy of ALK Inhibitors According to Body Mass Index in ALK Rearranged NSCLC Patients—A Retrospective Observational Study

No evidence exists as to whether body mass index (BMI) impairs clinical outcomes from ALK inhibitors (ALKi) in patients with ALK-rearranged non-small cell lung cancer (NSCLC). Retrospective data of patients affected by metastatic ALK-rearranged NSCLC treated with ALKi were collected. We divided patients into “low- BMI” (≤25 kg/m2) and “high- BMI” (>25 kg/m2) categories and correlated them with overall survival (OS) and progression-free survival (PFS). We included 40 patients treated with ALKi. We observed a 3-year OS of 81.5% in high-BMI vs. 49.6% in low-BMI categories (p = 0.049); the 3-year first-line PFS was superior in high-BMI vs. low-BMI patients (47% vs. 19%, p = 0.019). As expected, patients treated with Alectinib had a 55.6% 3-year PFS vs. 7.1% for others treated with ALKi (p = 0.025). High-BMI was associated with a 100% 3-year PFS rate vs. 25.4% in low-BMI Alectinib patients (p = 0.03). BMI was independently correlated with first-line PFS and OS at multivariate analysis with PS (HR 0.39, CI 95% 0.16–0.96, p = 0.042; HR 0.18, CI 95% 0.05–0.61, p = 0.006). High-BMI was associated with higher efficacy in ALK-rearranged patients. These results are particularly exciting for Alectinib and could be correlated to mechanisms that should be investigated in subsequent prospective studies.

Pathological Response and Tumor Immune Microenvironment Remodeling Upon Neoadjuvant ALK-TKI Treatment in ALK-Rearranged Non-Small Cell Lung Cancer.

Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKI; ALKi) have shown potent antitumor activity in metastatic non-small-cell lung cancer (NSCLC) with ALK rearrangement (ALK+); however, their efficacy in neoadjuvant settings has been poorly explored. This retrospective study aimed to examine the clinical activity and tumor immune microenvironment (TIME) changes of neoadjuvant ALKi therapy. ALK+ NSCLC patients treated with neoadjuvant ALKi at three hospitals in China between February 2018 and January 2023 were assessed. Data on clinical features and radiographic and pathological responses were collected and evaluated. Multiplex immunofluorescence was performed on pretreatment biopsy specimens and surgically resected specimens to investigate the impact of ALKi on TIME. A total of 12 patients with stage IIA-IIIB NSCLC who received neoadjuvant ALKi therapy were analyzed. The objective response rate was 91.7% (11/12) and the major pathological response (MPR) rate was 75.0% (9/12), with 58.3% (7/12) achieving a pathological complete response (pCR). After neoadjuvant ALKi therapy, we observed a significant increase in immune infiltration of CD8+ cells (histochemistry score [H-score]: median 10.51 vs. 24.01, p=0.028; density: median 128.38 vs. 694.09 cells/mm2, p=0.028; percentage: median 3.53% vs. 15.92%, p=0.028) and CD4+ cells (density: median 275.56 vs. 651.82 cells/mm2, p=0.028; percentage: median 5.98% vs. 10.46%, p=0.028). Similar results were found for CD4+FOXP3+, CD8+PD1+, CD8+PD1-, CD8+GB+, and CD8+GB- cells. However, macrophages, including CD68+CD163- M1 and CD68+CD163+ M2 macrophages, showed little change after neoadjuvant ALKi therapy. Neoadjuvant ALKi therapy achieved an encouraging MPR rate of 75% and enhanced immune infiltration, suggesting its safety and feasibility for ALK+ resectable NSCLC. This study advances our understanding of TIME changes by neoadjuvant ALKi therapy and merits further investigation.

High PD-L1 Expression Correlates with an Immunosuppressive Tumour Immune Microenvironment and Worse Prognosis in ALK-Rearranged Non-Small Cell Lung Cancer.

High tumour programmed cell death-ligand 1 (PD-L1) expression is associated with poor progression-free survival (PFS) after tyrosine kinase inhibitor (TKI) therapy in ALK-rearranged non-small cell lung cancer (NSCLC). However, the characteristics of the tumour microenvironment (TME) and their prognostic values in ALK-rearranged NSCLC are unknown. Here, we collected tumour tissues from pretreated ALK-rearranged NSCLC patients, immunohistochemical staining was used to assess PD-L1 expression, and tumour-infiltrating immune cells were determined via multiplex immunofluorescence staining (mIF). Our data showed that the median values of PFS for the high PD-L1 group and low PD-L1 group who received ALK-TKI treatment were 4.4 and 16.4 months, respectively (p = 0.008). The median overall survival (OS) of the two groups was 24.0 months and not reached, respectively (p = 0.021). Via univariate and multivariate analyses, a high PD-L1 expression and a worse ECOG PS were determined to be independent prognostic factors of OS (HR = 3.35, 95% CI: 1.23-9.11, p = 0.018; HR = 6.42, 95% CI: 1.45-28.44, p = 0.014, respectively). In addition, the high PD-L1 group had increased Tregs and exhausted CD8+ T cells in both the tumour and stroma (all p < 0.05). High PD-L1 expression was an adverse predictive and prognostic biomarker for ALK-rearranged NSCLC. The characteristics of the TME in patients with high PD-L1 expression were shown to have an immunosuppressive status.

Large-scale comparative analysis of clinico-genomic characteristics, treatment outcomes and resistant mechanisms of ALK/ROS1/RET-rearranged non-small cell lung cancer (NSCLC) in a nationwide genomic screening project (LC-SCRUM-Asia/TRY).

9026 Background: There is limited understanding of the clinico-genomic differences among ALK/ROS1/RET-rearranged NSCLC due to their low frequency. We aimed to characterize these fusions using a large-scale LC-SCRUM-Asia/TRY database. Methods: We conducted a prospective screening of treatment-naïve and refractory lung cancer to identify genomic alterations using RT-PCR and/or targeted next-generation sequencing (NGS) assays in LC-SCRUM-Asia/TRY. We compared clinico-genomic characteristics, treatment outcomes and resistant mechanisms among ALK/ROS1/RET-rearranged NSCLC. Results: Between February 2013 and December 2022, 18,616 lung cancer patients (pts) were enrolled in LC-SCRUM-Asia/TRY and 16,583 were NSCLC pts. ALK/ROS1/RET fusions were identified in 430 (2.6%)/240 (1.4%)/202 (1.2%) pts in NSCLC. The patient characteristics were as follows ( ALK/ROS1/RET): median age, 58/60/63 years; females, 53/54/54%; never-smokers, 57/55/59%; adenocarcinoma, 93/95/96%. The frequencies of brain metastasis at diagnosis were 26/20/19% (p = 0.15). Among pts tested by NGS, the frequencies of TP53, TET2 and NOTCH1 mutations were lower in ALK than in ROS1 and RET ( TP53; 23/34/27%, NOTCH1; 17/34/35%, TET2; 17/30/32%). Overall survival (OS) was significantly longer in ALK than in ROS1 (mOS [ ALK/ROS1/RET] 108.8 vs. 43.6 vs. not reached [NR] months, ALK vs. ROS1; p &lt; 0.01, ALK vs. RET; p = 0.04) among stage IV pts underwent TKI therapy. TP53 mutation was associated with shorter OS in all three fusions (mOS [ TP53 mt+/mt-] ALK; 35.7 vs. 108.8, p &lt; 0.01, ROS1; 26.4 vs. 47.4, p = 0.06, RET; 28.9 vs. 76.1 months, p = 0.05), shorter PFS with first line alectinib in ALK (mPFS [ TP53 mt+/mt-] 11.0 vs. 38.4 months, hazard ratio [HR] 2.5 [95% CI, 1.5-4.2], p &lt; 0.01) and shorter PFS with initial crizotinib in ROS1 (mPFS [ TP53 mt+/mt-] 5.8 vs. 25.2 months, HR 2.6 [95% CI, 1.3-4.8], p &lt; 0.01). There was no significant difference in PFS with first-line platinum plus pemetrexed among fusions (mPFS 12.6 vs. 10.7 vs. 9.2 months) and PFS with initial immune checkpoint inhibitors among fusions (mPFS 3.9 vs. 5.1 vs. 3.0 months). Among 60/13/10 re-biopsy samples refractory to TKI, on-target resistant mutations were identified in 14 (23%) /3 (23%) /1 (10%) samples. Conclusions: Pts with ALK/ROS1/RET-rearranged NSCLC shared similar characteristics, but the occurrence of concomitant mutations was lower in ALK than in ROS1 and RET. TP53 mutation was associated with worse prognosis in pts with ALK/ROS1/RET-rearranged NSCLC. Among those received TKI, pts with ALK-rearranged NSCLC had better prognosis than those with ROS1 and RET-rearranged NSCLC. The development of highly effective molecular targeted therapies for ROS1- and RET-rearranged NSCLC is warranted.

Explore ALK: Alectinib activity in patients with ALK+ metastatic non-small cell lung cancer—A national real world analysis (GFPC 03-2019).

9092 Background: Alectinib is a standard of care option in advanced ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) patients (pts), with efficacy established by phase 3 trials, in first-line and beyond. There are few efficacy data in unselected populations. Methods: The objective of this study was to evaluate the efficacy of alectinib in real-world setting. All ALK+ advanced NSCLC pts initiating alectinib, between December 13, 2017 (date of access in France) and June 27, 2020, whatever the line, were included in explore ALK study. Patient characteristics, alectinib duration of treatment (DOT), progression-free survival assessed locally (rwPFS), overall survival (OS) according to the prescription line of alectinib, the presence of brain metastases at alectinib initiation, response rate and tolerance were collected from the medical files. Results: The analysis included 223 pts: 46.2% were men, 84.7% had no smoking history or were former smokers, median age was 59 (22-101) years and 95% were adenocarcinomas. Alectinib was initiated as first-line treatment in 119 pts, with a PS of 0/1/&gt;1 in 42%/31%/27% of cases, a median number of metastatic sites of 2 (cerebral, hepatic, bone in 33%, 24% and 32% of cases). In first-line setting, after a median follow-up of 33.7 months (95%CI, 32.2-37.5), the median of rwPFS and DOT were 28.1 (95%CI, 20.7-40.4) and 26.9 (95%CI, 20.2-31.3) months, respectively. The median OS was not reach (NR), the 3-year OS rate was 72.1%. The rwPFS was not significantly different depending on whether or not the patient has brain metastases, 28.1 (95% CI, 14.5-NR) and 30.5 (85% CI, 18.9-40.4) months, respectively. The best response was complete (CR), partial (PR) and stable (SD) in 21%, 58% and 17%. The cerebral response, evaluable in 30/39 of the pts, was CR, PR and SD in 26%, 46% and 23% respectively; 33% of pts had a grade 3 adverse event, resulting in a temporary interruption of treatment in 7.6% of cases and a permanent discontinuation in 5.9% of cases. At the time of progression, 48.1% of pts had a new biopsy (66% of tissue biopsy). Efficacy data for alectinib prescribed as second line and above are summarized in the table. Conclusions: In this large real-world, cohort of unselected advanced ALK+ NSCLC pts, alectinib initiated in 1st-line or beyond provides similar efficacy and safety results as obtained in phase III clinical trials. [Table: see text]

Association between targeted cancer drug net health benefit and uptake, patient out-of-pocket spending, and total spending.

6644 Background: Targeted cancer drugs (TCDs) have revolutionized oncology, but they are widely variable in their clinical benefit and are often accompanied by high patient-out-pocket (OOP) costs. The ASCO Value Framework uses published clinical trial data on survival, toxicity, and potential for symptom palliation to quantify the net health benefit (NHB) of any given cancer drug. We aimed to evaluate the association between NHB and uptake, patient OOP spending, and total spending for eight oral TCDs approved for the first line treatment of an advanced solid tumor based on one or more clinical trials comparing to a non-TCD control arm. Methods: We conducted a retrospective cohort study of incident pharmacy claims for oral TCDs prescribed to patients aged 18-64 years between 2012-2020 in the nationwide Health Care Cost Institute de-identified commercial claims dataset. NHB scores were calculated for each TCD of interest using the ASCO Value Framework and categorized as high (&gt;60), medium (40-60), and low (&lt;40) net health benefit. Distributions of incident 28-day TCD supplies were plotted over time by NHB category. The primary outcome was patient OOP spending (patient copay + coinsurance + deductible), whereas the secondary outcome was total spending (patient OOP spending + pharmacy reimbursement). Generalized linear models were used to evaluate the association between each outcome of interest and TCD NHB, adjusted for cancer indication. Results: We included 8,524 incident pharmacy claims for eight TCDs with nine indications in breast cancer, non-small cell lung cancer (NSCLC), melanoma, and pancreatic cancer. NHB scores ranged from 7 (erlotinib for pancreatic cancer) to 81 (crizotinib for ALK-rearranged NSCLC), with 1,145 (13%), 6,608 (78%), and 771 (9%) of pharmacy claims falling into low-, medium-, and high-NHB categories, respectively. Medium- and high-NHB TCDs accounted for the majority of incident TCD prescriptions throughout the study period. Median patient OOP spending was $18.78 for the first 28-day TCD supply (IQR $0.00-$87.57), with 45% of patients paying $0 and 8% paying &gt;$1,000 OOP. Patient OOP spending was not significantly associated with TCD NHB category (difference $0.94, 95% CI -$49.99-$51.87 for medium vs low NHB; difference $58.86, 95% CI -$28.04-$145.75 for high vs low NHB). Median total spending was $10,118.79 (IQR $6,365.95-$10,600.37) for an incident 28-day TCD supply. There was a $1,083.56 increase in total spending for each 10-point increase in NHB score (95% CI $1,050.27-$1,116.84, p &lt;0.01 for H0 = $0). Conclusions: Although TCDs are widely variable in their NHB, low-NHB TCDs are not prescribed as frequently as medium- and high-NHB TCDs. Total spending on TCDs is high and positively associated with NHB. Commercially insured patients are largely shielded from high OOP spending on TCDs.

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 4015: EGFR activation via c-Jun axis promotes adaptive resistance to third generation ALK-TKI lorlatinib in ALK-rearranged non-small cell lung cancer cells

Abstract Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs), including lorlatinib have shown dramatic efficacy in patients with ALK-rearranged lung cancer; however, complete response in these patients is rare, as a small population of tumor cells survives due to adaptive resistance. In this preclinical study, we investigated the adaptive resistant mechanisms to lorlatinib and its therapeutic strategies to overcome, using in vitro and in vivo experiments. We have identified EGFR as an adaptive resistance mechanism of lorlatinib using phospho-RTK array and siRNA library. Cell line-based assay showed that exposure of lorlatinib accelerated EGFR signal activation as an adaptive response via activation of JNK cascade in ALK-rearranged lung cancer cells. Knockdown for EGFR suppressed the survival signal of ALK lung cancer cells when treated with lorlatinib. The combination of lorlatinib and erlotinib, a first-generation EGFR-TKI, was shown to enhance cell growth inhibition by inducing cell apoptosis via suppressing the anti-apoptotic factor Bcl-xl compared with lorlatinib monotherapy. Moreover, cell line-derived xenograft model indicated that the combination of lorlatinib plus erlotinib enhanced anti-tumor effects compared with lorlatinib monotherapy. Taken together, our results displayed that EGFR activation plays an important role in the initial adaptive resistance to lorlatinib for ALK-rearranged lung cancer. The combination of lorlatinib and erlotinib is expected as the promising strategy for those tumors. Citation Format: Yuki Katayama, Tadaaki Yamada, Kenji Morimoto, Hiroaki Ozasa, Shinsaku Tokuda, Koichi Takayama. EGFR activation via c-Jun axis promotes adaptive resistance to third generation ALK-TKI lorlatinib in ALK-rearranged non-small cell lung cancer cells. [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 4015.

Arterial and Venous Thromboembolism in ALK-Rearrangement-Positive Non-small Cell Lung Cancer: A Population-Based Cohort Study.

There is scarce data regarding the incidence of venous thromboembolism (VTE) and arterial thromboembolism (ATE) in the molecular subtypes of non-small cell lung cancer (NSCLC). We aimed to investigate the association between Anaplastic Lymphoma Kinase (ALK)-positive NSCLC and thromboembolic events. A retrospective population-based cohort study of the Clalit Health Services database, included patients with NSCLC diagnosed between 2012 and 2019. Patients exposed to ALK-tyrosine-kinase inhibitors (TKIs) were defined as ALK-positive. The outcome was VTE (at any site) or ATE (stroke or myocardial infarction) 6 months prior to the diagnosis of cancer, until 5 years post-diagnosis. The cumulative incidence of VTE and ATE and hazard-ratios (HR) with 95% CIs were calculated (at 6- 12- 24 and 60-months), using death as a competing risk. Cox proportional hazards multivariate regression was performed, with the Fine and Gray correction for competing risks. The study included 4762 patients, of which 155 (3.2%) were ALK-positive. The overall 5-year VTE incidence was 15.7% (95% CI, 14.7-16.6%). ALK-positive patients had a higher VTE risk compared to ALK-negative patients (HR 1.87 [95% CI, 1.31-2.68]) and a 12-month VTE incidence of 17.7% (13.9-22.7%) compared to 9.9% (9.1-10.9%) in ALK-negative patients. The overall 5-year ATE incidence was 7.6% [6.8-8.6%]. ALK positivity was not associated with ATE incidence (HR 1.24 [0.62-2.47]). In this study, we observed a higher VTE risk, but not ATE risk, in patients with ALK-rearranged NSCLC relative to those without ALK rearrangement. Prospective studies are warranted to evaluate thromboprophylaxis in ALK-positive NSCLC.

Clinical characteristics and targeted therapy of different gene fusions in non-small cell lung cancer: a narrative review.

Lung cancer is the most fatal malignant tumor in the world. Since the discovery of driver genes, targeted therapy has been demonstrated to be superior to traditional chemotherapy and has revolutionized the therapeutic landscape of non-small cell lung cancer (NSCLC). The remarkable success of tyrosine kinase inhibitors (TKIs) in patients with epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) fusions has shifted the treatment from platinum-based combination chemotherapy to targeted therapy. Although the incidence rate of gene fusion is low in NSCLC, it is of great significance in advanced refractory patients. However, the clinical characteristics and the latest treatment progress of patients with gene fusions in lung cancer have not been thoroughly explored. The objective of this narrative review was to summarize the latest research progress of targeted therapy for gene fusion variants in NSCLC to improve understanding for clinicians. We conducted a search of PubMed database and American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), and World Conference on Lung Cancer (WCLC) abstracts meeting proceedings from 1 January 2005 to 31 August 2022 with the following keywords "non-small cell lung cancer", "fusion", "rearrangement", "targeted therapy" and "tyrosine kinase inhibitor". We comprehensively listed the targeted therapy of various gene fusions in NSCLC. Fusions of ALK, ROS proto-oncogene 1 (ROS1), and rearranged during transfection proto-oncogene (RET) are relatively more common than others (NTRK fusions, NRG1 fusions, FGFR fusions, etc.). Among ALK-rearranged NSCLC patients treated with crizotinib, alectinib, brigatinib, or ensartinib, the Asian population exhibited a slightly better effect than the non-Asian population in first-line therapy. It was revealed that ceritinib may have a slightly better effect in the non-Asian ALK-rearranged population as first-line therapy. The effect of crizotinib might be similar in Asians and non-Asians with ROS1-fusion-positive NSCLC in first-line therapy. The non-Asian population were shown to be more likely to be treated with selpercatinib and pralsetinib for RET-rearranged NSCLC than the Asian population. The present report summarizes the current state of fusion gene research and the associated therapeutic methods to improve understanding for clinicians, but how to better overcome drug resistance remains a problem that needs to be explored.

Tumor Volume Nadir in Patients With ALK-Rearranged Non–Small-Cell Lung Cancer Treated With Alectinib

Patients with oncogene-driven advanced non-small-cell lung cancer (NSCLC) treated with effective targeted therapy demonstrate characteristic tumor volume dynamics with initial response, nadir, and subsequent regrowth. This study investigated tumor volume nadir and time to nadir in patients with ALK-rearranged advanced NSCLC treated with alectinib. In patients with advanced ALK-rearranged NSCLC treated with alectinib monotherapy, tumor volume dynamics were evaluated on serial computed tomography (CT) scans using a previously validated CT tumor measurement technique. A linear regression model was built to predict tumor volume nadir. Time-to-event analyses were performed to evaluate time to nadir. Among 45 patients who experienced initial volume decrease, 37 patients (25 with tumor regrowth and 12 without regrowth but >6 months follow-up) were studied for nadir volume (Vp). The linear model to predict tumor volume nadir was built using the baseline tumor volume (V0): V0-Vp = .696 × V0 + 5,326 (P < 2 × 10-16; adjusted R2 = 0.86). The percent volume changes at nadir (median, -90.9%, mean, -85.3%) showed larger decrease in patients who were treated with alectinib as first-line therapy than in the ≥2nd-line group and were independent of V0 and clinical variables. Time to nadir had a median of 11.5 months and was longer in the first-line group (P = .04). The tumor nadir volume in patients with ALK-rearranged advanced NSCLC treated with alectinib can be predicted by the liner regression model and consists of approximately 30% of the baseline volume minus 5 cm3, providing additional insights into precision therapy monitoring and potential guides for local ablative therapy to prolong disease control.

Adaptive resistance to lorlatinib via EGFR signaling in ALK-rearranged lung cancer

Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors rarely elicit complete responses in patients with advanced ALK-rearranged non-small cell lung cancer (NSCLC), as a small population of tumor cells survives due to adaptive resistance. Therefore, we focused on the mechanisms underlying adaptive resistance to lorlatinib and therapeutic strategies required to overcome them. We found that epidermal growth factor receptor (EGFR) signaling was involved in the adaptive resistance to lorlatinib in ALK-rearranged NSCLC, activation of which was induced by heparin-binding EGF-like growth factor production via c-Jun activation. EGFR inhibition halted ALK-rearranged lung cancer cell proliferation by enhancing ALK inhibition-induced apoptosis via suppression of Bcl-xL. Xenograft models showed that the combination of EGFR inhibitor and lorlatinib considerably suppressed tumor regrowth following cessation of these treatments. This study provides new insights regarding tumor evolution due to EGFR signaling after lorlatinib treatment and the development of combined therapeutic strategies for ALK-rearranged lung cancer.

PI3Kβ inhibition enhances ALK-inhibitor sensitivity in ALK-rearranged lung cancer.

Treatment with anaplastic lymphoma kinase (ALK) inhibitors significantly improves outcome for non-small-cell lung cancer (NSCLC) patients with ALK-rearranged tumors. However, clinical resistance typically develops over time and, in the majority of cases, resistance mechanisms are ALK-independent. We generated tumor cell cultures from multiple regions of an ALK-rearranged clinical tumor specimen and deployed functional drug screens to identify modulators of ALK-inhibitor response. This identified a role for PI3Kβ and EGFR inhibition in sensitizing the response regulating resistance to ALK inhibition. Inhibition of ALK elicited activation of EGFR, and subsequent MAPK and PI3K-AKT pathway reactivation. Sensitivity to ALK targeting was enhanced by inhibition or knockdown of PI3Kβ. In ALK-rearranged primary cultures, the combined inhibition of ALK and PI3Kβ prevented the EGFR-mediated ALK-inhibitor resistance, and selectively targeted the cancer cells. The combinatorial effect was seen also in the background of TP53 mutations and in epithelial-to-mesenchymal transformed cells. In conclusion, combinatorial ALK- and PI3Kβ-inhibitor treatment carries promise as a treatment for ALK-rearranged NSCLC.

Acquired L1196M ALK mutation in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma during alectinib administration.

Acquired L1196M ALK mutation in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma during alectinib administration.

Initial clinical experience with magnetic resonance-guided radiotherapy in pediatric patients: Lessons learned from a single institution with proton therapy.

Magnetic resonance-guided radiotherapy (MRgRT) is increasingly used in a variety of adult cancers. To date, published experience regarding the use of MRgRT in pediatric patients is limited to two case reports. We report on the use of MRgRT for pediatric patients at our institution during a four-year period and describe important considerations in the selection and application of this technology in children. All patients treated with MRgRT since inception at our institution between 4/2018 and 4/2022 were retrospectively reviewed. We also evaluated all pediatric patients treated at our institution during the same period who received either imaging or treatment using our magnetic resonance-guided linear accelerator (MR Linac). We summarize four clinical cases where MRgRT was selected for treatment in our clinic, including disease outcomes and toxicities and describe our experience using the MR Linac for imaging before and during treatment for image fusion and tumor assessments. Between 4/2018 and 4/2022, 535 patients received MRgRT at our center, including 405 (75.7%) with stereotactic ablative radiotherapy (SABR). During this period, 347 distinct radiotherapy courses were delivered to pediatric patients, including 217 (62.5%) with proton therapy. Four pediatric patients received MRgRT. One received SABR for lung metastasis with daily adaptive replanning and a second was treated for liver metastasis using a non-adaptive workflow. Two patients received fractionated MRgRT for an ALK-rearranged non-small cell lung cancer and neuroblastoma. No Grade 2 or higher toxicities were observed or reported during MRgRT or subsequent follow-up. Twelve patients underwent MR imaging without contrast during treatment for brain tumors to assess for tumor/cystic changes. Two patients treated with other modalities underwent MR simulation for target volume delineation and organ at risk sparing due to anatomic changes during treatment or unexpected delays in obtaining diagnostic MR appointments. In four pediatric patients treated with MRgRT, treatment was well tolerated with no severe acute effects. At our center, most pediatric patients are treated with proton therapy, but the cases selected for MRgRT demonstrated significant organ at risk sparing compared to alternative modalities. In particular, MRgRT may provide advantages for thoracic/abdominal/pelvic targets using gated delivery and adaptive replanning, but selected patients treated with fractionated radiotherapy may also benefit MRgRT through superior organ at risk sparing.