Response to crizotinib in advanced ALK-rearranged NSCLCs with different variants and abundance of ALK-fusion alleles.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20651-e20651 ◽  
Author(s):  
Jianming Ying ◽  
Yan Li ◽  
Tongtong Zhang ◽  
Wenbin Li ◽  
Pu-Yuan Xing ◽  
...  
Keyword(s):  
Clinical Efficacy ◽  
High Abundance ◽  
P Value ◽  
Alk Rearrangement ◽  
Lung Cancers ◽  
Anaplastic Lymphoma ◽  
Baseline Characteristics ◽  
Alk Positive ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

e20651 Background: Anaplastic lymphoma kinase ( ALK) rearrangements are present in approximately 5% of non-small-cell lung cancers (NSCLCs). NSCLCs with ALK-rearrangement can be effectively treated with crizotinib. However, magnitude and duration of responses are found to be heterogeneous. This study explored the clinical efficacy of crizotinib in different ALK variants and abundance levels using next-generation sequencing (NGS). Methods: Among 89 ALK-rearrangement patients treated with crizotinib, 47 patients were identified with tumor specimens that could be evaluated by NGS. We retrospectively evaluated the clinical efficacy of crizotinib in different ALK variants and the abundance of ALK-fusion alleles. Results: The median PFS of the 89 ALK-rearrangement patients was 14.1 months (95%CI: 11.27-18.43 months). Among the 47 patients with NGS results, the most frequent variants were variant 3a/b (29.79%, 14/47), variant 1 (25.53%, 12/47) and variant 2 (14.89%, 7/47). Rare EML4- ALK variants were detected in 6 cases (12.77%). Other new fusion partners were detected in 8 cases (17.02%). Patients with EML4- ALK variant 2 appeared to have longer PFS than other EML4- ALK variants with a borderline p value. Patients were categorized into three groups based on the abundance of ALK-fusion alleles: low-abundance group ( < 35%), middle-abundance group (≥35% and < 55%), and high-abundance group (55%). Middle-abundance group had a better PFS than both low-abundance group and high-abundance group (P = 0.01). After adjusting for other baseline characteristics, abundance levels of ALK-positive alleles and ALKvariant type were identified as important factors for predicting clinical efficacy of crizotinib. Conclusions: Our results indicate prolonged PFS in patients with EML4- ALK variant 2 versus other EML4- ALK patients. The abundance of ALK-fusion alleles also correlated with the extent of benefit from crizotinib treatment.

scholarly journals A novel GHR-ALK fusion gene in a patient with metastatic lung adenocarcinoma and its response to crizotinib: a case report

2021 ◽  
Vol 49 (9) ◽  
pp. 030006052110446
Author(s):  
Xue Pan ◽  
Anyuan Zhong ◽  
Yufei Xing ◽  
Xi Li ◽  
Haiwei Du ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Growth Hormone Receptor ◽  
Kinase Inhibitors ◽  
Fusion Gene ◽  
Fusion Partner ◽  
Alk Rearrangement ◽  
Lung Cancers ◽  
Anaplastic Lymphoma ◽  
Metastatic Lung ◽  
Generation Sequencing

Anaplastic lymphoma kinase ( ALK) rearrangement occurs in approximately 5% of non-small cell lung cancers (NSCLCS), and EML4-ALK is the most commonly observed ALK fusion variant in NSCLC. However, growth hormone receptor ( GHR) as the fusion partner for ALK and the clinical response to ALK tyrosine kinase inhibitors in patients with metastatic lung adenocarcinoma (LUAD) who carry the GHR-ALK variant have not been documented. This case describes a 63-year-old woman diagnosed with metastatic LUAD. Immunohistochemistry revealed positive ALK expression, and the patient was treated with crizotinib. After 3 weeks of treatment, the patient had a partial response. Because of treatment-related adverse events, the dose of crizotinib was reduced. After 3.7 months, computed tomography uncovered disease progression. Next-generation sequencing identified a novel GHR-ALK fusion in the plasma of the patient. The patient was treated again with crizotinib, but the disease progressed again 2 months later. Then, the patient received chemotherapy. She succumbed to her disease 11 months after the initial diagnosis. Our work provides evidence supporting the use of crizotinib in patients with metastatic LUAD harboring GHR-ALK.

scholarly journals EML4-ALK positive lung adenocarcinoma with skeletal muscle metastasis in the right calf which was treatable with lorlatinib after resistance to treatment with alectinib

2021 ◽  
Vol 14 (4) ◽  
pp. e240295
Author(s):  
Hironari Matsuda ◽  
Munechika Hara ◽  
Shin-Ichiro Iwakami ◽  
Kazuhisa Takahashi
Keyword(s):  
Skeletal Muscle ◽  
Lung Adenocarcinoma ◽  
Kinase Inhibitor ◽  
Stable Condition ◽  
Japanese Woman ◽  
Alk Rearrangement ◽  
Anaplastic Lymphoma ◽  
Resistance To Treatment ◽  
Alk Positive ◽  
The Right

This report concerns a patient with skeletal muscle metastases due to lung adenocarcinoma harbouring an echinoderm microtubule-associated protein-like-4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement, who was successfully treated with lorlatinib after resistance to alectinib. A right lower lobectomy based on a diagnosis of lung adenocarcinoma was performed on a 77-year-old Japanese woman. After 7 months of surgical resection, a mass in the right calf was observed. A fine-needle aspiration biopsy from the mass was performed and the mass was diagnosed as metastatic adenocarcinoma harbouring EML4-ALK rearrangement. Alectinib was administered for 10 months. Then, administration of lorlatinib, an ALK tyrosine kinase inhibitor classified as third generation, was initiated after resistance to treatment with alectinib. After starting treatment with lorlatinib, the gastrocnemius tumour diminished and has maintained a stable condition. Our case suggests that EML4-ALK positive lung adenocarcinoma is treatable with lorlatinib after resistance to treatment with alectinib.

scholarly journals Later-Line Treatment with Lorlatinib in ALK- and ROS1-Rearrangement-Positive NSCLC: A Retrospective, Multicenter Analysis

2020 ◽  
Vol 13 (11) ◽  
pp. 371
Author(s):  
Maximilian J. Hochmair ◽  
Hannah Fabikan ◽  
Oliver Illini ◽  
Christoph Weinlinger ◽  
Ulrike Setinek ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Real World ◽  
Kinase Inhibitors ◽  
Resistance Mutations ◽  
Real World Data ◽  
Alk Rearrangement ◽  
World Data ◽  
Anaplastic Lymphoma ◽  
Wide Range ◽  
Alk Positive

In clinical practice, patients with anaplastic lymphoma kinase (ALK)-rearrangement–positive non–small-cell lung cancer commonly receive sequential treatment with ALK tyrosine kinase inhibitors. The third-generation agent lorlatinib has been shown to inhibit a wide range of ALK resistance mutations and thus offers potential benefit in later lines, although real-world data are lacking. This multicenter study retrospectively investigated later-line, real-world use of lorlatinib in patients with advanced ALK- or ROS1-positive lung cancer. Fifty-one patients registered in a compassionate use program in Austria, who received second- or later-line lorlatinib between January 2016 and May 2020, were included in this retrospective real-world data analysis. Median follow-up was 25.3 months. Median time of lorlatinib treatment was 4.4 months for ALK-positive and 12.2 months for ROS-positive patients. ALK-positive patients showed a response rate of 43.2%, while 85.7% percent of the ROS1-positive patients were considered responders. Median overall survival from lorlatinib initiation was 10.2 and 20.0 months for the ALK- and ROS1-positive groups, respectively. In the ALK-positive group, lorlatinib proved efficacy after both brigatinib and alectinib. Lorlatinib treatment was well tolerated. Later-line lorlatinib treatment can induce sustained responses in patients with advanced ALK- and ROS1-positive lung cancer.

First-in-human phase I study of the ALK inhibitor LDK378 in advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3007-3007 ◽  
Author(s):  
Ranee Mehra ◽  
D. Ross Camidge ◽  
Sunil Sharma ◽  
Enriqueta Felip ◽  
Daniel Shao-Weng Tan ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Phase I Study ◽  
Tumor Regression ◽  
Duration Of Treatment ◽  
Alk Rearrangement ◽  
Anaplastic Lymphoma ◽  
Alk Inhibitor ◽  
Alk Positive ◽  
Ecog Ps

3007 Background: LDK378 is a novel, potent and selective small molecule anaplastic lymphoma kinase (ALK) inhibitor (IC50 0.00015 μM), that does not inhibit c-MET (IC50 3.2 μM). Tumor regression has been observed in ALK-driven NSCLC xenografts. A first-in-human, Phase I study is being conducted to determine the MTD and safety profile in patients (pts) with tumors with ALK rearrangement, amplification or mutation. Other objectives were safety, PK and antitumor activity in pts with ALK-driven NSCLC, both naïve to ALK inhibitors and relapsed following previous ALK inhibitor treatment, and other ALK-positive cancers. Methods: Adult pts with advanced malignancies harboring a genetic alteration in ALK who progressed on standard therapy or for whom there was no effective therapy, were given once daily oral LDK378 on a continuous 21-day schedule. Dose escalation, starting at 50 mg/day, was guided by a Bayesian logistic regression model (BLRM) to determine the MTD. Results: At a January 5th 2012 cutoff,31 pts (primary site: lung 26 pts; breast 3 pts; other 2 pts; median age 52 years; 87% ECOG PS 0/1) were enrolled and received LDK378 at doses of 50–750 mg/day. Two dose limiting toxicities, Grade (Gr) 3 alanine aminotransferase elevation (1 pt), and Gr 3 hypophosphatemia (1 pt) occurred in 8 pts at a 400 mg dose level. BLRM allowed dose escalation, and there were no DLTs in 4 pts at 500 mg. Median duration of treatment with LDK378 was 7 weeks (range <1–22+). At the cutoff date, 13 (42%) pts discontinued treatment: 1 (3%) due to adverse events (AEs), and 12 (39%) due to disease progression; 18 (58%) pts were still on treatment. The most frequent AEs (all Gr) were nausea (45%), vomiting (36%), and diarrhea (29%). The most frequent Gr 3/4 AEs were diarrhea and dyspnea (2 pts [7%] each). At doses ≥400 mg steady state exposures exceeded efficacious exposures in xenograft models. Of 16 pts with available response data (RECIST, per investigator) there were 4/6 responses in crizotinib (CRZ)-treated pts, and 2/10 responses in CRZ-naïve pts, of whom 7 were treated below 400 mg. All responses were in NSCLC. Conclusions: Daily oral LDK378 is well tolerated up to 500 mg/day, and escalation continues at 750 mg/day. Preliminary responses have been seen in both CRZ-naïve and CRZ-relapsed pts.

scholarly journals Canadian consensus: inhibition of ALK-positive tumours in advanced non-small-cell lung cancer

2016 ◽  
Vol 23 (3) ◽  
pp. 196 ◽  
Author(s):  
B. Melosky ◽  
J. Agulnik ◽  
R. Albadine ◽  
S. Banerji ◽  
D.G. Bebb ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Alk Rearrangement ◽  
Alk Inhibitors ◽  
Anaplastic Lymphoma ◽  
Alk Positive ◽  
Nonsquamous Nsclc

Anaplastic lymphoma kinase (ALK) is an oncogenic driver in non-small-cell lung cancer (NSCLC). Chromosomal rearrangements involving the ALK gene occur in up to 4% of nonsquamous NSCLC patients and lead to constitutive activation of the ALK signalling pathway. ALK-positive NSCLC is found in relatively young patients, with a median age of 50 years. Patients frequently have brain metastasis.Targeted inhibition of the ALK pathway prolongs progression-free survival in patients with ALK-positive advanced NSCLC. The results of several recent clinical trials confirm the efficacy and safety benefit of crizotinib and ceritinib in this population.Canadian oncologists support the following consensus statement: All patients with advanced nonsquamous nsclc (excluding pure neuroendocrine carcinoma) should be tested for the presence of an ALK rearrangement. If an ALK rearrangement is present, treatment with a targeted ALK inhibitor in the first-line setting is recommended. As patients become resistant to first-generation ALK inhibitors, other treatments, including second-generation ALK inhibitors can be considered.

scholarly journals Anaplastic lymphoma kinase rearrangements in non-small cell lung cancer in Jordan

2021 ◽  
Vol 156 (Supplement_1) ◽  
pp. S151-S151
Author(s):  
M A Sughayer ◽  
B Maraqa ◽  
M Al-Ashhab
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Stage Iv ◽  
Small Cell ◽  
P Value ◽  
Small Cell Lung ◽  
Alk Rearrangement ◽  
Alk Positive ◽  
Nsclc Patients

Abstract Introduction/Objective ALK rearrangement is an important oncogenic driver in a substantial portion of non-small cell lung cancer (NSCLC) patients ranging from 2-7%. Treatment options such as ALK tyrosine kinase inhibitors (TKI) improve progression-free survival and overall survival. Candidates for such treatment are selected based on the identification of the ALK rearrangement. While fluorescence in situ hybridization (FISH) was considered the gold standard method, the availability of a robust FDA-approved companion diagnostic immunohistochemistry (IHC) assay has led to a paradigm shift in ALK testing. The purpose of this study is to determine the prevalence of ALK rearrangement in Jordanian NSCLC patients along with their clinicopathological characteristics and to compare the results of IHC and FISH methods for detecting ALK rearrangements. Methods/Case Report A retrospective study was conducted on 449 Jordanian King Hussein Cancer Center patients with NSCLC whose biopsy samples were tested for ALK rearrangement using FISH and or IHC (clone D5F3) in the period between 2018 and 2020. Results (if a Case Study enter NA) During the study period, the rate of ALK positivity by either IHC or FISH method was 4 percent (18 ALK positive cases out of 449 cases of non-small cell lung cancer). Seven cases were positive for both IHC and FISH, and nine cases were positive for IHC with no confirmation by FISH method; one case was ALK positive by IHC and negative by FISH with a significant response to ALK TKI; one case was IHC negative but FISH positive, with no ALK TKI therapy. The calculated sensitivity of ALK D5F3 immunostain compared to FISH results in the current study is 87.5% while the specificity is 96%. ALK positive patients were significantly younger than those with negative results (p-value=0.051), and women were three times more likely than men to have the rearrangement (p-value=0.013). Rearrangement was more likely to be found in nonsmokers/light or ex-smokers (p-value= 0.013). All patients had clinical stage IV or III disease at presentation with stage IV found in tow thirds of the patients. Conclusion ALK rearrangement is found in 4% of all NSCLC in Jordan. Patients are more likely to be younger, females and light or nonsmokers with an advanced stage disease at presentation. IHC is an acceptable alternative to FISH for ALK testing with reasonable sensitivity and specificity in addition to its advantages in terms of robustness, turnaround time and cost savings

scholarly journals Impact of ALK Inhibitors in Patients With ALK-Rearranged Nonlung Solid Tumors

2021 ◽  
pp. 756-766
Author(s):  
Yuki Takeyasu ◽  
Hitomi S. Okuma ◽  
Yuki Kojima ◽  
Tadaaki Nishikawa ◽  
Maki Tanioka ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Alk Rearrangement ◽  
Free Survival ◽  
Anaplastic Lymphoma ◽  
Treatment Interruptions ◽  
Alk Positive

PURPOSE Anaplastic lymphoma kinase ( ALK) rearrangement is a well-known driver oncogene in non–small-cell lung cancer and has also been identified in other types of tumors. However, there is limited evidence on the clinical response to ALK tyrosine kinase inhibitors (TKIs), such as alectinib and crizotinib, in rare tumors with ALK fusion. We evaluated the therapeutic effect of ALK-TKIs in rare ALK-rearranged tumors. PATIENTS AND METHODS Between April 2012 and April 2019, clinical outcomes and characteristics of patients with ALK-rearranged nonlung solid tumors who received ALK-TKIs (alectinib and/or crizotinib) outside of clinical trials were reviewed. Expression and/or rearrangement of ALK was evaluated by immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing. The tumor response was assessed according to RECIST (version 1.1). Progression-free survival was estimated from initial ALK-TKI initiation until progression. RESULTS We identified seven patients (inflammatory myofibroblastic tumors, n = 3; ALK-positive histiocytosis, n = 1; histiocytic sarcoma, n = 1; osteosarcoma, n = 1; and parotid adenocarcinoma, n = 1), with a median age of 17 years. Two rare ALK fusions, namely, CTNNA1-ALK and ITSN2-ALK, were identified. As initial ALK-TKI therapy, five patients received alectinib and two received crizotinib. The objective response rate for the initial ALK-TKI therapy was 85.7% (95% CI, 44 to 97), including two patients who received alectinib and achieved complete response. The median progression-free survival was 8.1 months (range, 1.7 to not estimable). There were no treatment interruptions or dose reductions because of adverse events caused by alectinib. CONCLUSION This study highlights the potential benefit of ALK-TKIs, especially alectinib, in patients with ALK-rearranged nonlung solid tumors.

scholarly journals Alectinib-Induced Pleural and Pericardial Effusions in ALK-Positive NSCLC

2021 ◽  
pp. 1323-1327
Author(s):  
Maiken Parm Ulhoi ◽  
Boe Sandahl Sorensen ◽  
Peter Meldgaard
Keyword(s):  
Progressive Disease ◽  
Heart Function ◽  
Circulating Tumor Dna ◽  
Driver Mutations ◽  
First Line ◽  
Alk Positive ◽  
Next Generation Sequencing Ngs ◽  
Tumor Dna ◽  
Generation Sequencing ◽  
Mild Toxicity

Alectinib is the first-line targeted treatment for advanced ALK-positive non-small-cell lung cancer. Although it has a relatively mild toxicity profile, adverse events (AEs) do occur. We present a case of alectinib-induced bilateral pleural effusions and pericardial effusion that has not previously been reported. The patient developed severe dyspnea 3 months after starting alectinib. He underwent thorough clinical examination including evaluations of heart function. The heart function was normal. There was no sign of pneumonitis or progressive disease on the CT scans. Cytology samples of the pleural fluid from multiple thoracocenteses were examined and showed no malignant cells. Next-generation sequencing (NGS) analysis of circulating tumor DNA from sequential blood samples was also carried out. NGS identified no known driver mutations associated with the effusions. Hence, the effusions were suspected to be an alectinib-induced AE. Alectinib was withdrawn, and the patient commenced brigatinib. The effusions subsequently regressed.

scholarly journals Patterns of Metastatic Spread and Mechanisms of Resistance to Crizotinib in ROS1-Positive Non–Small-Cell Lung Cancer

2017 ◽  
pp. 1-13 ◽  
Author(s):  
Justin F. Gainor ◽  
Diane Tseng ◽  
Satoshi Yoda ◽  
Ibiayi Dagogo-Jack ◽  
Luc Friboulet ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Molecular Mechanisms ◽  
Small Cell ◽  
Metastatic Spread ◽  
Imaging Data ◽  
Resistance Mutations ◽  
Small Cell Lung ◽  
Lung Cancers ◽  
Anaplastic Lymphoma ◽  
Alk Positive

Purpose The ROS1 tyrosine kinase is activated through ROS1 gene rearrangements in 1% to 2% of non–small-cell lung cancers (NSCLCs), which confer sensitivity to treatment with the anaplastic lymphoma kinase (ALK)/ROS1/mesenchymal-epithelial transition factor inhibitor crizotinib. Currently, insights into patterns of metastatic spread and mechanisms of crizotinib resistance among patients with ROS1-positive disease are limited. Patients and Methods We reviewed clinical and radiographic imaging data of patients with ROS1- and ALK-positive NSCLC to compare patterns of metastatic spread at initial metastatic diagnosis. To determine molecular mechanisms of crizotinib resistance, we analyzed repeat biopsy specimens from a cohort of patients with ROS1-positive disease who progressed on crizotinib. Results We identified 39 and 196 patients with advanced ROS1- and ALK-positive NSCLC, respectively. Patients with ROS1-positive disease had significantly lower rates of extrathoracic metastases ( ROS1, 59.0%; ALK, 83.2%; P = .002), including lower rates of brain metastases ( ROS1, 19.4%; ALK, 39.1%; P = .033), at initial metastatic diagnosis. Despite similar overall survival between patients with ALK- and ROS1-positive NSCLC treated with crizotinib (median, 3.0 v 2.5 years, respectively; P = .786), patients with ROS1-positive NSCLC also had a significantly lower cumulative incidence of brain metastases (34% v 73% at 5 years; P < .001). In addition, we identified 16 patients who underwent a total of 17 repeat biopsies after progression on crizotinib. ROS1 resistance mutations were identified in 53% of specimens, including nine (64%) of 14 non–brain metastasis specimens. ROS1 mutations included G2032R (41%), D2033N (6%), and S1986F (6%). Conclusion Compared with ALK rearrangements, ROS1 rearrangements are associated with lower rates of extrathoracic metastases, including fewer brain metastases, at initial metastatic diagnosis. ROS1 resistance mutations, particularly G2032R, appear to be the predominant mechanism of resistance to crizotinib, which underscores the need to develop novel ROS1 inhibitors with activity against these resistant mutants.

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