U.S. Food and Drug Administration approval: crizotinib for treatment of advanced or metastatic non-small cell lung cancer that is anaplastic lymphoma kinase positive.

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.

Development and regulatory strategies for drug and diagnostic co-development.

At the 5th FDA-Drug Industry Association (DIA) Workshop on 'Pharmacogenomics in Drug Development and Regulatory Decision Making', track four focused on the current thinking and issues in the co-development of therapeutic drugs or biologics, and their companion diagnostic products. Identification and validation of genomic and other biomarkers are becoming important components of drug-development strategies, and recent successes show the power of personalized approaches to change the benefit-risk paradigm for new drugs.

Progression of fibrosis in advanced chronic hepatitis C: evaluation by morphometric image analysis.

UNLABELLED: Fibrosis progression in chronic liver disease has usually been evaluated by liver biopsy using insensitive semiquantitative numerical scores. An alternative to this is to measure fibrous tissue quantitatively using morphometric image analysis. The aim of this study was to quantify fibrosis progression in a cohort of patients with treatment-refractory chronic hepatitis C enrolled in a placebo-controlled clinical trial of interferon gamma-1b (IFN-gamma 1b) for the treatment of advanced hepatic fibrosis. We used morphometry to quantify the amount of fibrous tissue in liver biopsies performed at baseline and after 48 weeks in 245 patients who had paired unfragmented, adequate-sized specimens and correlated the results with clinical and laboratory parameters. Eighty-seven patients were treated with placebo and 158 with IFN-gamma 1b. No effect of the drug on fibrosis was found in the trial, and so data from all 245 patients were combined for analysis. At baseline, 78% had cirrhosis; 22%, bridging fibrosis. The mean morphometrically determined collagen content increased by 58% between baseline and 48 weeks. There were statistically significant but weak correlations of fibrosis with platelet count, albumin, bilirubin, INR, and hyaluronic acid; however, changes in these did not correlate with or predict changes in fibrosis in the liver biopsy. CONCLUSION: In advanced chronic hepatitis C, fibrosis increases at a rapid pace that can only be detected by morphometry. This technique can be used in future therapeutic trials of agents to inhibit fibrosis progression.

Correlation of comparative genomic hybridization results of 100 archival uveal melanomas with patient survival.

Comparative genomic hybridization (CGH) was used to elucidate DNA sequence copy number imbalances in 100 archival formalin-fixed, paraffin-embedded (FFPE) uveal melanoma cases. Of these 100 cases, 51 were from patients who survived >or=9 years post diagnosis without evidence of metastasis; the remaining 49 patients died from metastatic disease. Viable probe was generated from 82 of the 100 cases, allowing correlation of CGH findings with survival for all but 18 cases. Copy number imbalances revealed by CGH were tested for univariate prognostic significance. The most powerful predictor of a poor prognosis was gain of 18q11.2, which was subsequently compared with other significant chromosomal regions, as well as histologic and clinical factors, in a multivariate analysis. There was also evidence of differential X chromosome involvement in the survival correlations between male and female cases, which may be of significance to prognosis. This large-scale CGH analysis of archival material is intended to direct further gene-specific study of malignancy in uveal melanoma.

Molecular cytogenetic evaluation of 10 uveal melanoma cell lines.

Uveal melanoma is the most common intraocular tumor in adults and often results in unilateral blindness and/or death. Previous cytogenetic characterizations of this tumor consistently revealed chromosomal abnormalities involving chromosomes 3, 6, and 8; reports of other abnormalities vary in frequency. We defined cytogenetic abnormalities of this tumor using complementary in situ hybridization techniques on 10 uveal melanoma cell lines. Synthesis of comparative genomic hybridization (CGH) and spectral karyotyping (SKY) results revealed that chromosomal rearrangement is involved in DNA sequence copy number abnormalities throughout the genome, but monosomy 3 was not found. Monosomy 3 is thought to be a significant prognostic indicator, so its absence was investigated further. Fluorescence in situ hybridization (FISH) for chromosome 3 revealed approximately 1 centromere signal per cell, but probes for 3p and 3q revealed multiple telomere signals per cell, suggesting chromosomal rearrangement without whole-chromosome loss. Based on combined CGH, SKY, and FISH data, we propose that chromosome 3 is more frequently involved in chromosomal rearrangements than whole-chromosome loss in uveal melanoma. Future approaches should be designed to confirm and enhance the resolution of regions of imbalance in primary tumors. Once identified, conserved chromosomal alterations that contribute to uveal melanoma may reveal the underlying aspects of uveal melanoma onset, metastasis and resistance to current treatment modalities.