Biomarkers in lung cancer.

Here we review the role of tissutal and circulating biomarkers in the management of lung cancer. In the past they were considerate quite ineffective tools as regards prognosis and prediction of treatment activity, nowadays instead, they are becoming a crucial key point as potential predictive issues in driving therapy, with possibly prognostic values as well

Evaluation of the Effect of Lorlatinib on CYP2B6, CYP2C9, UGT, and P-Glycoprotein Substrates in Patients with Advanced Non-Small Cell Lung Cancer

Lorlatinib; Glycoprotein; Advanced non-small cell lung cancerLorlatinib; Glicoproteïna; Càncer de pulmó de cèl·lules no petitesLorlatinib; Glicoproteína; Cáncer de pulmón de células no pequeñasBackground and Objective Lorlatinib is a tyrosine kinase inhibitor approved for the treatment of advanced anaplastic lymphoma kinase–positive non-small cell lung cancer. This study assessed the effect of steady-state lorlatinib on the metabolic enzymes cytochrome P450 (CYP) 2B6, CYP2C9, and uridine 5′-diphospho-glucuronosyltransferase (UGT) and the P-glycoprotein (P-gp) transporter. Methods Thirty-two patients received a single oral dose of a probe drug on Day − 2 to determine the pharmacokinetics of the probe drug alone. Starting on Day 1, patients received 100 mg oral lorlatinib daily. On Day 15, a single oral dose of the probe drug was administered concurrently with lorlatinib. Pharmacokinetic parameters for these probe substrates were assessed. Results Plasma exposures of all probe substrates were reduced by lorlatinib compared with the probe alone. The greatest reduction in area under the plasma concentration–time curve from time zero to infinity (AUC∞) and maximum (peak) plasma drug concentration (Cmax) (67% and 63% decrease, respectively) was observed with the P-gp probe substrate fexofenadine. Lorlatinib coadministration also decreased the AUC∞ and Cmax of bupropion (CYP2B6 probe substrate) by 25% and 27%, tolbutamide (CYP2C9 probe substrate) by 43% and 15%, and acetaminophen (UGT probe substrate) by 45% and 28%, respectively. Conclusions Lorlatinib is a net moderate inducer of P-gp and a weak inducer of CYP2B6, CYP2C9, and UGT after steady state is achieved with daily dosing. Medications that are P-gp substrates with a narrow therapeutic window should be avoided in patients taking lorlatinib; no dose modifications are needed with substrates of CYP2B6, CYP2C9, or UGT. ClinicalTrials.gov: NCT01970865.This study was sponsored by Pfizer

Biomarkers in neuroendocrine tumors.

Here, we review the role of clinical biomarkers (tissue and circulating markers) in the management of neuroendocrine tumors. These tumors may originate in different organs, from cells embriologically different but expressing common phenotypic characteristics, such as the immuno-reactivity for markers of neuro endocrine differentiation (defined as "pan-neuroendocrine"), the capacity to sec rete specific or aspecific peptide and hormones, and the expression of some receptors, that are at the basis of the current diagnostic and therapeutic approach

Intracranial and extracranial efficacy of lorlatinib in patients with ALK-positive non-small-cell lung cancer previously treated with second-generation ALK TKIs

Lorlatinib; Càncer de pulmó de cèl·lules no petites; ALK TKI de segona generacióLorlatinib; Cáncer de pulmón de células no pequeñas; ALK TKI de segunda generaciónLorlatinib; Non-small-cell lung cancer; Second-generation ALK TKIsBackground Lorlatinib, a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), has substantial activity against ALK-positive non-small-cell lung cancer (NSCLC). This study assessed the overall, intracranial, and extracranial efficacy of lorlatinib in ALK-positive NSCLC that progressed on second-generation ALK TKIs. Patients and methods In the ongoing phase II study (NCT01970865), patients with ALK-positive advanced NSCLC treated with ≥1 prior second-generation ALK TKI ± chemotherapy were enrolled in expansion cohorts (EXP) based on treatment history. Overall, intracranial and extracranial antitumor activity were assessed independently per modified Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Results Of the 139 patients with ≥1 prior second-generation ALK TKI (EXP3B-5), 28 received one prior second-generation ALK TKI (EXP3B), 65 two prior ALK TKIs (EXP4), and 46 three prior ALK TKIs (EXP5). In EXP3B-5, the objective response rate (ORR) [95% confidence intervals] was 39.6% (31.4-48.2), intracranial ORR (IC-ORR) was 56.1% (42.4-69.3), extracranial ORR (EC-ORR) was 36.7% (28.7-45.3), median duration of response (DOR) was 9.6 months [5.6-16.7; IC-DOR, 12.4 (6.0-37.1); EC-DOR, 9.7 (6.1-33.3)], median progression-free survival was 6.6 (5.4-7.4) months, and median overall survival was 20.7 months (16.1-30.3). In EXP3B, the ORR was 42.9% (24.5-62.8), the IC-ORR was 66.7% (29.9-92.5), and the EC-ORR was 32.1% (15.9-52.4). In EXP4 and EXP5, the ORR was 38.7% (29.6-48.5), the IC-ORR was 54.2% (39.2-68.6), and the EC-ORR was 37.8% (28.8-47.5). Conclusions Lorlatinib had clinically meaningful intracranial and extracranial antitumor activity in the post-second-generation ALK TKI setting, with elevated intracranial versus extracranial ORR, particularly in patients with fewer lines of therapy.This work was supported by Pfizer Inc. (no grant number)

Therapeutical Options in ROS1—Rearranged Advanced Non Small Cell Lung Cancer

ROS proto-oncogene 1 (ROS1) rearrangements occur in 0.9–2.6% of patients with non small cell lung cancer (NSCLC), conferring sensitivity to treatment with specific tyrosine-kinase inhibitors (TKI). Crizotinib, a first-generation TKI, was the first target-therapy approved for the first-line treatment of ROS1-positive NSCLC. Recently, entrectinib, a multitarget inhibitor with an anti-ROS1 activity 40 times more potent than crizotinib and better activity on the central nervous system (CNS), received approval for treatment-naive patients. After a median time-to-progression of 5.5–20 months, resistance mechanisms can occur, leading to tumor progression. Therefore, newer generation TKI with greater potency and brain penetration have been developed and are currently under investigation. This review summarizes the current knowledge on clinicopathological characteristics of ROS1-positive NSCLC and its therapeutic options

Target Therapies in Lung Cancer

Targeting intracellular signaling molecules is an attractive approach for treatment of malignancies. In particular lung cancer has reached a plateau regarding overall survival, and target therapies could offer the possibility to improve patients' outcome beyond cytotoxic activity. The goal for target therapies is to identify agents that target tumor-specific molecules, thus sparing normal tissues; those molecules are called biomarkers, and their identification is recommended because it has a predictive value, for example, provides information on outcome with regard to a specific treatment. The increased specificity should lead to decreased toxicity and better activity. Herein we provide an update of the main target therapies in development or already available for the treatment of nonsmall cell lung cancer

Antiblastic Treatment, for Solid Tumors, during Pregnancy: A Crucial Decision:

Cancer is the second leading cause of death during the reproductive years complicating between 0.02% and 0.1% of pregnancies. The incidence is expected to rise with the increase in age of childbearing. The most common types of pregnancy-associated cancers are: cervical cancer, breast cancer, malignant melanoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma and ovarian cancer. The relatively rare occurrence of pregnancy-associated cancer precludes conducting large, prospective studies to examine diagnostic, management and outcome issues. The treatment of pregnancy-associated cancer is complex since it may be associated with adverse fatal effects. In pregnant patients diagnosed with cancer during the first trimester, treatment with multidrug anti-cancer chemotherapy is associated with an increased risk of congenital malformations, spontaneous abortions or fetal death, and therefore, should follow a strong recommendation for pregnancy termination. Second and third trimester exposure is not associated with teratogenic effect but increases the risk of intrauterine growth retardation and low birth weight. There are no sufficient data regarding the teratogenicity of most cytotoxic drugs. Almost all chemotherapeutic agents were found to be teratogenic in animals and for some drugs only experimental data exist. Moreover, no pharmacokinetic studies have been conducted in pregnant women receiving chemotherapy in order to understand whether pregnant women should be treated with different doses of chemotherapy. This article reviews the available data regarding the different aspects of the treatment of cancer during pregnancy

Treatment of lung microcytoma with neuroendocrine differentiation in elderly patient

We describe the case of a 80-year-old patient with lung microcytoma and comorbidity (diabetes, COPD and hypertensive cardiomiopaty). To manage the complexity of the elderly patient with comorbidity, he was evaluated by a Comprehensive Geriatric Assessment (CGA). Radiotherapy and chemotherapy were excluded because of the low Performance Status of the patient. A treatment with octerotide LAR was administered, allowing a good clinical benefit

Tomotherapy after Pleurectomy/Decortication or Biopsy for Malignant Pleural Mesothelioma Allows the Delivery of High Dose of Radiation in Patients with Intact Lung

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