azd-6244 and Adenocarcinoma--Follicular

A multicenter, open-label, phase II trial was conducted to evaluate the efficacy, safety, and tolerability of selumetinib in iodine-refractory papillary thyroid cancer (IRPTC).. Patients with advanced IRPTC with or without follicular elements and documented disease progression within the preceding 12 months were eligible to receive selumetinib at a dose of 100 mg twice daily. The primary endpoint was objective response rate using Response Evaluation Criteria in Solid Tumors. Secondary endpoints were safety, overall survival, and progression-free survival (PFS). Tumor genotype including mutations in BRAF, NRAS, and HRAS was assessed.. Best responses in 32 evaluable patients out of 39 enrolled were 1 partial response (3%), 21 stable disease (54%), and 11 progressive disease (28%). Disease stability maintenance occurred for 16 weeks in 49%, 24 weeks in 36%. Median PFS was 32 weeks. BRAF V600E mutants (12 of 26 evaluated, 46%) had a longer median PFS compared with patients with BRAF wild-type (WT) tumors (33 versus 11 weeks, respectively, HR = 0.6, not significant, P = 0.3). The most common adverse events and grades 3 to 4 toxicities included rash, fatigue, diarrhea, and peripheral edema. Two pulmonary deaths occurred in the study and were judged unlikely to be related to the study drug.. Selumetinib was well tolerated but the study was negative with regard to the primary outcome. Secondary analyses suggest that future studies of selumetinib and other mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK; MEK) inhibitors in IRPTC should consider BRAF V600E mutation status in the trial design based on differential trends in outcome.

Topics: Adenocarcinoma, Follicular; Adult; Aged; Aged, 80 and over; Benzimidazoles; Carcinoma; Carcinoma, Papillary; Diarrhea; Exanthema; Fatigue; Female; Genotype; Humans; Iodine Radioisotopes; Kaplan-Meier Estimate; Male; Middle Aged; Mutation; Pharmacogenetics; Proto-Oncogene Proteins B-raf; ras Proteins; Thyroid Cancer, Papillary; Thyroid Neoplasms; Treatment Outcome

Over the past 5 years, patients with progressive radioactive iodine-refractory thyroid cancer have responded to "targeted" multikinase inhibitors, which inhibit angiogenesis and not the tumor cell. Here, selumetinib targets the mitogen-activated protein kinase pathway in papillary thyroid carcinoma and shows limited single-agent activity in the patients with tumors that harbor the (V600E)BRAF mutation.

Topics: Adenocarcinoma, Follicular; Benzimidazoles; Carcinoma; Carcinoma, Papillary; Female; Humans; Male; Pharmacogenetics; Thyroid Cancer, Papillary; Thyroid Neoplasms