ALK-positive NSCLC Patients Research Articles

New findings on the incidence and management of CNS adverse reactions in ALK-positive NSCLC with lorlatinib treatment

To explore the presentation and control of CNS adverse reactions in patients with ALK-positive NSCLC treated with lorlatinib. This study includes a retrospective case report from Sir Run Run Shaw Hospital on a lorlatinib-treated patient with CNS adverse reactions and a systematic literature review of similar cases until January 2023. The report detailed a case of a 74-year-old male with Grade III CNS adverse reactions 25 days after starting lorlatinib, which were reversible with dose modification and pharmacotherapy. The review indicated a 19.39% occurrence rate of such reactions, with a 17% improvement rate post-dose adjustment. CNS adverse reactions frequently occur in ALK-positive NSCLC patients on lorlatinib, yet they are reversible with appropriate management. Research should continue to optimize treatment protocols to decrease these reactions' frequency.

Superparamagnetic Iron Oxide Nanoparticles Reprogram the Tumor Microenvironment and Reduce Lung Cancer Regrowth after Crizotinib Treatment.

ALK-positive NSCLC patients demonstrate initial responses to ALK tyrosine kinase inhibitor (TKI) treatments, but eventually develop resistance, causing rapid tumor relapse and poor survival rates. Growing evidence suggests that the combination of drug and immune therapies greatly improves patient survival; however, due to the low immunogenicity of the tumors, ALK-positive patients do not respond to currently available immunotherapies. Tumor-associated macrophages (TAMs) play a crucial role in facilitating lung cancer growth by suppressing tumoricidal immune activation and absorbing chemotherapeutics. However, they can also be programmed toward a pro-inflammatory tumor suppressive phenotype, which represents a highly active area of therapy development. Iron loading of TAMs can achieve such reprogramming correlating with an improved prognosis in lung cancer patients. We previously showed that superparamagnetic iron oxide nanoparticles containing core-cross-linked polymer micelles (SPION-CCPMs) target macrophages and stimulate pro-inflammatory activation. Here, we show that SPION-CCPMs stimulate TAMs to secrete reactive nitrogen species and cytokines that exert tumoricidal activity. We further show that SPION-CCPMs reshape the immunosuppressive Eml4-Alk lung tumor microenvironment (TME) toward a cytotoxic profile hallmarked by the recruitment of CD8+ T cells, suggesting a multifactorial benefit of SPION-CCPM application. When intratracheally instilled into lung cancer-bearing mice, SPION-CCPMs delay tumor growth and, after first line therapy with a TKI, halt the regrowth of relapsing tumors. These findings identify SPIONs-CCPMs as an adjuvant therapy, which remodels the TME, resulting in a delay in the appearance of resistant tumors.

Abstract 7504: Longitudinal multi-omics characterization of circulating tumor cells from ALK positive NSCLC patients

Abstract Introduction: Anaplastic lymphoma kinase positive non-small cell lung cancer (ALK+NSCLC) represents a distinct subtype of NSCLC characterized by oncogenic ALK gene mutations leading to ALK overexpression and activation in tumor cells. ALK+ NSCLC will frequently develop mutations during treatment, leading to nonresponse and eventually cancer relapse. Therefore, there is a critical need for sensitive technologies to monitor ALK+ NSCLC disease status in patients over time. To facilitate longitudinal monitoring, there has been a rapid evolution in diagnostic technologies leveraging circulating tumor cells (CTCs) as a liquid biopsy tool. CTCs can be collected non-invasively at various intervals throughout patient treatment. Moreover, they shed from solid tumors and disseminate into the bloodstream, which makes isolating CTCs a valuable source of genomic, transcriptomic, and proteomic insights pertaining to the primary tumor. In this study, we present a comprehensive workflow for conducting multi-omic analysis on CTCs derived from ALK+ NSCLC patients. Methods: Blood samples were collected from a cohort of ALK+ NSCLC patients, and CTCs were isolated using a high throughput, label free microfluidic device, Labyrinth. Enriched CTCs were immunofluorescently stained for cytokeratin, CD45, DAPI, epithelial cell adhesion molecule (EpCAM), and vimentin markers. Heterogeneous CTC populations with hybrid epithelial/mesenchymal (EM) phenotypes are reported. Fluorescence in situ hybridization (FISH) was performed on enriched CTC samples. DNA was extracted and sequenced using a 523 gene targeted sequencing panel. Single cell RNA-seq technology was performed in parallel on CTC samples to investigate the gene expression throughout treatment. Results: The median concentration of CTCs in the ALK+ NSCLC cohort (n=33) is 137 CTCs per ml of blood, and 64% of CTCs are in an EM hybrid state. In ALK+ NSCLC patients (n=3) with an average of 4.6 visits per sample, we observed a trend of decreasing CTC concentration for patients with partial response to the treatment. The presence of ALK fusion in ALK+ NSCLC patient’s CTC is confirmed by FISH. Oncogenic mutations (JAK1, SPEN, ERBB4, NTRK3) are observed in bulk CTC samples from two NSCLC patients. Single cell RNA sequencing was performed on three ALK+ NSCLC patients; 58, 199, and 700 potential CTCs were detected with positive cytokeratin expression and no white blood cell marker expression. Conclusions: This study examined the feasibility of using CTCs for studying and monitoring the clinical status of the ALK+ NSCLC patients as well as the genomic and transcriptomic signatures within their tumors. More patients will need to be processed in order to validate our workflow and reinforce our conclusions. Citation Format: Yuru Chen, Shamileh Fouladdel, Harrison Ball, Zhaoping Qin, Albert Liu, Xu Cheng, Liwei Bao, Habib Serhan, Bryce Vandenburg, Varun Kathawate, Larua Goo, Peter Ulintz, Nathan Merrill, Aaron Udager, Angel Qin, Sofia D. Merajver, Sunitha Nagrath. Longitudinal multi-omics characterization of circulating tumor cells from ALK positive NSCLC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7504.

Management strategies for intracranial progression in ALK-positive non-small cell lung cancer: a real-world cohort study.

ALK-positive NSCLC patients exhibit a particularly high propensity for the development of brain metastases. Current guidelines suggest transit to next-line therapy (SysTx) or local radiotherapy (RadTx) including whole-brain radiotherapy and radiosurgery. However, the clinical impact of these two strategies remains unclear. We conducted a retrospective analysis focusing on patients with stage IV ALK-positive NSCLC who underwent first-line ALK TKI treatment. Patients with intracranial progression may receive two different treatment strategies: SysTx and RadTx. Our objective was to investigate the outcomes associated with these two distinct treatment pathways. A total 20 patients of ALK-positive NSCLC who received first-line ALK TKI therapy and subsequently developed intracranial progression were enrolled. About 55% of patients had brain metastasis initially. Nine patients (45%) were treated with crizotinib at first. Patients treated with crizotinib demonstrated a significantly shorter intracranial PFS1 (crizotinib: 8.27 months vs. others: 27.0 months, p = 0.006). Following intracranial progression, approximately 60% of patients transitioned to the next line of systemic treatment (SysTx), while the remaining 40% opted for local cranial radiotherapy (RadTx). Intriguingly, our analysis revealed no statistically significant difference in intracranial progression-free survival (PFS2) between these two distinct treatment strategies. (SysTx: 20.87 months vs. RadTx: 28.23 months, p = 0.461). The intracranial progression-free survival showed no difference between the two strategies suggesting that both local radiotherapy and systemic therapy may be valid options. Individualized strategy, molecular analysis, and multidisciplinary conferences may all play a pivotal role in decision-making.

A retrospective study of ensartinib-treated ALK-positive locally advanced or metastatic NSCLC patients in China.

This retrospective study aimed to assess the efficacy and safety of ensartinib in Chinese patients with ALK-positive advanced NSCLCin real-world clinical practice. Clinical data from ALK-positive NSCLC patients treated with ensartinib in China were collected and analyzed. Efficacy end points included objective response rate and progression-free survival. Safety profiles were also evaluated. A total of 682 patients were included in this study. The study demonstrated promising efficacy with an objective response rate of 54.0%, and the median progression-free survival was not estimable. Ensartinib exhibited a manageable safety profile with treatment-related adverse events (TRAEs) consistent with prior clinical trials. The most common TRAE was rash (21.1%) and no TRAE led to death. Ensartinib is active and well tolerated for ALK-positive NSCLC patients in real-world clinical settings.

P2.10-07 ORA-LM: Molecular Analysis in Cerebrospinal Fluid of ALK or EGFR Positive NSCLC Patients with Leptomeningeal Metastases

P2.10-07 ORA-LM: Molecular Analysis in Cerebrospinal Fluid of ALK or EGFR Positive NSCLC Patients with Leptomeningeal Metastases

1509TiP The 1825-EORTC, ALKALINE: Activity of lorlatinib based on ALK resistance mutations on blood in ALK positive NSCLC patients previously treated with second generation ALK inhibitor

1509TiP The 1825-EORTC, ALKALINE: Activity of lorlatinib based on ALK resistance mutations on blood in ALK positive NSCLC patients previously treated with second generation ALK inhibitor

Survival outcomes in ALK-positive NSCLC patients (p) treated 1st line brigatinib and impact of the ALK fusion variant.

e21015 Background: There is limited data on brigatinib (a next-generation anaplastic lymphoma kinase (ALK) inhibitor) efficacy according to the ALK fusion variant. Here we investigate the prevalence of ALK fusion variants and evaluate treatment outcomes in ALK-positive NSCLC treated with first-line brigatinib. Methods: This is an open-label, non-randomized, phase II, exploratory, multi-center clinical trial. Stage IV, ALK-positive NSCLC p were treated with brigatinib 90mg for the first 7 days (D 1-7 at cycle 1) and then 180 mg daily thereafter for QW4 cycles of duration (28 days ±3days). Brigatinib was administered until loss of clinical benefit, unacceptable toxicity, p or physician decision to discontinue, or death. Response to treatment was evaluated as per RECIST v1.1. ALK rearrangement was identified locally by immunohistochemistry and confirmed by fluorescence in situ hybridization. In addition, baseline tissue samples were analyzed by NGS using the Oncomine™ Focus Assay in a centralized laboratory. Results: Between May 2020 and October 2021, 33 p were enrolled from eight different institutions. One p was considered not valid because there no tissue or plasma sample was available at baseline. Therefore, 32 p were finally considered for the study. Baseline characteristics were as follows: median age (range): 53 (35-86) years; female, n = 15 (47%); ECOG PS of 0 n = 6 (19%), 1 n = 23 (72%), 2 n = 3 (9%); never smoker, n = 14 (44%). All tumors were adenocarcinoma. The average number of metastases per p was four. In total, seven (22%) p had brain metastases. A sample was valid for NGS analysis in 29 cases. ALK fusion partners were EML4 in 28 cases (97%) and HIP1 in one case (3%). The ALK fusion variant 1 was the most frequently detected (n = 13, 45%), followed by variant 3 (n = 9; 31%), and variant 2 (n = 4; 14%). The EML4(6)-ALK(19) variant was detected in 2 cases, and variant 8 was detected in one case. The median follow-up time was 18 months. During the study, 13 deaths were recorded, and progressive disease (PD) was observed in 15 p. With a data maturity of 87%, median progression-free survival (PFS) was 16.7 months (95%CI 6.2-NR), and median overall survival (OS) was NR (95%CI 12.4-NR). There were no significant differences in survival outcomes according to the type of variant. The same was true when grouping long (variants 1,2 and 8) and short (variant 3, EML4(6) - ALK(19)) variants. The p whose tumor harbored the HIP1(21)-ALK(20) variant was alive and with and in partial response at the time of data cutoff. On the other hand, a patient whose tumor harbored the short variant EML4(6) - ALK(19) along with the KRAS G12C mutation was diagnosed with disease progression after three months of treatment initiation and deceased after eight months from the start of treatment. Conclusions: In this interim analysis we were unable to demonstrate a significant difference in survival outcomes according to variant type. Clinical trial information: NCT04223596 .

320MO Envonalkib vs crizotinib in treatment-naïve advanced ALK-positive NSCLC: A randomized, multicenter, phase III trial

Envonalkib (TQ-B3139, Env) is a novel small molecule ALK/ROS1/c-Met inhibitor. Here, we presented the primary analysis results of a phase III trial, aiming to evaluate the efficacy and safety of Env versus crizotinib (Cri) in advanced ALK-positive NSCLC patients (pts) who had not received a prior ALK inhibitor.

Real-World Treatment Sequencing, Toxicities, Health Utilities, and Survival Outcomes in Patients with Advanced ALK-Rearranged Non-Small-Cell Lung Cancer

ObjectivesThis real-world analysis describes treatment patterns, sequencing and clinical effectiveness, toxicities, and health utility outcomes in advanced-stage, incurable ALK-positive NSCLC patients across five different ALK-TKIs. Materials and MethodsClinicodemographic, treatment, and toxicity data were collected retrospectively in patients with advanced-stage ALK-positive NSCLC at Princess Margaret Cancer Centre. Patient-reported symptoms, toxicities, and health utilities were collected prospectively. ResultsOf 148 ALK-positive NSCLC patients seen July 2009-May 2021, median age was 58.9 years; 84 (57%) were female; 112 (76%) never-smokers; 54 (47%) Asian and 40 (35%) white; 139 (94%) received at least one ALK-TKI: crizotinib (n = 74; 54%) and alectinib (n = 61; 44%) were administered mainly as first-line ALK-TKI, ceritinib, brigatinib and lorlatinib were administered primarily after previous ALK-TKI failure. Median overall survival (OS) was 54.0 months; 31 (21%) patients died within two years of advanced-stage diagnosis. Treatment modifications were observed in 35 (47%) patients with crizotinib, 19 (61%) with ceritinib, 41 (39%) with alectinib, 9 (41%) with brigatinib and 8 (30%) with lorlatinib. Prevalence of dose modifications and self-reported toxicities were higher with early versus later generation ALK-TKIs (P<.05). The presence of early treatment modification was not negatively associated with progression-free survival (PFS) and OS analyses. ConclusionSerial ALK-TKI sequencing approaches are viable therapeutic options that can extend quality of life and quantity-of-life, though a fifth of patients died within two years. No best single sequencing approach could be determined. Clinically relevant toxicities occurred across all ALK-TKIs. Treatment modifications due to toxicity may not necessarily compromise outcomes, allowing multiple approaches to deal with ALK-TKI toxicities.

First-in-human phase I study of TQ-B3139 (CT-711) in advanced non-small cell lung cancer patients with ALK and ROS1 rearrangements

BackgroundTQ-B3139 is a novel ALK tyrosine kinase inhibitor (TKI) against a broad range of ALK mutations. The aim of this first-in-human phase I trial was to investigate the safety, tolerability, pharmacokinetics, and clinical efficacy of TQ-B3139 in ALK or ROS1 positive advanced NSCLC patients. MethodsFollowing a 3 + 3 design, patients received escalating daily dose of TQ-B3139 (50–800 mg) continuously in 28-day cycles. Expansion stage started at dose of 200 mg twice daily (BID). The primary objectives were the safety, dose-limited toxicities (DLT) and recommended phase II dose (RP2D); secondary objectives included pharmacokinetics and antitumor activity. Non-obligatory tumor samples at baseline were collected and sequenced. ResultsThe study enrolled 63 patients. Fifty-nine (93.4%) patients experienced treatment-related adverse events (TRAEs), mostly grade 1–2 vomiting (79.3%), diarrhea (76.1%) or nausea (68.2%). 1 (1/6) DLT occurred at 600 mg BID and 1 (1/3) at 800 mg BID. Based on safety and pharmacokinetics data, the RP2D was selected as 600 mg BID. At a dose level ≥200 mg BID, the overall response rate (ORR) was 76.7% (33/43), and the median progression free survival (mPFS) was 25.2 months (95%CI 11.9-NR) for TKI-naive patients. For TKI-treated patients, the ORR was 37.5% (6/16), and the mPFS was 5.4 months (95%CI 3.6–9.1). The ORR was 66.7% (2/3) in patients with ROS1 fusion at dose level ≥200 mg BID. In patients with measurable brain metastases, the intracranial ORR was 70% (7/10), with median intracranial PFS of 15.9 months. In TKI-treated patients, variant 3 and TP53 alteration were associated with poor PFS. ConclusionsTQ-B3139 was well-tolerated and exhibited promising anti-tumor activities in patients with ALK and ROS1 positive advanced NSCLC. Clinical trial numberNCT03099330.

A phase II randomized, open-labelled, multicenter study of safety and efficacy of combination brigatinib and carboplatin-pemetrexed therapy or brigatinib monotherapy as first-line treatment in patients with advanced ALK-positive non–small cell lung cancer (IFCT-2101 MASTERPROTOCOL ALK).

TPS9144 Background: Second generation ALK tyrosine kinase inhibitors (ALK-TKI), including brigatinib, provide substantial therapeutic benefit in first-line treatment of ALK-positive NSCLC patients (pts) but relapse eventually occurs in all pts due to development of drug resistance, possibly caused by emergence of drug-tolerant cells (DTC). Combining chemotherapy to TKI may prevent DTC emergence in preclinical studies, and results in prolonged progression-free survival (PFS) and overall survival in EGFR-mutant NSCLC. We hypothesize that combination of second generation ALK-TKI with chemotherapy will improve clinical outcomes in advanced ALK-positive NSCLC patients. The IFCT-2101 MASTERPROTOCOL ALK trial will evaluate the efficacy and safety of brigatinib and carboplatin-pemetrexed combination in treatment-naïve metastatic ALK-positive NSCLC. Methods: The IFCT-2101 MASTERPROTOCOL ALK randomized, open-label phase II trial will enrol 110 pts in 30 French centers over 24 months. Eligible pts will have metastatic NSCLC with ALK-fusion according to local testing, be untreated for advanced disease, and have an ECOG Performance Status (PS) of 0-1 and at least one measurable lesion per RECIST 1.1. Pts with asymptomatic and stable brain metastases (BM) will be eligible. Exclusion criteria include leptomeningeal metastases. Patients will be randomized 1:1 to receive brigatinib monotherapy (Arm A) or combination brigatinib and carboplatin-pemetrexed therapy (Arm B), with PS (0 vs 1) and BM (presence vs absence) as stratification factors. Brigatinib will be administered at a dose of 90 mg QD for a 7-day lead-in period followed by 180 mg QD continuously, in 28-day cycles. In Arm B, 4 cycles of carboplatin (AUC 5) and pemetrexed (500 mg/m2) therapy every 3 weeks will be added at Day 8 of brigatinib treatment. Treatment will continue until progression, intolerable toxicity or discontinuation. The first 26 pts enrolled in Arm B will represent the population of a safety phase, during which adverse events (AE) will be closely monitored by an independent data monitoring committee. The primary endpoint is investigator-assessed 12-month PFS rate. Secondary endpoints include independently-reviewed 12-month PFS rate, overall response rate (ORR), 12-month intracranial PFS and ORR, incidence, nature and severity of AEs, and impact of ALK-fusion detection, co-mutations and clearance of circulating tumor (ct) DNA (Guardant360) on outcome. Exploratory objectives include the evaluation of early blood ctDNA decrease on patient outcome. The study is enrolling and primary completion date is March 2025. Clinical trial information: NCT05200481.

A Systematic Review of Companion Diagnostic Tests by Immunohistochemistry for the Screening of Alectinib-Treated Patients in ALK-Positive Non-Small Cell Lung Cancer.

Companion diagnostic tests and targeted therapy changed the management of non-small cell lung cancer by diagnosing genetic modifications and enabling individualized treatment. The purpose of this systematic review is to assess the clinical applicability of companion diagnostic tests (IHC method) by comparing the effects of alectinib and crizotinib in patients with ALK-positive NSCLC. We searched for literature up to March 2022 in PubMed, Web of Science, Cochrane, and Google Scholar. The inclusion criteria were randomized controlled trials comparing the effectiveness of alectinib and crizotinib using an IHC-based companion diagnostic test. The primary outcome was progression-free survival (PFS). The secondary outcomes were objective response rate (ORR), duration of response (DOR), and overall survival (OS). PFS was longer in alectinib (68.4 [61.0, 75.9]) than crizotinib (48.7 [40.4, 56.9]). This indicated that alectinib had a superior efficacy to that of crizotinib (HR range 0.15–0.47). In all secondary outcomes, alectinib was better than crizotinib. Particularly for the ORR, the odds ratio (OR) confirmed that alectinib had a lower risk rate (OR: 2.21, [1.46–3.36], p = 0.0002, I2 = 39%). Therefore, the companion diagnostic test (immunohistochemistry) is an effective test to determine whether to administer alectinib to ALK-positive NSCLC patients.

94 - Real-world-outcomes for ALK positive advanced NSCLC patients treated in South Yorkshire

94 - Real-world-outcomes for ALK positive advanced NSCLC patients treated in South Yorkshire

154P Intracranial efficacy of alectinib in ALK-positive NSCLC patients with CNS metastases: A multicenter retrospective study

Background: CNS metastases in patients with ALK-positive NSCLC are a cause of substantial morbidity and mortality. Alectinib had demonstrated promising intracranial efficacy in several prospective clinical trials. But there was limited data on intracranial response of Alectinib in real world setting.

P84.01 The ARIA Study: Activity of Next-Generation ALK TKIs Based on ALK Resistance Mutations Detected by Liquid Biopsy in ALK Positive NSCLC Patients.

P84.01 The ARIA Study: Activity of Next-Generation ALK TKIs Based on ALK Resistance Mutations Detected by Liquid Biopsy in ALK Positive NSCLC Patients.

FP14.12 Quality of Life and Subgroup Analysis in a Phase 3 Randomized Study of Ensartinib vs Crizotinib in ALK–Positive NSCLC Patients: eXalt3.

Ensartinib (X-396) is a novel second-generation ALK tyrosine kinase inhibitor (TKI). In a phase 3 study interim analysis, ensartinib showed statistically significant improvement of median PFS over crizotinib in patients with ALK+ NSCLC who were ALK TKI naive or received up to one prior chemotherapy line, including higher efficacy against brain metastases. Ensartinib was well tolerated, with low grade rash, pruritus, edema, and transaminitis as the most frequent treatment-related AEs. Here we plan to present subgroups analyses and the quality of life outputs of the phase 3 eXalt3 study (NCT02767804). Patients with locally tested ALK+ NSCLC (ITT population) were randomized 1:1 to ensartinib (225 mg QD orally) or crizotinib (250 mg BID orally). No crossover was allowed. Patients were stratified by prior chemotherapy, ECOG PS, brain metastases, and geographic region. The modified ITT (mITT) population was prespecified to include all centrally ALK+ patients by Abbott FISH test. The primary endpoint was blinded independent review committee (BIRC)–assessed progression-free survival (PFS; RECIST v.1.1). Secondary endpoints included overall survival (OS), overall response rate (ORR), and time to treatment failure (TTF) in the brain and patients reported outcomes (PRO). PRO data collection included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (QLQ-C30). A linear mixed model for repeated measures was used to analyze change from baseline in the Global Health Status/Quality of Life subscale (GHS/QOL), with a change of greater than or equal to ten points deemed meaningful. Time to symptom deterioration will be presented. In total, 290 patients were randomized (ensartinib [n=143]; crizotinib [n=147]).Median age was 54.1 y, 26% of patients had prior chemotherapy, and 36% of patients had baseline CNS metastases (5% had prior brain radiotherapy). The mITT population included 247 patients (ensartinib [n=121]; crizotinib [n=126]). At the July 1, 2020, data cutoff, 139 BIRC-assessed PFS events (73%) occurred in the ITT population and 119 (63%) in the mITT population. Median PFS was 25.8 months with ensartinib vs 12.7 months with crizotinib (HR, 0.52; P=.0003 by log-rank test) with a median follow-up of 23.8 and 20.2 months in the ITT population. Median PFS was not reached with ensartinib vs 12.7 months with crizotinib in the mITT population (HR, 0.48; P=.0002 by log-rank test). New subgroup analyses in mITT for ensartinib showed a trend for higher efficacy by prior chemotherapy vs no chemotherapy (mPFS NR vs 25.8). Both global health status (GHS) as well as 5 functional and 9 symptom domains within EORTC QLQ-C30 had clinical meaningful improvement over time for ensartinib. Ensartinib delays the time to worsening of GHS with HR =0.83 (95% CI [0.57, 1.20]) vs crizotinib. Complete subgroup analyses (forest plot and multivariate analyisis) will be presented at the conference as well as OS updates. Comprehenive EORTC QLQ-C30 and Lung Cancer Symptom Scale scores will also be reported at the conference. In ALK+ NSCLC patients ensartinib represents a new option in first-line setting. QOLs data support its favorable safety profile. Relevant subgroups analyses to evaluate its clinical impact will be presented at the meeting.

Impact of STAT1 polymorphisms on crizotinib-induced hepatotoxicity in ALK-positive non-small cell lung cancer patients.

Crizotinib is the first-line small molecule tyrosine kinase inhibitor for ALK-positive non-small cell lung cancer. In this study, a retrospective pharmacogenomics investigation was conducted to explore the relationship between genes related to RTK downstream signaling pathways and crizotinib-induced hepatic toxicity in ALK-positive NSCLC patients. The variable importance analysis of random forest algorithm was applied to identify the significant features which contribute to the crizotinib sensitivity in Cancer Cell Line Encyclopedia (CCLE) database. The KEGG and reactome pathway enrichment analysis were conducted with EnrichR. The differential expression genes were identified with R package DESeq2 in CCLE liver derived cell lines between crizotinib sensitive and resistant groups. From 2012 to 2015, 42 NSCLC patients were enrolled in this study. 90 polymorphisms were genotyped using the Sequenom Massarray system. Sequencing of HGFR (c-Met) genes was carried out on the Ion Torrent Proton. In total, 66.7% NSCLC patients suffered from crizotinib-induced liver toxicity and 11.9% progressed to severe hepatic toxicity. The features with the top importance from classification and regression random forest model were enriched in RTK downstream signaling pathways (JAK/STAT, RAS/RAF/MAPK, PI3K/AKT pathways) and immune system-related pathways. Collagen family genes (COL1A1, COL1A2, COL6A1, COL5A1) and other extracellular matrix protein (TNC, TAGLN, TENM2, EDIL3, VCAN, CNN1, SH3BP4, TAGLN), which were closely related to MAPK-ERK signaling pathways, were significantly enriched in crizotinib resistant cell lines. In multiple logistic regression, STAT1 rs10208033 (T > C) was significantly associated with crizotinib-induced liver toxicity (OR = 6.733, 95% CI 1.406-32.24, P = 0.017). Compared with non-CC, OR is 5.5 (95% CI 1.219-24.81, P = 0.027) for STAT1 rs10208033 CC genotypeto develop crizotinib-induced liver toxicity. Further cell viability test in human fetal hepatocyte line, L-02, reveals that the STAT1 inhibitor might protect hepatocyte cells from the toxicity caused by crizotinib. Polymorphism of rs10208033 is a potential biomarker for predicting crizotinib-induced hepatotoxicity. These results suggest that STAT1 plays an important role in crizotinib-induced hepatotoxicity. Further studies are needed to confirm our finding and understand the underlying mechanisms.

ALK variants, PD-L1 expression, and their association with outcomes in ALK-positive NSCLC patients

It remains unclear how programmed death-ligand 1 (PD-L1) expression interacts with anaplastic lymphoma kinase (ALK) mutation, its variants, and the outcome of treatment. One hundred and twenty four out of 1255 patients (9.9%) were deemed ALK-positive by the Ventana IHC assay. PD-L1 status and ALK variants were available in 100 and 59 patients, respectively. PD-L1 positive (TPS ≥ 1%) and strong positive (TPS ≥ 50%) rate was 50% and 16%, respectively. A total of 64 variant types were detected in 59 patients. V1 (32.8%) and V3a/b (28.1%) were the most common variants. There was no significant association between ALK variants and the PD-L1 expression. The presence of V3a/b subtype independently predicted a worse overall survival in patients receiving ALK inhibitor(s) (aHR 5.10 [95% CI 1.22–21.25], P = 0.025) and platinum plus pemetrexed (aHR 9.62 [95% CI 1.90–48.80], P = 0.006). While incorporating ALK variants and PD-L1 expression together, patients with non-V3a/b/positive PD-L1 showed a trend towards longer OS. In conclusion, ALK-positive NSCLC patients possess a high PD-L1 expression rate. Although there was no significant association between PD-L1 expression and ALK variants, the outcome of ALK-positive patients could be sorted by these two biomarkers.

Abstract 579: Ensartinib (X-396), a novel ALK TKI, in Chinese ALK-positive non-small cell lung cancer: A phase I, dose-escalation and expansion study

Abstract Background: Ensartinib (X-396) is a novel ALK inhibitor with high activity against a broad range of crizotinib-resistant ALK mutations (such as G1269A, F1174, C1156Y, and T1151) and CNS metastases. This Phase I study (NCT02959619) determined the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D), investigated the safety and PK, and explored the clinical efficiency for the compound as monotherapy in Chinese ALK+ NSCLC patients. Methods: Patients with advanced ALK+ NSCLC were treated with oral ensartinib (150, 200, 225, or 250 mg once daily) using a conventional 3+3 dose escalation design. The dose-escalation evaluated patients in 28-day cycles. In the dose-expansion phase, ensartinib was given at the recommended dose to further explore PK and clinical efficacy. Treatment was continued until disease progression, or unacceptable toxicity. Results: Between March, 2017 and August, 2018, 48 patients were enrolled. 43 patients were locally detected ALK positive by FISH or IHC (VANTANA), 5 patients harbored with ROS1 fusion. In 43 ALK positive patients, 32 patients were ALK TKI-naïve while 11 patients progressed on prior molecular targeted therapy (including 10 crizotinib-treatment and 2 ceritinib- or alectinib-treatment). Two DLTs were observed in the 250 mg dose cohort (grade 3 rash). All patients experienced at least one treatment-related adverse event, in which 19 (39.6%) had grade 3 or higher events with skin rash (16.7%) as the most common one. Ensartinib was moderately absorbed (median time to max concentration: 3.00-4.00 h) and slowly eliminated (mean half-life: 21.0-30.2 h). In multiple dose administration, a steady-state concentration of ensartinib was reached after 8-15 days. The geometric mean AUC0-tau and Cmax of ensartinib at 225 mg were 6950 h*ng/mL and 435 ng/mL, respectively. The ratio of drug concentration in cerebrospinal fluid (CSF) to that in plasma was 1.31-2.05% in 6 patients treated with ensartinib. Objective tumor responses were observed across all dose cohorts. In 46 evaluable patients, the objective response rates (ORR) and disease control rates (DCR) were 71.7% (1 CR and 32 PR) and 84.8% (6 SD), respectively. In ALK positive patients, the ORR and DCR were 80.5% (33/41) and 87.8% (36/41). The ORRs and DCRs at ≥225mg were 68.6% (24/35) and 85.7% (30/35), respectively. The confirmed ORR was 90.0% (27/30) in ALK TKI-naive patients compared to 54.5% (6/11) in ALK TKI-resistant patients. The ORR and DCR in 16 patients with baseline brain metastases were 75% and 75%, respectively. At data cut-off (07-Nov-2019), the median PFS for all 46 evaluable patients was 17.1 months (95% CI 6.3-27.9), and was 20.4 months (95% CI 13.2-27.6) for ALK positive patients, 8.6 months (95% CI 0-24.8) for ROS1 fusion patients. The median PFS was 24.5 months (95% CI 17.4-31.6) and 4.2 months (95% CI 0-8.9) for ALK TKI-naive and ALK TKI-resistant patients, respectively. Conclusions: Ensartinib was well tolerated in Chinese ALK-positive NSCLC patients with high antitumor activity. RP2D was established at 225 mg QD. Ensartinib could penetrate the blood-brain barrier with a CSF/plasma concentration ratio of 1.65%, supporting its remarkable intracranial efficacy. A global randomized phase 3 trial of ensartinib versus crizotinib in NSCLC patients who have not previously been treated with ALK TKIs is underway (NCT02767804). Citation Format: Hongyun Zhao, Yuxiang Ma, Yang Zhang, Shaodong Hong, Wenfeng Fang, Yunpeng Yang, Jianjin Huang, Jing Zhao, Yan Huang, Lieming Ding, Li Mao, Giovanni Selvaggi, Li Zhang. Ensartinib (X-396), a novel ALK TKI, in Chinese ALK-positive non-small cell lung cancer: A phase I, dose-escalation and expansion study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 579.