crizotinib and Hypogonadism

Molecular profiling of nonsmall cell lung cancer (NSCLC) contributes to better understanding the different molecular subtypes of this heterogeneous group of diseases. The discovery of oncogenic ALK rearrangements in NSCLC and the subsequent success in their therapeutic targeting with crizotinib reinforces the benefits of a precision approach to systemic anticancer therapy. In addition, the rapid development of crizotinib from first discovery thorough accelerated US Food and Drug Administration approval, and late stage confirmatory clinical trials, exemplifies the success of the drug development strategy of close collaboration between clinicians, industry and regulatory authorities. In this review we describe the identification of ALK rearranged NSCLC, clinical characteristics of such patients, and clinical outcomes when treated with crizotinib.

Topics: Anaplastic Lymphoma Kinase; Bradycardia; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Crizotinib; Drug Resistance, Neoplasm; Gene Rearrangement; Humans; Hypogonadism; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

Non-small cell lung cancer (NSCLC) is a heterogenous group of disorders that can be subclassified based upon molecular characterization. Anaplastic lymphoma kinase translocation and MET aberrations occur in a subset of NSCLC. Anaplastic lymphoma kinase/MET have been shown to be inhibited by the small molecule tyrosine kinase inhibitor crizotinib. Recently, crizotinib was shown to decrease testosterone in males. Herein, we describe the effects of crizotinib on multiple hormonal axes.. Seven consecutive patients with NSCLC who were receiving crizotinib as part of their standard care were evaluated for hormonal disruptions.. Primary hypogonadism was detected in 4/5 of males, whereas mildly elevated prolactin was observed in 4/7 patients. Hypocalcemia was observed in 3/7 patients. Interestingly, 5/7 patients had elevated levels of insulin-like growth factor-1 (IGF-1) levels, and the remaining 2 individuals had levels that were near the upper limits of the normal range.. Because of cellular cross-talk between MET and IGF-1 signaling, elevated IGF-1 levels induced by crizotinib treatment may have implications for long-term drug efficacy. Furthermore, this finding suggests a potential avenue of therapeutic synergy, namely coordinate inhibition of the MET and IGF-1 signaling pathways. Finally, as crizotinib has been recently approved, it is prudent to check hormone and calcium biomarkers and correct noted deficiencies for improved outcomes and quality of life.

Topics: Anaplastic Lymphoma Kinase; Calcium; Carcinoma, Non-Small-Cell Lung; Crizotinib; Endocrine Disruptors; Female; Humans; Hypogonadism; Insulin-Like Growth Factor I; Lung Neoplasms; Luteinizing Hormone; Male; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Reference Values; Testosterone

Crizotinib (XALKORI(™), Pfizer) is a tyrosine kinase inhibitor of ALK, MET, and ROS1, which is currently approved for the second line treatment for ALK-rearranged lung cancer. This work from an expert group, based on the review of the data from the Profile studies, aims to provide practical elements in order to optimize the tolerability of crizotinib. Specific major or frequent side effects of crizotinib are discussed: visual disturbances, cardiac effects, elevated transaminases, and hypogonadism. In the routine practice, patients should be advised about visual disturbances, especially with regard to driving in low brightness. Digestive disorders related to crizotinib are exceptionally persistent or severe. Dietary measures and symptomatic treatments usually control these disorders. It is recommended to perform an electrocardiogram before introduction of crizotinib, to identify prolonged QT interval. Torsades de pointes may produce dizziness or syncope. Hypogonadism should be considered in case of fatigue, decreased libido, and even depression, taking into account that these symptoms may be related to cancer; testosterone serum level should be measured to identify patients that may be eligible to receive a supplementation. Monitoring of liver function tests, including transaminases and bilirubin, is necessary. To conclude, these practical elements are helpful to optimize treatment with crizotinib in patients with ALK-rearranged lung cancer; in the future, academic initiatives should be taken to study these aspects, based on the monitoring of large cohorts of patients treated with crizotinib.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; Digestive System Diseases; Gene Rearrangement; Humans; Hypogonadism; Liver; Lung Neoplasms; Patient Education as Topic; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Torsades de Pointes; Vision Disorders

Crizotinib is a tyrosine kinase inhibitor active against ALK, MET, and ROS1. We previously reported that crizotinib decreases testosterone in male patients. The detailed etiology of the effect, its symptomatic significance, and the effectiveness of subsequent testosterone replacement have not been previously reported.. Male cancer patients treated with crizotinib had total testosterone levels measured and results compared with non-crizotinib-treated patients. Albumin, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), and/or luteinizing hormone (LH) were tracked longitudinally. A subset of patients had free testosterone levels measured and a hypogonadal screening questionnaire administered. Patients receiving subsequent testosterone supplementation were assessed for symptomatic improvement.. Mean total testosterone levels were -25% below the lower limit of normal (LLN) in 32 crizotinib-treated patients (27 of 32 patients below LLN, 84%) compared with +29% above LLN in 19 non-crizotinib-treated patients (6 of 19 below LLN, 32%), P = .0012. Levels of albumin and SHBG (which both bind testosterone) declined rapidly with crizotinib, but so did FSH, LH, and free testosterone, suggesting a centrally mediated, true hypogonadal effect. Mean free testosterone levels were -17% below LLN (19 of 25 patients below LLN, 76%). Eighty-four percent (16 of 19) with low free levels, and 79% (19/24) with low total levels had symptoms of androgen deficiency. Five of 9 patients (55%) with low testosterone given testosterone supplementation had improvement in symptoms, coincident with increases in testosterone above LLN.. Symptoms of androgen deficiency and free or total/free testosterone levels should be tracked in male patients on crizotinib with consideration of testosterone replacement as appropriate.

Topics: Adult; Aged; Aged, 80 and over; Androgens; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Crizotinib; Follicle Stimulating Hormone; Humans; Hypogonadism; Lung Neoplasms; Luteinizing Hormone; Male; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Serum Albumin; Sex Hormone-Binding Globulin; Surveys and Questionnaires; Testosterone

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

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

The androgen receptor is a ligand inducible transcription factor that is involved in a broad range of physiological functions. Here we describe the discovery of a new class of orally available selective androgen receptor modulators. The lead compound, 6-[(2R,5R)-2-methyl-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl]-4-trifluoromethylquinolin-2(1H)-one (6a), showed excellent anabolic activity in muscle with reduced effect on the prostate in a rat model of hypogonadism. The compound also improved bone strength in a rat model of post-menopausal osteoporosis.

Topics: Administration, Oral; Anabolic Agents; Androgen Receptor Antagonists; Androgens; Animals; Biological Availability; Bone Density Conservation Agents; Female; Humans; Hypogonadism; Male; Muscle, Skeletal; Organ Size; Osteoporosis, Postmenopausal; Prostate; Pyrrolidines; Quinolines; Quinolones; Rats; Stereoisomerism; Structure-Activity Relationship