crizotinib and Neoplasm-Metastasis

Gastric cancer is one of the most common gastrointestinal tumors. Most patients have been in advanced stage at diagnosis and lack effective treatment. Molecular targeted drugs have become new therapeutic strategies. MET is an important driving gene for the development of gastric cancer. MET gene amplification and protein over-expression are closely related to the invasion and metastasis, late stage and poor prognosis of gastric cancer. Crizotinib is a small molecule inhibitor against MET. There are few reports of crizotinib in gastric cancer patients with c-MET amplification. This article reports a case of c-MET gene amplification in advanced gastric cancer with liver metastases. After 2 months of treatment with crizotinib, liver lesions were completely relieved and progression-free survival lasted for up to 20 months.

Topics: Adenocarcinoma; Crizotinib; Disease Progression; Disease-Free Survival; Drug Resistance, Neoplasm; Humans; Immunohistochemistry; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Proto-Oncogene Proteins c-met; Stomach Neoplasms; Treatment Failure; Treatment Outcome

Lung cancer during pregnancy is a very rare disease with less than 70 cases published to date. Information about specific lung cancer as adenocarcinoma is even more limited. Genetic techniques can detect oncogene mutations which seem to be more frequent among cases of lung cancer in pregnant women and could determine both the treatment and prognosis. We present a recent case seen at our hospital and a literature review.

Topics: Adenocarcinoma of Lung; Adult; Anaplastic Lymphoma Kinase; Crizotinib; Female; Humans; Lung Neoplasms; Neoplasm Metastasis; Pregnancy; Pregnancy Complications, Neoplastic; Protein Kinase Inhibitors

Ceritinib shows a promising efficacy in patients with anaplastic lymphoma kinase (ALK)-rearrangement non-small-cell lung cancer (NSCLC). The present systematic review determined the whole body and intracranial effectiveness and safety of ceritinib in crizotinib-naive versus crizotinib-pretreated regimens in ALK-rearrangement NSCLC. A comprehensive search of databases, including PubMed, EMBASE, Ovid, Web of Science, and COCHRANE, was performed to identify clinical trials in English-language journals. We estimated the pooled progression-free survival (PFS) and overall response rate (ORR) for ceritinib in whole body and intracranial responses to find differences between crizotinib-naive and crizotinib-pretreated regimens. The intracranial disease control rate in both crizotinib-naive and crizotinib-pretreated regimens was also estimated. The pooled efficacy parameters were as follows: ORR, 56.9% (95% confidence interval [CI], 53.6%-60.1%); PFS, 8.26 months (95% CI, 6.18-11.07 months); intracranial ORR, 41.3% (95% CI, 35.3%-47.6%); and intracranial disease control rate, 79.8% (95% CI, 73.8%-84.7%). The pooled ceritinib for crizotinib-naive showed a trend toward greater ORR and longer PFS compared with ceritinib for crizotinib-pretreated (68.9% and 14.62 months vs. 48.2% and 6.32 months, respectively). The intracranial ORR for ceritinib as the initial regimen was 50.6% compared with 33.6% for crizotinib-pretreated. The discontinuation and dose reduction rates were 3.1% and 38.4%, respectively. The most common grade 3/4 adverse effects were increased alanine aminotransferase (25.5%), increased γ-glutamyltransferase (12.6%), and increased aspartate aminotransferase (11.1%). Ceritinib is an effective agent for both crizotinib-naive and crizotinib-pretreated patients with locally advanced or metastatic ALK-rearranged NSCLC. Ceritinib has significant activity in crizotinib-naive patients with brain metastases.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Crizotinib; Gene Rearrangement; Humans; Lung Neoplasms; Neoplasm Metastasis; Pyrimidines; Sulfones; Survival Analysis

Papillary renal cell carcinoma (pRCC) is the 2nd most frequent histological type of kidney cancer and accounts for approximately 15% of all renal cell carcinoma. It has a poorer prognosis than clear cell RCC (ccRCC) with a lack of standard treatments.. We report the case of a 51 year old man with a metastatic pRCC (hepatic dome and left colonic peritoneal carcinomatosis) progressive after sunitinib, with a MET amplification. The patient was enrolled in the UNICANCER-sponsored AcSé crizotinib trial (NCT02034981), designed to give an access to crizotinib for patients with tumors harboring a genomic alteration on one of the biological targets of the drug. With 2nd line crizotinib (250 mg twice/day), the patient had a very good tolerance, a partial response in the target lesions using RECIST 1.1, and a 19 months' clinical efficacy.. In metastatic pRCC with a MET amplification, crizotinib maybe a potential met-inhibitory therapeutic option.

Topics: Antineoplastic Agents; Biomarkers; Carcinoma, Papillary; Carcinoma, Renal Cell; Crizotinib; Gene Amplification; Humans; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Tomography, X-Ray Computed

The US FDA granted approval for crizotinib as the first-line treatment for patients with echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase rearranged metastatic non-small-cell lung cancer, on November 20, 2013. Crizotinib is a customized and improved therapeutic option for patients with non-small-cell lung cancer that enhances overall survival without increasing toxicity. In the future, new targeted therapies may achieve additional indications for treating patients with lung cancer. This article summarizes data from crizotinib studies.

Topics: Animals; Carcinoma, Non-Small-Cell Lung; Crizotinib; Gene Rearrangement; Humans; Lung Neoplasms; Molecular Targeted Therapy; Neoplasm Metastasis; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Survival Rate

With therapeutic approaches based on oncogene addiction offering significant anticancer benefit, the identification of anaplastic lymphoma kinase (ALK) rearrangements is a key aspect of the management of lung cancers. The EML4-ALK gene fusion is detected in 4-8% of all lung cancers, predominantly in light smokers or nonsmokers. Crizotinib, the first agent to be approved in this indication, is associated with a median progression-free survival of 10.9 months when given as first-line treatment and 7.7 months when administered after chemotherapy. Median overall survival with crizotinib in the second-line setting is 20.3 months. Second-generation ALK inhibitors are currently being evaluated, with early studies giving impressive results, notably in patients resistant to crizotinib or with brain metastases. Among available chemotherapies, pemetrexed appears to be particularly active in this population. Despite this progress, several questions remain unanswered. What detection strategies should be favoured? What underlies the mechanisms of resistance and what options are available to overcome them? What are the best approaches for progressing patients? This review provides an overview of current data in the literature and addresses these questions.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Crizotinib; Disease-Free Survival; Drug Resistance, Neoplasm; Humans; In Situ Hybridization, Fluorescence; Lung Neoplasms; Neoplasm Metastasis; Piperidines; Predictive Value of Tests; Prognosis; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Smoking; Sulfones

Crizotinib was granted accelerated approval by the Food and Drug Administration in 2011 for the treatment of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). To evaluate the efficacy and safety of crizotinib, we performed a meta-analysis of published clinical trials using the random effect model.. The efficacy and safety of crizotinib was evaluated based on 1-year overall survival (OS), progression-free survival (PFS), overall response rate (ORR), partial response, complete response, stable disease, and dose reduction or cessation because of crizotinib toxicity.. Six clinical trials were included in the meta-analysis. Crizotinib treatment demonstrated a 1-year OS of 66.8% (95% CI, 52.2-78.8%) and a PFS of 8.6 months (95% CI, 7.3-9.9 months). The aggregate ORR, partial response and complete response rates were 61.2%, 59.8% and 1.5%, respectively. The proportion of patients achieving stable disease was 42.6% (95% CI, 17.3-72.5%). The most frequently reported adverse effects of crizotinib were mild visual disturbances, nausea, vomiting, diarrhea, constipation, edema, reduction in glomerular filtration rate, and generally reversible but sometimes severe elevations in aspartate aminotransferase and alanine aminotransferase. The proportion of patients who required dose reduction or cessation because of crizotinib toxicity was 6.5% (95% CI, 4.1-10.1%).. This meta-analysis revealed extended survival and improved response rates in patients treated with crizotinib. As a novel, targeted anticancer agent, crizotinib appears to be a favorable treatment option for patients with locally advanced or metastatic ALK-positive NSCLC.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Crizotinib; Humans; Lung Neoplasms; Neoplasm Metastasis; Neoplasm Staging; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Treatment Outcome

Ensartinib is a potent new-generation ALK inhibitor with high activity against a broad range of known crizotinib-resistant ALK mutations and CNS metastases. We aimed to assess the efficacy and safety of ensartinib in ALK-positive patients with non-small-cell lung cancer (NSCLC), in whom crizotinib therapy was unsuccessful. The associations between ensartinib efficacy and crizotinib-resistant mutations were also explored.. We did a single-arm, open-label, phase 2 study at 27 centres in China. Patients were aged 18 years or older, had stage IIIb or stage IV ALK-positive NSCLC that had progressed while they were on crizotinib therapy, an Eastern Cooperative Oncology Group performance status of 2 or less, had measurable disease, and had received fewer than three previous treatments. Patients with CNS metastases were included if these metastases were asymptomatic and did not require steroid therapy. All patients received 225 mg ensartinib orally once daily on a continuous dosing schedule. The primary outcome was the proportion of patients with an objective response according to the Response Evaluation Criteria in Solid Tumors (version 1.1), as assessed by an independent review committee in all patients who received at least one dose of ensartinib with no major violations of the inclusion criteria (ie, the full analysis set). Safety was assessed in all enrolled patients who received at least one dose of ensartinib. This trial was registered with ClinicalTrials.gov, NCT03215693.. Between Sept 28, 2017, and April 11, 2018, 160 patients were enrolled and had at least one dose of ensartinib (safety analysis set). Four patients had inclusion violations and were excluded from the efficacy analysis, which thus included 156 patients (full analysis set). 97 (62%) patients in the full analysis set had brain metastases. 76 (52% [95% CI 43-60]) of 147 patients in the full analysis set, with responses that could be assessed by the independent review committee, had an objective response. 28 (70% [53-83]) of 40 patients with measurable brain metastases as assessed by the independent review committee had an intracranial objective response. 145 (91%) of 160 patients had at least one treatment-related adverse event, which were mostly grade 1 or 2. The most common treatment-related adverse events were rash (89 [56%]), increased alanine aminotransferase concentrations (74 [46%]), and increased aspartate aminotransferase concentrations (65 [41%]).. Ensartinib has activity and is well tolerated in patients with crizotinib-refractory, ALK-positive NSCLC, including those with brain metastases. The role of ensartinib in patients in whom other second-generation ALK inhibitors have been unsuccessful warrants further studies.. Betta Pharmaceuticals.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; China; Crizotinib; Female; Humans; Lung Neoplasms; Male; Neoplasm Metastasis; Piperazines; Protein Kinase Inhibitors; Pyridazines

Despite improved progression-free survival, most patients treated with the first generation ALK inhibitor crizotinib ultimately experience central nervous system (CNS) progression. Brain metastases (BM) are associated with high clinical burden in patients with advanced anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC). In this study we estimate the real-world economic burden of BM in newly diagnosed ALK+ NSCLC patients and investigate whether alectinib, a second generation ALK inhibitor that delays CNS progression, may help reduce healthcare costs in patients with ALK+ NSCLC.. Cost of BM was measured in ALK+ NSCLC patients identified from a stacked PharMetrics Plus and MarketScan claims database from January 2008 to March 2016 and December 2015, respectively. Per patient per month (PPPM) cost of BM was calculated as the difference in baseline-adjusted total costs in patients with and without BM over a variable follow-up period of up to 24 months. Cumulative incidence of new BM was derived from 88 alectinib-treated and 93 crizotinib-treated patients without baseline BM in a randomized phase III clinical trial, ALEX (NCT02075840). Costs of BM per patient were then calculated by applying the PPPM BM cost to the number of incident BM patients in each treatment cohort.. 207 patients with no BM and 198 with BM were selected from the claims database. Total cost of BM was estimated at $6,029 PPPM. 24-month cumulative incidence rates of BM from the clinical trial were 7.2% and 45.3% for alectinib and crizotinib, respectively. Over follow-up, alectinib was estimated to reduce BM-related costs by $41,434 per patient compared to crizotinib.. BM is associated with substantial economic burden. Alectinib was estimated to reduce BM-related costs by preventing or delaying the occurrence of BM compared to crizotinib.

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cost of Illness; Crizotinib; Follow-Up Studies; Humans; Incidence; Lung Neoplasms; Neoplasm Metastasis; Piperidines; United States

Findings from the global phase III ALEX trial unequivocally show that alectinib is superior to crizotinib as first-line therapy for ALK+ non-small cell lung cancer. Alectinib more than doubled progression-free survival, significantly reduced the incidence of brain and CNS metastases, and should be considered the new standard of care.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Crizotinib; Disease-Free Survival; Drug Resistance, Neoplasm; Humans; Neoplasm Metastasis; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

: On March 11, 2016, after an expedited 5-month review, the U.S. Food and Drug Administration expanded the crizotinib metastatic non-small cell lung cancer (mNSCLC) indication to include the treatment of patients whose tumors harbor a ROS1 rearrangement. The approval was based on a clinically meaningful, durable objective response rate (ORR) in a multicenter, single-arm clinical trial (ROS1 cohort of Trial PROFILE 1001) in patients with ROS1-positive mNSCLC. The trial enrolled 50 patients (age range: 25-77 years) whose tumors were prospectively determined to have a ROS1 gene rearrangement by break-apart fluorescence in situ hybridization (96%) or reverse transcriptase polymerase chain reaction (4%) clinical trial assays. Crizotinib demonstrated an ORR of 66% (95% confidence interval [CI]: 51%-79%) with a median duration of response of 18.3 months by independent radiology review and 72% (95% CI: 58%-84%) by investigator review. Patients received crizotinib 250 mg twice daily and had a median duration of exposure of 34.4 months. The toxicity profile in ROS1-positive patients was generally consistent with the randomized safety data in the U.S. Product Insert from two ALK-positive mNSCLC trials. The most common (≥25%) adverse reactions and laboratory test abnormalities included vision disorders, elevation of alanine transaminase and aspartate transaminase levels, nausea, hypophosphatemia, diarrhea, edema, vomiting, constipation, neutropenia, and fatigue. There were no treatment-related deaths. A favorable benefit-to-risk evaluation led to the traditional approval of crizotinib for this new supplemental indication.. Given the results from the ROS1 cohort of the clinical trial PROFILE 1001, crizotinib represents a new treatment option and the first approved therapy for patients with metastatic non-small cell lung cancer whose tumors are ROS1 positive. Crizotinib demonstrated efficacy irrespective of prior treatment status.

Topics: Adult; Aged; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Gene Rearrangement; Humans; Male; Middle Aged; Neoplasm Metastasis; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Pyridines; Risk Assessment; United States; United States Food and Drug Administration

On August 26, 2011, crizotinib received accelerated approval for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is ALK-positive as detected by a test approved by the U.S. Food and Drug Administration (FDA). Approval was based on two single-arm trials demonstrating objective response rates (ORRs) of 50% and 61% and median response durations of 42 and 48 weeks. On November 20, 2013, crizotinib received regular approval based on confirmation of clinical benefit in study A8081007, a randomized trial in 347 patients with ALK-positive advanced NSCLC who had previously received one platinum-containing regimen. Patients were assigned (1:1) to receive crizotinib 250 mg orally twice daily or standard of care (docetaxel or pemetrexed). The primary endpoint was progression-free survival (PFS) determined by independent radiology review; secondary endpoints were ORR and overall survival (OS). PFS was significantly longer in the crizotinib arm, with median PFS of 7.7 and 3.0 months in the crizotinib and chemotherapy arms, respectively, and a 46% absolute increase in ORR but no difference in OS between treatment arms at the interim analysis. The most common adverse drug reactions (>25%) in crizotinib-treated patients were vision disorders, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue. The most serious toxicities of crizotinib were hepatotoxicity, interstitial lung disease or pneumonitis, and QT-interval prolongation. Crizotinib's rapid clinical development program (6 years from identification of ALK rearrangements in a subset of NSCLC to full FDA approval) is a model of efficient drug development in this new era of molecularly targeted oncology therapy.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Crizotinib; Docetaxel; Drug Approval; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pemetrexed; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Taxoids; Treatment Outcome; United States; United States Food and Drug Administration; Young Adult

Metastatic gastric cancer patients with poor eastern cooperative oncology group performance status (PS) (≥3) were lack of effective anti-tumor strategies. They always lived with poor PS, severe and multiple symptoms, and usually resulted in extremely limited survival time. Herein, we reported a patient diagnosed with gastric cancer metastasized to multiple bones, along with lymphangitis carcinomatosa in lungs, harboring Her-2 and c-MET amplification with poor PS, positively responded to combinational therapy with trastuzumab and crizotinib.. The patient complained of persistent cough and fatigue for 2 months, otherwise, she denied smoking, alcohol history, or any other medical or family history.. With the biopsy results from gastroscopy, as well as computer tomography for chest and abdomen, the patient was diagnosed as gastric adenocarcinoma, with metastasis on lungs, left adrenal gland, retroperitoneal lymph nodes, and multiple bones.. Because of the poor PS (PS = 3), as well as Her-2 and c-MET amplification, the patient received combination treatment with trastuzumab and crizotinib as salvage strategy.. After 2 months' exposure of trastuzumab and crizotinib, symptoms including persistent cough, and chest distress were alleviated significantly. Simultaneously, chest computer tomography showed significant dissipation of lymphangitis carcinomatosa, as well as apparent reduction of pleural effusion. No adverse reactions including nausea, vomiting, diarrhea, or hypertension was observed during the following 2 months.. The present case suggested that combinational therapy with trastuzumab and crizotinib might be effective in metastatic gastric cancer patients harboring Her-2 and c-MET amplification, even with a poor PS. It was also implied that gene sequencing might be valuable, especially in patients with limited treatment strategies.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Crizotinib; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Middle Aged; Neoplasm Metastasis; Proto-Oncogene Proteins c-met; Receptor, ErbB-2; Stomach Neoplasms; Trastuzumab

CD44v6, a splice variant of the cell surface glycoprotein CD44, acts as a co-receptor for c-Met and is upregulated in tumors with high metastatic potential.

Topics: Animals; Apoptosis; Cell Line; Cell Line, Tumor; Cell Movement; Cell Proliferation; Crizotinib; Female; HEK293 Cells; Hepatocyte Growth Factor; Humans; Hyaluronan Receptors; MAP Kinase Signaling System; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Peptides; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Up-Regulation

Topics: Aged; Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Colorectal Neoplasms; Crizotinib; Female; Gene Rearrangement; Humans; Lactams; Neoplasm Metastasis; Piperidines; Pyrazoles; Treatment Outcome

The establishment of clinically relevant models for tumor metastasis and drug testing is a major challenge in cancer research. Here we report a physiologically relevant assay enabling quantitative analysis of metastatic capacity of tumor cells following implantation into the chorioallantoic membrane (CAM). Engraftment of as few as 10

Topics: Animals; Antineoplastic Agents; Benzamides; Carcinoma, Non-Small-Cell Lung; Chick Embryo; Chorioallantoic Membrane; Cisplatin; Crizotinib; Docetaxel; Drug Screening Assays, Antitumor; Gefitinib; Male; Neoplasm Metastasis; Neoplastic Cells, Circulating; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms

Approximately 3%-5% of lung adenocarcinoma is driven by anaplastic lymphoma kinase (ALK) fusion oncogene, whose activity can be suppressed by multiple ALK inhibitors. Crizotinib and ceritinib have demonstrated superior efficacy to platinum-based chemotherapy as front-line treatment for patients with ALK-positive advanced non-small cell lung cancer (NSCLC). However, the direct comparison between them in the front-line setting remains lacking.. A total of 48 patients with ALK-positive, previously untreated advanced NSCLC, who received crizotinib and ceritinib as front-line treatment were retrospectively investigated. The efficacy and pattern of disease progression were analyzed.. Patients receiving ceritinib treatment were significantly younger than those receiving crizotinib treatment (52.0 vs. 63.0, P = 0.016). The median progression-free survival (PFS) was significantly longer with ceritinib than with crizotinib treatment (32.3 vs. 12.9 months; log-rank P = 0.020); the hazard ratio for disease progression or death, 0.27 (95% CI, 0.08-0.90; P = 0.033). An objective response was noted in all patients in the ceritinib group and in 23 patients in the crizotinib group (74.2%; 95% CI, 59.0 to 88.5). The rate of systemic progression was significantly lower over time with ceritinib treatment compared to crizotinib treatment (cause-specific hazard ratio, 0.21; 95% CI 0.06-0.73; P = 0.014). Serious adverse events were noted in one (2.9%) patient showing elevated liver function in the crizotinib group and three (23.1%) patients showing diarrhea in the ceritinib group. Dose reduction was needed in five out of 13 (38.5%) patients receiving ceritinib treatment.. Ceritinib showed higher efficacy associated with a better control of systemic progression compared to crizotinib for the front-line treatment of ALK-positive advanced NSCLCs.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Oncogene Proteins, Fusion; Prognosis; Pyrimidines; Sulfones

De novo mesenchymal-epithelial transition (MET) amplification represents an uncommon oncogenic event in patients with non-small-cell lung cancer, and little is known about the clinicopathologic characteristics, treatment, and prognosis of these patients.. Patient data were retrospectively collected in 5 hospitals in China from 2014 to 2016. All MET amplification was identified with fluorescence in-situ hybridization. A MET/centromere ratio (MET/CEN) of ≥ 1.8 was defined as positive for MET amplification.. Amplification of the de novo MET gene was identified in 47 patients with lung cancer. Thirty-two patients had a MET/CEN > 5, while 12 patients had intermediate-level amplification and only 3 had low-level amplification. Nine of 40 patients with advanced stage disease had brain metastases, and 15 had a solid predominant subtype of adenocarcinoma. Fifteen patients were treated with crizotinib. Of these, 11 patients (73.3%) had a partial response, 3 (20%) stable disease, and 1 (6.7%) progressive disease. The median progression-free survival of the 15 patients treated with crizotinib was 6.5 months (95% confidence interval, 2.7-10.3). Notably, treatment efficacy was more pronounced in patients with high-level MET amplification than in those with intermediate-level amplification (8.6 vs. 4.4 months, P = .008). The overall survival of patients with and without crizotinib treatment was 31.0 and 13.7 months, respectively (P = .001).. We observed a trend toward a high prevalence of the solid predominant subtype of adenocarcinoma and of brain metastases in this group of patients. Patients with de novo MET amplification benefit from crizotinib treatment, especially those with high-level amplification.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; China; Crizotinib; Drug Resistance, Neoplasm; Female; Gene Amplification; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Proto-Oncogene Proteins c-met; Retrospective Studies; Survival Analysis; Treatment Outcome

Topics: Adult; Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Central Nervous System; Crizotinib; Drug Approval; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Male; Neoplasm Metastasis; Organophosphorus Compounds; Pyrazoles; Pyrimidines; Recurrence; Treatment Outcome

The purpose of this study was to evaluate the relationships between the resistance of anaplastic lymphoma kinase (ALK)‒positive non-small cell lung cancer (NSCLC) to ALK inhibitors and the programmed cell death-1/programmed cell death-ligand 1 (PD-L1) pathway, we evaluated alterations in PD-L1 following acquisition of resistance to ALK inhibitors in ALK-positive lung cancer.. We established ALK inhibitor-resistant cell lines (H3122CR1, LR1, and CH1) by exposing the parental H3122 ALK-translocated NSCLC cell line to ALK inhibitors. Then, the double-resistant cell lines H3122CR1LR1 and CR1CH1 were developed by exposing the H3122CR1 to other ALK inhibitors. We compared the alterations in PD-L1 expression levels using western blotting, flow cytometry, and quantitative polymerase chain reaction. We also investigated gene expression using RNA sequencing. The expression of PD-L1 in the tumors from 26 ALK-positive metastatic NSCLC patients (11 ALK inhibitor-naïve and 15 ALK inhibitor-resistant patients) was assessed by immunohistochemistry and analyzed.. PD-L1 was expressed at higher levels in ALK inhibitor-resistant cell lines than in the ALK inhibitor-naïve parental cell line at the total protein, surface protein, and mRNA levels. Furthermore, PD-L1 expression in the double-resistant cell lines was much higher than that in the single resistant cell lines. RNA sequencing demonstrated that expression of immune-related genes were largely involved in ALK inhibitor resistance. The mean value of the PD-L1 H-score was 6.5 pre-treatment and 35.0 post-treatment, and the fold difference was 5.42 (p=0.163).. PD-L1 expression increased following acquisition of ALK inhibitor resistance in ALK-positive NSCLC cell lines and tumors.

Topics: Anaplastic Lymphoma Kinase; B7-H1 Antigen; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Crizotinib; Drug Resistance, Neoplasm; Female; Gene Expression Profiling; Gene Rearrangement; Humans; Lung Neoplasms; Male; Neoplasm Metastasis; Protein Kinase Inhibitors; Sequence Analysis, RNA; Translocation, Genetic; Up-Regulation

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Crizotinib; DNA-Binding Proteins; Female; Gene Rearrangement; High-Throughput Nucleotide Sequencing; Humans; Lung Neoplasms; Middle Aged; Mutation; Neoplasm Metastasis; Protein Kinase Inhibitors; Receptor, trkA; Remission Induction; Transcription Factors; Withholding Treatment

Central nervous system (CNS) progression is a common manifestation of acquired resistance to crizotinib in anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC). However, an optimal tailored treatment approach has not been established in patients with CNS failure during crizotinib treatment.. Patients with ALK-rearranged NSCLC with CNS progression during crizotinib treatment between January 2013 and December 2016 were included for analysis. Clinical data for different treatments after CNS failure during crizotinib treatment were retrospectively collected.. Among the 44 patients who had CNS progression during crizotinib treatment, 19, 15, 8, and 2 patients received crizotinib treatment beyond progressive disease (CBPD), a second ALK tyrosine kinase inhibitor (TKI), chemotherapy, and best supportive care, respectively. Post progression survival offered by treatment with a second ALK TKI was significantly more favorable than that of chemotherapy (P < .001) or CBPD (P = .045). In addition, patients who received sequential treatment with a second ALK TKI had significantly longer intracranial time to progression (IC-TTP) compared with those treated with chemotherapy (P < .01) or CBPD after radiotherapy (P = .003). In the 7 patients who received brigatinib, the median IC-TTP was 21.8 months (95% confidence interval, 11.7-32.0). The additional use of CNS radiotherapy in patients treated with a second ALK TKI showed no significance in terms of IC-TTP (P = .54).. Although CBPD is an option in patients with isolated CNS progression during crizotinib treatment, sequential treatment with a second ALK TKI, particularly brigatinib, might be preferable. The newly approved TKI, brigatinib, showed promise in the control of brain metastases, even without radiotherapy.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Crizotinib; Female; Gene Rearrangement; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organophosphorus Compounds; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Survival Analysis

Topics: Adult; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disseminated Intravascular Coagulation; Dyspnea; Female; Gene Rearrangement; Hemoptysis; Humans; Lung Neoplasms; Neoplasm Metastasis; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Remission Induction; Respiratory Distress Syndrome

Topics: Adenocarcinoma; Antineoplastic Agents; Crizotinib; Drug Resistance; ErbB Receptors; Erlotinib Hydrochloride; Gene Dosage; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Neoplasm Metastasis; Proto-Oncogene Proteins c-met

We present a 45-year-old patient diagnosed with anaplastic lymphoma kinase (ALK)-rearranged metastatic lung cancer who developed grade 4 interstitial lung disease (ILD) while on crizotinib treatment and was lately treated with brigatinib with no reappearance of ILD. To our knowledge, this is the first case report of successful treatment with brigatinib after crizotinib-induced ILD. Even though ILD secondary to brigatinib has been reported in clinical trials, no pulmonary toxicity has been seen in our patient, suggesting no crosslink lung toxicity between crizotinib and brigatinib.

Topics: Adenocarcinoma; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Crizotinib; Drug Substitution; Female; Gene Rearrangement; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Middle Aged; Neoplasm Metastasis; Oncogene Proteins, Fusion; Organophosphorus Compounds; Pyrimidines; Treatment Outcome

ALK-tyrosine kinase inhibitors (TKIs) have been proven effective for treating ALK-positive non-small cell lung cancer (NSCLC), although patients present with variable responses and disease progression courses. The detailed underlying molecular mechanisms require further investigation to yield a better prognosis.. Targeted next-generation sequencing (NGS) mutation profiling was performed on samples from 42 NSCLC patients confirmed positive for ALK rearrangements by fluorescence in situ hybridization or immunohistochemistry who experienced disease progression after crizotinib treatment.. ALK rearrangements were not confirmed in six patients (14%) with other potential oncogenic drivers identified by NGS, who therefore did not respond to crizotinib and had significantly shorter overall survival (OS) compared to NGS ALK -positive patients. Fifteen ALK activating mutations were detected in 8 out of 26 post-treatment samples (31%), among which ALK L1196M and G1269A were the most common acquired mutations detected in half of the patients with ALK activating mutations. Dynamic monitoring of the genetic evolution in one patient revealed both spatial and temporal heterogeneity of resistant mechanisms during different ALK-TKI treatment courses. Activation of ALK downstream or bypass pathways was detected in patients without ALK activating mutations, such as genetic alterations in PIK3CA, MET, and KRAS. Interestingly, we identified two patients with acquired mutations in the DNA mismatch repair gene POLE, which resulted in a dramatically increased tumor mutation burden, and might contribute to the poor response to crizotinib.. Heterogeneous resistant mechanisms have been identified and correlate to diverse responses to crizotinib. Comprehensive and dynamic mutation profiling is required to better predict clinical outcomes.

Topics: Anaplastic Lymphoma Kinase; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Crizotinib; DNA Mutational Analysis; Drug Resistance, Bacterial; Gene Expression Profiling; Humans; Lung Neoplasms; Mutation; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Protein Kinase Inhibitors

To investigate the effect of hMTH1 (human mutT homologue 1) on inducing the metastasis and recurrence of parotid adenoma, which may provide a new therapeutic direction for the prevention and treatment of parotid adenoma.. 30 cases of paraffin-embedded specimens of parotid adenoid cystic carcinoma (ACC) tissues and fresh parotid glands surgically resected in our hospital were collected as experimental group. 30 cases of surgically resected pleomorphic adenoma (PA) in the same period were selected as another experimental group. Meanwhile, 30 cases of normal parotid gland tissues (N) were collected as control group. The mRNA and protein expressions of hMTH1 in parotid gland tissues of patients with parotid adenoma before and after surgery were detected by Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and Western blotting, respectively. HMTH1 expression levels in parotid gland tissues were also detected by immunohistochemistry. Proliferation, apoptosis and DNA damage of ACC-M cells treated with S-Crizotinib were detected by cell counting kit-8 (CCK-8) assay, flow cytometry and single cell gel electrophoresis, respectively.. Both mRNA and protein expressions of hMTH1 in experimental group were significantly higher than those of control group. Moreover, a higher expression of hMTH1 was observed in ACC than that of PA, indicating that hMTH1 expression was positively correlated with the malignant degree of parotid adenoma. Furthermore, postoperative hMTH1 expression levels in patients with parotid adenoma were significantly lower than those before treatment, which were remarkably increased in recurrent patients. In vitro experiments demonstrated that S-Crizotinib, the hMTH1 inhibitor, could inhibit proliferation and induce apoptosis and DNA damage of ACC-M cells.. HMTH1 was upregulated in patients with parotid adenoma and recurrent patients after surgery. Meanwhile, S-Crizotinib induced DNA damage in ACC-M cells, indicating that hMTH1 induced the metastasis and recurrence of parotid adenoma by repairing DNA damage, providing a new strategy for the prevention and treatment of parotid adenoma.

Topics: Adenoma, Pleomorphic; Adolescent; Adult; Aged; Apoptosis; Carcinoma, Adenoid Cystic; Case-Control Studies; Cell Proliferation; Child; Crizotinib; DNA Damage; DNA Repair Enzymes; Humans; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Parotid Gland; Parotid Neoplasms; Phosphoric Monoester Hydrolases; Young Adult

Crizotinib has achieved astonishing success in advanced non-small-cell lung cancer (NSCLC) patients harboring anaplastic lymphoma kinase (ALK) rearrangement. However, no real-world studies described the clinicopathological characteristics and treatment of such patients in China. Patients were consecutively collected from Sun Yat-sen University Cancer Center. Chi-square test was applied to explore the relationship between ALK fusion status and metastasis sites. Kaplan-Meier methods and multivariable analyses were used to estimate progression-free survival (PFS). A total of 291 advanced NSCLC patients (ALK (+), N = 97; both ALK & epidermal growth factor receptor (EGFR) (-), N = 194) were enrolled. The occurrence of brain metastasis in ALK-positive patients was significantly higher than double-negative ones both at baseline (26.5% vs. 16.5%, P = 0.038) and during treatment (25.8% vs. 11.9%, P = 0.003), but opposite for pleural effusion (6.2% vs. 26.9%, P < 0.001 at baseline; 3.1% vs. 10.3%, P = 0.031 during treatment). ALK-positive patients of 53.6% used crizotinib, whereas others only received chemotherapy (37.1%) or supportive care (9.3%). Usage of crizotinib prolonged PFS compared with chemotherapy in ALK-positive patients (median PFS 17.6 m vs. 4.8 m, P < 0.001). ALK-positive NSCLC had more brain metastasis and less pleural effusion than double-negative ones. Crizotinib showed better PFS than chemotherapy in advanced ALK-positive NSCLC at any line. However, half advanced ALK-positive patients never received crizotinib, which was grim and need improving.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Therapy; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Survival Analysis; Treatment Outcome; Young Adult

Targeted therapy in lung cancer changes the prognostic and treatment of patients. MET is an oncogene including exon 14 mutations and gene amplification associated with worse prognosis. We here report the case of a 47-year-old former smoker, woman, with a stage IV lung adenocarcinoma with multiple chemotherapy failure. A MET amplification was identified and the patient consequently received crizotinib. A major response was observed after eight weeks of treatment. MET amplification screening appears to be interesting with some oncogenic-addicted tumor response rate. Those patients should be enrolled in clinical trials dedicated to tumor with MET alteration.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Crizotinib; Female; Gene Amplification; Humans; Lung Neoplasms; Middle Aged; Molecular Targeted Therapy; Mutation; Neoplasm Metastasis; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines

Presence of anaplastic lymphoma kinase (ALK) rearrangement is an indication for crizotinib in the treatment of patients with advanced or metastatic lung adenocarcinoma. Here, we sought to elucidate the association between clinicopathological features and ALK rearrangement status in Chinese patients with advanced lung adenocarcinoma harboring an ALK rearrangement.. ALK rearrangement status was determined using immunohistochemistry (IHC) in tumor tissues from 120 patients with advanced lung adenocarcinoma, and further assessed by fluorescence in situ hybridization (FISH) assay. The associations between ALK rearrangement status and clinicopathological features were analyzed.. According to IHC testing, the ALK-positive rate among the advanced lung adenocarcinoma patients was 6.67% (8/120). FISH validation found 5 patients with ALK rearrangement among the 8 IHC-positive cases. No significant difference was observed regarding age, sex, or smoking status between FISH-positive and -negative patients (p > 0.05). None of the 5 FISH-positive patients benefited from first-line chemotherapy.. IHC can be used as a reliable method for ALK rearrangement screening in patients with lung adenocarcinoma, but further FISH validation is imperative. Presence of ALK rearrangement predicts a more aggressive biological behavior of the tumor and might be indicative of poor response to chemotherapy.

Topics: Adenocarcinoma; Adult; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; China; Crizotinib; Female; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Risk Factors; Young Adult

Currently, only trastuzumab, ramucirumab, and apatinib effectively treat gastric cancer. Thus, additional novel targets are required for this disease.. We investigated the immunohistochemical and fluorescence in situ hybridization expression of MET, ROS1, and ALK in four gastric cell lines and a cohort of 98 gastric cancer patients. Crizotinib response was studied in vitro and in vivo.. Crizotinib potently inhibited in vitro cell growth in only one cell line, which also showed MET amplification. A positive correlation between crizotinib sensitivity and MET overexpression was observed (P = 0.045) in the histoculture drug response assay. Meanwhile, patient-derived tumor xenograft mouse models transplanted with tissues with higher MET protein expression displayed a highly selective sensitivity to crizotinib. In the 98 patients, MET overexpression was found in 42 (42.9 %) and MET was amplified in 4 (4.1 %). ROS1 and ALK overexpression were found in 25 (25.5 %) and 0 patients, respectively. However, none of the patients screened harbored ALK or ROS1 rearrangements. No significant association was found between overall survival and MET or ROS1 status. We also observed a stage IV gastric cancer patient with MET amplification who experienced tumor shrinkage and clinical benefit after 3 weeks of crizotinib as fourth-line treatment.. Crizotinib may induce clinically relevant anticancer effects in MET-overexpressed or MET-amplified gastric cancer patients.

Topics: Adult; Aged; Aged, 80 and over; Animals; Apoptosis; Biomarkers, Tumor; Blotting, Western; Cell Proliferation; Crizotinib; Drug Resistance, Neoplasm; Female; Fluorescent Antibody Technique; Follow-Up Studies; Humans; Immunoenzyme Techniques; In Situ Hybridization, Fluorescence; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Neoplasm Grading; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Stomach Neoplasms; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Cancer cells with high metastatic potential and stem cell-like characteristics express the cell surface marker CD44. CD44 isoforms that include the v6 exon are co-receptors for the receptor tyrosine kinases MET and Vascular Endothelial Growth factor Receptor-2 (VEGFR-2). We studied CD44v6 signaling in several pancreatic cancer cell lines, and its role in tumor growth and metastasis in several models of pancreatic cancer.. We analyzed the effects of v6 peptides that interfere with the co-receptor functions of CD44v6 for MET and VEGFR-2 in tumors and metastases grown from cells that express different CD44 isoforms, including CD44v6. The peptides were injected into rats with syngeneic tumors and mice with orthotopic or xenograft tumors. We also tested the effects of the peptides in mice with xenograft tumors grown from patient tumor samples and mice that express an oncogenic form of RAS and develop spontaneous pancreatic cancer (KPC mice). We measured levels of CD44v6 messenger RNA (mRNA) in pancreatic cancer tissues from 136 patients.. Xenograft tumors grown from human cancer cells injected with v6 peptides were smaller and formed fewer metastases in mice. The v6 peptide was more efficient than the MET inhibitor crizotinib and/or the VEGFR-2 inhibitor pazopanib in reducing xenograft tumor growth and metastasis. Injection of KPC mice with the v6 peptide increased their survival time. Injection of mice and rats bearing metastases with the v6 peptide induced regression of metastases. Higher levels of CD44v6 mRNA in human pancreatic tumor tissues were associated with increased expression of MET, tumor metastasis, and shorter patient survival times.. Peptide inhibitors of CD44v6 isoforms block tumor growth and metastasis in several independent models of pancreatic cancer. The v6 peptides induced regression of metastases. Levels of CD44v6 mRNA are increased, along with those of MET mRNA, in patients with metastatic pancreatic tumors, compared with nonmetastatic tumors; the increased levels correlated with shorter patient survival time.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Crizotinib; Gene Expression Regulation, Neoplastic; Genes, ras; Humans; Hyaluronan Receptors; Indazoles; Kaplan-Meier Estimate; Lung Neoplasms; Male; Mice, Nude; Mice, Transgenic; Mutation; Neoplasm Metastasis; Pancreatic Neoplasms; Peptides; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Pyrimidines; Rats; RNA, Messenger; Signal Transduction; Sulfonamides; Time Factors; Transfection; Tumor Burden; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays

Inflammatory myofibroblastic tumors (IMT) are rare tumors in children and young adults, considered by the World Health Organization to be intermediate malignancies and rarely metastasizing, with the presence of an anaplastic lymphoma kinase rearrangement in about 50% of the cases. We report the case of a teenager who presented with a metastatic aggressive IMT that was life-threatening despite multiple treatments, and which responded repeatedly to anaplastic lymphoma kinase-targeted crizotinib therapy. Crizotinib induced drastic primary tumor regression, which was sufficient to allow surgical resection and to control distant disease. This case shows that crizotinib is a promising therapy in IMT, even in adolescents and young adults.

Topics: Adolescent; Anaplastic Lymphoma Kinase; Crizotinib; Female; Gene Rearrangement; Humans; Inflammation; Neoplasm Metastasis; Neoplasms, Muscle Tissue; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

EGFR tyrosine kinase inhibitors and crizotinib are nowadays the optimal treatment for metastatic lung cancer with activation of EGFR mutations and ALK rearrangement. In addition, several targeted agents are in development for lung cancer with other oncodrivers. In France, since 2011, six oncodrivers are routinely tested in patients with stage IV. The aim of this study was to assess whether systematic detection of oncodrivers and matched targeted therapy improve overall survival in patients with advanced lung adenocarcinoma.. This study included all consecutive patients treated in our department for advanced lung adenocarcinoma from January 2012 to December 2013. We studied the impact in survival according to the presence of the driver and the targeted therapy.. Among the 261 patients included, oncodrivers alterations were found in 43.5% of patients: EML4-ALK fusion genes (2.1%), EGFR (10.3%), KRAS (27.7%), BRAF (2.5%), HER2 (0.8%), and PI3KCA (0.8%) mutations. Twenty-nine percent of patients (n=32) with oncodrivers received matched targeted therapy. Patient treated by targeted agent appropriate to an oncogenic driver had a median survival of 21.1 months (95% CI: 14.7-27.5). The patients (n=79) who did not receive targeted therapy had a median survival of 6.6 months (95% CI: 4.3-8.9). The patients (n=150) without identified driver had a median survival of 9.7 months (95% CI: 6.7-11.7); P<0.001.. An actionable oncodriver was routinely detected in nearly half of patients with advanced lung adenocarcinoma. This systematic detection may influence treatment outcomes, notably with matched targeted therapy.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Crizotinib; Early Detection of Cancer; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Mass Screening; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Nuclear Proteins; Oncogene Proteins, Fusion; Oncogenes; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyrazoles; Pyridines; Receptor, ErbB-2; Survival Analysis; Transcription Factors

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Crizotinib; Humans; Neoplasm Metastasis; Pyrazoles; Pyridines; Randomized Controlled Trials as Topic; Receptor Protein-Tyrosine Kinases

We report on the case of a patient affected by advanced non-small cell lung cancer (NSCLC) harboring an anaplastic lymphoma kinase (ALK) gene rearrangement who did not respond to crizotinib but subsequently benefited from treatment with ceritinib (LDK378). Although second-generation ALK inhibitors have shown activity in patients pretreated with crizotinib who experienced secondary resistance, this is the first report to date describing their efficacy in a case of primary resistance. Of note, none of the previously described molecular mechanisms explaining resistance to crizotinib was detected on either the initial or post-crizotinib biopsies. We hypothesize that crizotinib was powerless in controlling disease progression due to its inadequate inhibition of ALK signaling. Although we lack any molecular evidence elucidating the primary crizotinib resistance, we believe that ceritinib treatment led to tumor regression thanks to its superior biological potency.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease Progression; Drug Resistance, Neoplasm; Drug Substitution; Humans; Immunohistochemistry; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Tomography, X-Ray Computed; Translocation, Genetic; Treatment Outcome

Second-generation ALK inhibitors are recently available for ALK+ non-small cell lung cancer (NSCLC) patients previously treated with crizotinib. This study described characteristics, treatment sequencing, and outcomes among locally advanced/metastatic crizotinib-experienced ALK+ NSCLC patients.. From July 2014 to June 2015, a retrospective patient chart review was conducted among physicians from the US, EU, Korea, and Latin America. Participating clinicians identified their ALK+ NSCLC patients who received crizotinib and reported on their clinical characteristics, treatments, and survival using a pre-defined case report form. Kaplan-Meier analyses were used to describe overall survival (OS) and clinician-defined progression-free survival (PFS).. Participating clinicians reviewed charts of 158 ALK+ NSCLC patients treated with crizotinib during the study period. Crizotinib was most commonly received in the second-line setting (41% of patients), though this varied across geographical regions. Roughly half (53%) of the patients who discontinued crizotinib received further antineoplastic therapy; second-generation ALK inhibitors (44%) and chemotherapy (42%) regimens were used most frequently. Following crizotinib discontinuation, median OS was 8.2 months. Among patients who did not initiate a second-generation ALK inhibitor following crizotinib, median OS was 4.9 months; among those who did, median OS was not reached. Among patients who received chemotherapy immediately following crizotinib discontinuation, time to clinician-defined PFS from post-crizotinib chemotherapy initiation was 3.6 months.. Following crizotinib discontinuation, many patients received no further antineoplastic therapy, and OS was poor among patients who did not receive a second-generation ALK inhibitor. Recently available second-generation ALK inhibitors may provide important treatment options for ALK+ NSCLC patients.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Health Care Surveys; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Practice Patterns, Physicians'; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Retreatment; Retrospective Studies; Risk Factors; Survival Analysis

We report a case of crizotinib effectiveness in a heavily pretreated patient with a metastatic NSCLC initially considered IHC-positive and FISH-negative for ALK rearrangement. After repeated analyses of tumor samples, borderline ALK FISH-positivity (18.5% positive cells) was demonstrated.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Crizotinib; Fatal Outcome; Female; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lung Neoplasms; Neoplasm Metastasis; Neoplasm Staging; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

Crizotinib is an orally administered drug for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non‑small cell lung cancer (NSCLC). Despite the impressive efficacy of crizotinib in the treatment of ALK‑positive lung cancer, acquired resistance eventually develops in the majority of patients. The microRNA (miR)‑200c reverses the resistance of lung cancer cells to various chemotherapeutic drugs and molecular targeted drugs, however, whether it can reverse the resistance of crizotinib remains unknown. The present study established a crizotinib resistant cell line (NCI‑2228/CRI), which was derived from the parental NCI‑2228 cell line by long‑term exposure to increasing concentrations of crizotinib. Through overexpression and suppression of miR‑200c expression, the characteristics associated with epithelial‑mesenchymal transition (EMT), including morphology, EMT marker proteins and cellular mobility, were investigated. Cell viability and invasion assays demonstrated that high expression of miR‑200c significantly inhibited the proliferation, migration and invasion of NCI‑2228 cells compared with the negative control. A luciferase reporter assay indicated that miR‑200c directly targeted the 3'‑untranslated region of zinc finger E‑box binding homeobox 1. Additionally, reverse transcription‑quantitative polymerase chain reaction analysis demonstrated that the mRNA levels of N‑cadherin and Vimentin were decreased in NCI‑2228 cells transfected with miR‑200c mimic compared with negative control cells, whereas the mRNA level of E‑cadherin was increased. In addition, EMT was reversed by miR‑200c, which suggests that miR‑200c may serve a role in mediating the sensitivity of NCI‑2228/CRI cells to crizotinib. The present study may therefore contribute to improving the sensitivity of ALK positive lung cancer cells to crizotinib.

Topics: Anaplastic Lymphoma Kinase; Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Cell Proliferation; Crizotinib; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Neoplasm Metastasis; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; RNA, Messenger; Zinc Finger E-box-Binding Homeobox 1

Epidermal growth factor receptor (EGFR) gene mutations and anaplastic lymphoma kinase (ALK) gene rearrangements are key therapeutic targets for biomarker-driven treatment with an EGFR or ALK tyrosine kinase inhibitor (TKI) in patients with metastatic non-small cell lung cancer (NSCLC). To appropriately guide treatment decisions, since 2011, the National Comprehensive Cancer Network and the American Society of Clinical Oncology therefore recommend EGFR and ALK analysis in tumor samples obtained at the time of diagnosis in patients with non-squamous NSCLC. Currently, there are limited data on utilization patterns and cost of biopsy procedures and biomarker tests in patients with metastatic NSCLC who receive an EGFR or ALK TKI.. To (a) describe utilization patterns and costs associated with biopsy procedures and biomarker testing in patients with NSCLC who received erlotinib or crizotinib between 2009 and 2012 and (b) investigate the timing of these procedures relative to the erlotinib or crizotinib index date.. Adult patients with metastatic lung cancer were identified by ICD-9-CM diagnostic codes within the Truven Health Analytic MarketScan database. Patients were included in the analysis if they had an index erlotinib or crizotinib claim between January 1, 2009, and September 30, 2012 (index period) and were continuously enrolled for ≥ 12 months before the index claim. Because there is no specific ICD-9-CM diagnostic code for NSCLC, patients with metastatic lung cancer who received erlotinib or crizotinib were considered to have metastatic NSCLC. Using CPT and ICD-9-CM codes, lung biopsy procedures performed during the 24 months before or 12 months after the index claim date were identified. For every patient, biomarker testing claims for EGFR and ALK were identified using the molecular pathology stacked CPT code during the 2 months before or 1 month after the index date. The frequency of claims for biopsy procedures and biomarker testing was analyzed descriptively. The overall summary measures for biomarker testing, especially frequency of EGFR testing in patients receiving erlotinib, was also described as before and after 2011, the year when biomarker testing became part of the guidelines. Per patient and overall costs for biopsy procedures and biomarker testing were calculated from payer and patient perspectives.. Of the 4,926 identified patients, 4,801 (97.5%) received erlotinib, and 125 (2.5%) received crizotinib. Biopsy procedure claims were identified for 3,579 (72.7%) patients, including 3,503 (73.0%) erlotinib recipients and 76 (60.8%) crizotinib recipients. Biomarker testing claims were identified for 675 (13.7%) patients, including 634 (13.2%) erlotinib recipients and 41 (32.8%) crizotinib recipients. Overall, most biomarker testing procedures (476 of 741) were identified in 435 (of 675) patients after year 2011. Also, among erlotinib recipients, percentage of patients receiving EGFR testing was increased over the index period. Per patient mean (SD) numbers of biopsy procedures and biomarker tests were 1.2 (1.1) and 0.2 (0.4), respectively. In the outpatient setting, per patient mean (SD) cost per biopsy procedure was $1,223 ($1,899) from the payer perspective and $60 ($147) from the patient perspective, whereas in the inpatient setting, it was $8,163 ($18,712) and $180 ($691), respectively. Among patients receiving at least 1 biomarker test, the per patient mean (SD) cost for the overall population was $891 ($1,062) and $43 ($229); for erlotinib recipients, it was $906 ($1,084) and $42 ($228); and for crizotinib recipients, it was $664 ($576) and $55 ($243) in payer and patient perspectives, respectively.. This study provides insight into the use and cost of biopsy and biomarker testing procedures in patients with metastatic NSCLC. The low frequency of biomarker testing highlights the need for more awareness of testing to guide treatment decisions in these patients. Costs associated with biopsy procedures and biomarker testing provide insight into the economic impact on metastatic NSCLC patients treated with targeted therapy.. This study was sponsored by Merck & Co. Shinde is a study manager working for Merck under contract with AllSourcePPS, an Agile 1 company in Huntington Beach, California. Cao and Kothari are employees of Merck & Co., Kenilworth, New Jersey. Study concept and design were contributed primarily by Shinde and Kothari. Data analysis was performed by Cao. Data interpretation was performed by Shinde, Cao, and Kothari. Shinde wrote the manuscript with assistance from Cao and Kothari. The revision was completed primarily by Shinde and Kothari.

Topics: Adolescent; Adult; Aged; Anaplastic Lymphoma Kinase; Biomarkers, Tumor; Biopsy; Crizotinib; ErbB Receptors; Erlotinib Hydrochloride; Female; Humans; Insurance, Health; Lung Neoplasms; Male; Middle Aged; Molecular Diagnostic Techniques; Neoplasm Metastasis; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Retrospective Studies; Young Adult

Brain metastases (BM) are highly prevalent among anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC) patients; yet little is known about their real-world treatment patterns and clinical and economic burdens. This study aimed to describe these patients' treatment patterns, symptoms, and costs.. Retrospective study pooling data from three large administrative databases in the US (08/2011-06/2013). ALK+ NSCLC patients with BM and continuous enrollment for ≥ 60 days before and ≥ 30 days after the first observed BM diagnosis were identified by pharmacy records for crizotinib among patients with lung cancer and BM diagnostic codes.. Treatment patterns, symptoms, healthcare resource utilization, and costs, before and after BM diagnosis.. Of the 213 crizotinib patients with BM diagnoses meeting the selection criteria, 23.0% had BM prior to NSCLC diagnosis; 47.4% had BM prior to crizotinib initiation; 19.2% during crizotinib treatment; and 10.3% post-crizotinib treatment. For those diagnosed with BM after NSCLC diagnosis, the median time between the NSCLC and BM diagnoses was 88 days. Following the first observed BM diagnosis, 88.7% used chemotherapy, 63.4% had radiotherapy, and 31.9% had stereotactic radiosurgery. The prevalence of BM-related symptoms substantially increased post-BM-diagnosis: fatigue (from 15% to 39%), headaches (from 5% to 24%), and depression (from 5% to 15%). Monthly costs per patient averaged $5983 before the BM diagnosis and $22,645 after diagnosis. Patients' resource utilization increased significantly post-BM-diagnosis, with a 3-fold increase in OP visits and a 6-fold increase in IP stays. Post-BM-diagnosis costs were driven by pharmacy (42.0%), inpatient (29.6%), and outpatient costs (26.0%).. The study sample was limited to crizotinib-treated patients.. Post-BM-diagnosis, patients experience high symptom burden. Post-BM-diagnosis, treatment is highly variable and costly: average monthly costs per patient almost quadrupled post-BM-diagnosis.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biomarkers; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Comorbidity; Crizotinib; Cross-Sectional Studies; Female; Health Resources; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Retrospective Studies; United States

A 44-year-old woman who was diagnosed with anaplastic lymphoma kinase-positive lung adenocarcinoma developed brain metastases, multiple spinal metastases and meningeal dissemination. Crizotinib was administered after the failure of first-line chemotherapy. Esophagitis and liver damage were induced by the twice-daily administration of crizotinib at 250 mg and 200 mg, respectively. The alternate-day administration of crizotinib (250 mg, twice daily) was able to control disease progression without any adverse effects for several months. We evaluated the relationship between the serum concentration of crizotinib and the development of esophagitis and liver damage. The alternate-day administration of crizotinib is one of the strategies for managing the severe toxicity of crizotinib.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adult; Anaplastic Lymphoma Kinase; Chemical and Drug Induced Liver Injury; Crizotinib; Drug Administration Schedule; Esophagitis; Female; Humans; Lung Neoplasms; Neoplasm Metastasis; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Treatment Outcome

On August 26, 2011, the U.S. Food and Drug Administration (FDA) approved crizotinib (XALKORI Capsules, Pfizer Inc.) for treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK) positive as detected by an FDA-approved test. The Vysis ALK Break-Apart FISH Probe Kit (Abbott Molecular, Inc.) was approved concurrently. In two multicenter, single-arm trials, patients with locally advanced or metastatic ALK-positive NSCLC previously treated with one or more systemic therapies received crizotinib orally at a dose of 250 mg twice daily. In 119 patients with ALK-positive NSCLC by local trial assay, the objective response rate (ORR) was 61% [95% confidence intervals (CI), 52%-70%] with a median response duration of 48 weeks. In 136 patients with ALK-positive NSCLC by the to-be-marketed test, the ORR was 50% (95% CI, 42%-59%) with a median response duration of 42 weeks. The most common adverse reactions (≥25%) were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Accelerated approval was granted on the basis of the high ORRs and durable responses. On November 20, 2013, crizotinib received full approval based on an improvement in progression-free survival in patients with metastatic ALK-positive NSCLC previously treated with one platinum-based chemotherapy regimen.

Topics: Administration, Oral; Adult; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Crizotinib; Diarrhea; Drug Administration Schedule; Drug Approval; Female; Humans; In Situ Hybridization, Fluorescence; Lung Neoplasms; Male; Middle Aged; Multicenter Studies as Topic; Nausea; Neoplasm Metastasis; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Treatment Outcome; United States; United States Food and Drug Administration; Vision Disorders; Vomiting

Uveal melanoma is the most common primary intraocular malignant tumor in adults and half of the primary tumors will develop fatal metastatic disease to the liver and the lung. Crizotinib, an inhibitor of c-Met, anaplastic lymphoma kinase (ALK), and ROS1, inhibited the phosphorylation of the c-Met receptor but not of ALK or ROS1 in uveal melanoma cells and tumor tissue. Consequently, migration of uveal melanoma cells was suppressed in vitro at a concentration associated with the specific inhibition of c-Met phosphorylation. This effect on cell migration could be recapitulated with siRNA specific to c-Met but not to ALK or ROS1. Therefore, we developed a uveal melanoma metastatic mouse model with EGFP-luciferase-labeled uveal melanoma cells transplanted by retro-orbital injections to test the effect of crizotinib on metastasis. In this model, there was development of melanoma within the eye and also metastases to the liver and lung at 7 weeks after the initial transplantation. When mice were treated with crizotinib starting 1 week after the transplantation, we observed a significant reduction in the development of metastases as compared with untreated control sets. These results indicate that the inhibition of c-Met activity alone may be sufficient to strongly inhibit metastasis of uveal melanoma from forming, suggesting crizotinib as a potential adjuvant therapy for patients with primary uveal melanoma who are at high risk for the development of metastatic disease.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Crizotinib; Disease Models, Animal; Gene Expression; Gene Knockdown Techniques; Hepatocyte Growth Factor; Humans; Male; Melanoma; Mice; Neoplasm Metastasis; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; RNA, Small Interfering; Tumor Burden; Uveal Neoplasms; Xenograft Model Antitumor Assays

Anaplastic lymphoma kinase-positive non-small cell lung carcinoma patients are generally highly responsive to the dual anaplastic lymphoma kinase and MET tyrosine kinase inhibitor crizotinib. However, they eventually acquire resistance to this drug, preventing the anaplastic lymphoma kinase inhibitors from having a prolonged beneficial effect. The molecular mechanisms responsible for crizotinib resistance are beginning to emerge, e.g., in some anaplastic lymphoma kinase-positive non-small cell lung carcinomas the development of secondary mutations in this gene has been described. However, the events behind crizotinib-resistance currently remain largely uncharacterized. Thus, we report on an anaplastic lymphoma kinase-positive non-small cell lung carcinoma patient with concomitant occurrence of epidermal growth factor receptor and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations upon development of crizotinib-resistance.. A 61-year-old Caucasian never-smoking male was diagnosed with anaplastic lymphoma kinase -positive pulmonary adenocarcinoma, stage T4N3M1b. Treatment with crizotinib initially resulted in complete objective response in the thorax and partial response in the abdomen, but after 8 months of therapy the patient acquired resistance and progressed. Biopsies from new metastases revealed development of epidermal growth factor receptor and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations concomitant with the original anaplastic lymphoma kinase gene rearrangement and without signs of anaplastic lymphoma kinase fusion gene amplification or secondary anaplastic lymphoma kinase mutations.. To our knowledge, this is the first report of an anaplastic lymphoma kinase-positive pulmonary adenocarcinoma, which upon emergence of crizotinib resistance acquired 2 new somatic mutations in the epidermal growth factor receptor and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog genes, respectively, concomitant with the original anaplastic lymphoma kinase rearrangement. Thus, these 3 driver mutations, usually considered mutually exclusive, may coexist in advanced non-small cell lung carcinoma that becomes resistant to crizotinib, presumably because heterogeneous tumor clones utilize epidermal growth factor receptor and/or V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog signaling to circumvent the inhibition of anaplastic lymphoma kinase-mediated signaling by crizotinib. The identification of new targetable somatic mutations by tumor re-biopsy may help clarify the mechanism behind the development of the acquired crizotinib resistance and pave the way for combined strategies involving multiple targeted therapies.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Crizotinib; Drug Resistance, Neoplasm; ErbB Receptors; Fatal Outcome; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Neoplasm Metastasis; Neoplasm Staging; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Pyrazoles; Pyridines; ras Proteins; Receptor Protein-Tyrosine Kinases

Because novel therapeutic options are limited in Ewing sarcomas (ES), we investigated the expression, genetic aberrations and clinical relevance of MET and anaplastic lymphoma kinase (ALK) in ES and determined the relevance of targeting these receptors. MET and ALK protein expression was determined immunohistochemically in 31 (50 samples) and 36 (59 samples) ES patients, respectively. Samples included primary tumors, postchemotherapy resections, metastases and relapses. MET and ALK RTK domains were sequenced in respectively 33 and 32 tumors. Five ES cell lines were treated in vitro with the MET/ALK-inhibitor crizotinib, the ALK-inhibitor NVP-TAE684 or the MET-inhibitor cabozantinib and analyzed by MTT assays. Modest to high MET and ALK expression was detected in the majority of ES (86 and 69%, respectively). ALK expression was significantly lower in postchemotherapy resections compared to paired untreated primary tumors (p = 0.031, z = -2.310, n = 11). In primary tumors (n = 20), membranous MET expression significantly correlated with a poor overall survival (OS) (60 vs. 197 months, p = 0.014). There was a trend toward a poor event-free survival (67 vs. 111 months, p = 0.078) and OS (88 vs. 128 months, p = 0.074) in patients with highest ALK levels (n = 29). ALK or MET RTK domain aberrations were demonstrated in 5/32 (16%) and 3/33 (9%) tumors, respectively. Crizotinib (IC50 1.22-3.59 μmol/L), NVP-TAE684 (IC50 0.15-0.79 μmol/L) and cabozantinib (IC50 2.69-8.27 μmol/L) affected ES cell viability in vitro. Altogether, our data suggest that MET and ALK are potential novel therapeutic targets in ES and targeting these receptors may be of great interest to rationally design future studies in ES.

Topics: Adolescent; Adult; Anaplastic Lymphoma Kinase; Anilides; Child; Child, Preschool; Chromosome Aberrations; Crizotinib; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Inhibitory Concentration 50; Male; Middle Aged; Neoplasm Metastasis; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Recurrence; Sarcoma, Ewing; Tetrazolium Salts; Thiazoles; Treatment Outcome; Young Adult

The functional role of pericytes in cancer progression remains unknown. Clinical studies suggest that low numbers of vessel-associated pericytes correlated with a drop in overall survival of patients with invasive breast cancer. Using genetic mouse models or pharmacological inhibitors, pericyte depletion suppressed tumor growth but enhanced metastasis. Pericyte depletion was further associated with increased hypoxia, epithelial-to-mesenchymal transition (EMT), and Met receptor activation. Silencing of Twist or use of a Met inhibitor suppressed hypoxia and EMT/Met-driven metastasis. In addition, poor pericyte coverage coupled with high Met expression in cancer cells speculates the worst prognosis for patients with invasive breast cancer. Collectively, our study suggests that pericytes within the primary tumor microenvironment likely serve as important gatekeepers against cancer progression and metastasis.

Topics: Animals; Antineoplastic Agents; Benzamides; Benzenesulfonates; Breast Neoplasms; Cell Hypoxia; Cell Line, Tumor; Crizotinib; Epithelial-Mesenchymal Transition; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Imatinib Mesylate; Indoles; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Neoplasm Metastasis; Niacinamide; Pericytes; Phenylurea Compounds; Piperazines; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Signal Transduction; Sorafenib; Sunitinib; Tumor Cells, Cultured

The objective of this study was to document the differences in testosterone (T) levels between crizotinib-treated and noncrizotinib-treated patients with metastatic nonsmall cell lung cancer (NSCLC).. Testosterone levels were measured in 19 men with metastatic NSCLC who received crizotinib and in 19 men with metastatic NSCLC who did not receive crizotinib. Clinical characteristics of the patients were compared, and additional hormone assays were performed as appropriate. Two patients who began crizotinib and 4 patients who had dose interruptions or who stopped crizotinib therapy had serial hormone measurements, permitting the documentation of dynamic hormone changes on and off crizotinib treatment.. Total T levels were low (<241 ng/dL) in 19 of 19 (100%) crizotinib-treated men and in 6 of 19 men (32%) with metastatic NSCLC who did not receive crizotinib (mean T levels, 131 ng/dL and 311 ng/dL, respectively; P = .0002). Only 1 in 5 patients who had anaplastic lymphoma kinase (ALK) gene rearrangements and had not yet received crizotinib had low T. The initiation of crizotinib in 2 patients who had previously normal T levels was associated with a rapid decreases in T and in luteinizing hormone and follicle stimulating hormone levels within 14 to 21 days. Discontinuation of crizotinib led to increases back to normal T levels.. Crizotinib therapy caused rapid suppression of T levels in men. The current results indicated that the site of action must include a central (hypothalamic or pituitary) effect, but additional direct testicular effects could not be excluded. Further work is required to assess the correlation between low T levels and crizotinib side effects as well as the exact molecular mechanism and site of drug toxicity.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Hypogonadism; Male; Middle Aged; Neoplasm Metastasis; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Testosterone

Deregulated expression of the hepatocyte growth factor (HGF) receptor, c-Met, in cancer contributes to tumor progression and metastasis. The objective of this study was to determine whether blocking c-Met with an orally available c-Met inhibitor, PF-2341066, reduces tumor burden and increases survival in a xenograft model of ovarian cancer metastasis. Treatment of mice injected interperitoneally with SKOV3ip1 cells showed reduced overall tumor burden. Tumor weight and the number of metastases were reduced by 55% (P < .0005) and 62% (P < .0001), respectively. Treatment also increased median survival from 45 to 62 days (P = .0003). In vitro, PF-2341066 reduced HGF-stimulated phosphorylation of c-Met in the tyrosine kinase domain as well as phosphorylation of the downstream signaling effectors, Akt and Erk. It was apparent that inhibition of the pathways was functionally important because HGF-induced branching morphogenesis was also inhibited. In addition, proliferation and adhesion to various extracellular matrices were inhibited by treatment with PF-2341066, and the activity of matrix metalloproteinases was decreased in tumor tissue from treated mice compared with those receiving vehicle. Overall, these data indicate that PF-2341066 effectively reduces tumor burden in an in vivo model of ovarian cancer metastasis and may be a good therapeutic candidate in the treatment of patients with ovarian cancer.

Topics: Animals; Apoptosis; Blotting, Western; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Crizotinib; Female; Hepatocyte Growth Factor; Humans; Immunohistochemistry; Mice; Mice, Nude; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neoplasm Metastasis; Ovarian Neoplasms; Phosphorylation; Piperidines; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Signal Transduction; Survival Analysis; Tumor Burden; Xenograft Model Antitumor Assays