ceritinib and Neoplasm-Metastasis

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

The discovery of ALK rearrangement in non-small-cell lung cancer (NSCLC) triggered rapid clinical development of a family of specific drugs targeting this alteration, called ALK inhibitors. Despite high rate of responses, the vast majority of patients treated with first-generation ALK inhibitor crizotinib will ultimately develop disease progression. The second-generation ALK inhibitor, ceritinib, is an oral, small-molecule that inhibits the ALK kinase activity with a potency 20-fold greater than crizotinib, being able to tackle some of the principal mechanisms of resistance to crizotinib. Evidences from five large prospective clinical trials have so far showed impressive activity of ceritinib in ALK inhibitor pretreated and naive NSCLC patients. This review will focus on the preclinical and clinical data available regarding ceritinib pharmacology, clinical efficacy and safety profile.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Molecular Targeted Therapy; Neoplasm Metastasis; Neoplasm Staging; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Non-small cell lung cancer (NSCLC) represents the paradigm of personalized treatment of human cancer. Several oncogenic druggable alterations have been so far identified, with anaplastic lymphoma kinase (ALK) gene rearrangements representing one of the newest and most appealing. Crizotinib is now recognized as the standard of care in ALK-positive NSCLC due to the positive results of recently published trials. Unfortunately, resistance inevitably occurs within the first year of treatment. Overcoming resistance is the major challenge in clinical oncology, and novel potent ALK inhibitors are currently under evaluation, including ceritinib. Ceritinib is an oral, potent, second-generation ALK inhibitor demonstrating activity in patients who develop resistance to crizotinib. Recent data also suggested efficacy in ALK-inhibitor-naive population, thus supporting investigation of the drug in front-line setting.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Gene Order; Humans; Lung Neoplasms; Neoplasm Metastasis; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

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

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

We herein report a 75-year-old woman with insulin-treated diabetes and metastatic anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer who received ceritinib, a second-generation ALK inhibitor, and achieved dramatic tumor reduction. However, her fasting blood glucose increased, particularly markedly in the first two weeks after ceritinib administration, and did not normalize even increasing the total insulin dose. After discontinuing ceritinib, her glucose levels rapidly reduced. Ceritinib can aggravate hyperglycemia in patients with diabetes who lack compensatory insulin secretion, due to its inhibitory effects on the insulin receptor. Careful monitoring for ceritinib-induced hyperglycemia should be performed, especially in the first two weeks after ceritinib administration.

Topics: Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biomarkers; Biomarkers, Tumor; Blood Glucose; Carcinoma, Non-Small-Cell Lung; Diabetes Mellitus, Type 2; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Insulins; Lung Neoplasms; Neoplasm Metastasis; Pyrimidines; Sulfones

Tyrosine kinase inhibitors are now major actors for the treatment of non-small-cell metastatic lung cancers where ROS 1 gene rearrangement is present. Because of the rapid development of these new therapies, developing information about their monitoring and knowledge about their potential toxicities is essential. We describe the case of a patient who was treated with ceritinib as a third line approach for a metastatic lung adenocarcinoma with ROS1 rearrangement. After two months, the patient developed acute respiratory distress with pericarditis and pleurisy. A hypersensitivity reaction was suggested and supported by favorable clinical and radiological outcomes within three days following ceritinib discontinuation and systemic corticosteroid introduction. Pleural effusion, pericarditis and diffuse pulmonary infiltration associated to ceritinib have not often been described previously. Despite few data of pulmonary toxicity related to ceritinib, the current observation highlights the need for caution and regular monitoring when using these inhibitors.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cardiotoxicity; Drug Hypersensitivity; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Neoplasm Metastasis; Pericarditis; Pleural Effusion; Pyrimidines; Respiratory Distress Syndrome; Sulfones

Pancreatic metastasis from non-small cell lung cancer (NSCLC) is usually asymptomatic or presents with abdominal pain, acute pancreatitis, or jaundice. A lung primary is associated with worse survival compared to pancreatic metastases from other organs. Surgical treatment of solitary metastasis to the pancreas from NSCLC has been reviewed in several studies, one of which had a notable disease-free interval. To our knowledge, there are no prior reports of targeted therapy of pancreatic metastasis of NSCLC followed by a significant response. Herein we report the case of a 31-year-old female with a solitary pancreatic metastasis from ALK-rearranged lung adenocarcinoma despite treatment with chemotherapy and crizotinib; she presented with symptoms of hyperglycemia. Targeted therapy with ceritinib (LDK378) led to symptomatic improvement and a significant radiologic response in the lung and pancreas, but not in the brain.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Female; Humans; Hyperglycemia; Lung Neoplasms; Magnetic Resonance Imaging; Molecular Targeted Therapy; Mutation; Neoplasm Metastasis; Neoplasm Staging; Protein Kinase Inhibitors; Pyrimidines; Radiotherapy, Adjuvant; Receptor Protein-Tyrosine Kinases; Sulfones; Tomography, X-Ray Computed; Translocation, Genetic; Treatment Outcome

We report an ALK-rearranged adenocarcinoma of the lung presenting as a pituitary metastasis, clinically simulating a pituitary adenoma. The patient, a 50 year-old, former-smoking woman was admitted with a Parinaud's syndrome characterized by progressive oculomotor impairment of visual verticality, bitemporal hemianopsia and nystagmus. Imaging studies showed a sellar tumor and the biopsy revealed a TTF-1 and napsin positive lung adenocarcinoma strongly expressing synaptophysin and CD56, also harboring ALK rearrangement. A subsequent CT scan disclosed the primary lung mass of the left upper lobe. The patient progressed after 4 cycles of cisplatin/pemetrexed as first line treatment, but showed a partial response and a significant clinical benefit from the combination of ceritinib and nivolumab in a phase Ib trial. Despite its central nervous system tropism, ALK-rearranged adenocarcinoma manifesting with pituitary gland involvement was never reported. Second generation ALK inhibitors seem the best therapeutic strategy.

Topics: Adenocarcinoma of Lung; Adenoma; Anaplastic Lymphoma Kinase; Biomarkers, Tumor; Female; Gene Rearrangement; Humans; Immunohistochemistry; Lung Neoplasms; Middle Aged; Neoplasm Metastasis; Pituitary Gland; Pituitary Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Sulfones

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

Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancers (NSCLC) account for 3% to 7% of all NSCLC and require a standard treatment by crizotinib. However, crizotinib resistance is frequent within the first 12 months of treatment. Ceritinib is a novel tyrosine kinase inhibitor of ALK recently introduced in France for metastatic or locally advanced crizotinib-resistant ALK NSCLC. We report the first use of ceritinib in our institution with a spectacular tumoral response after only 3 months of treatment. This case demonstrates the major role of F-FDG PET/CT for monitoring the effectiveness of this new treatment.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Fluorodeoxyglucose F18; Humans; Lung Neoplasms; Neoplasm Metastasis; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors; Pyrimidines; Radiopharmaceuticals; Receptor Protein-Tyrosine Kinases; Sulfones