Future oncology
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Ruxolitinib (INCB018424) is the first potent, selective, oral inhibitor of JAK1 and 2 being developed for clinical use. Its major cellular and systemic effects are proliferation inhibition, apoptosis induction and reduction in cytokine plasma levels, all mediated by the drug's inhibition of JAKs' ability to phosphorylate STAT. In initial clinical trials of its use in myelofibrosis, ruxolitinib exhibited durable efficacy in reduction of splenomegaly and alleviation of constitutional symptoms. ⋯ The dose-limiting toxicity was thrombocytopenia. In preliminary findings of a Phase III trial in patients with primary, postpolycythemia-vera, or postessential-thrombocythemia myelofibrosis, administration at an initial dosage of 15 or 20 mg twice daily led to a spleen-volume response rate (≥ 35% reduction at 24 weeks) of 41.9 versus 0.7% for placebo (p < 0.0001); furthermore, 45.9% of the ruxolitinib recipients had ≥ 50% improvement in symptom score (on the modified Myelofibrosis Symptom Assessment Form version 2.0) versus 5.3% for placebo (p < 0.0001). Ruxolitinib recipients also showed improvement in parameters of quality of life.
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Crizotinib is an oral small-molecule inhibitor of ALK and c-Met tyrosine kinases that is being developed by Pfizer. ALK mutations or gene rearrangements result in growth factor-independent ALK activation. Most of the available clinical data with crizotinib are in patients with tumors that have an activated ALK, and the drug has shown very promising clinical benefit in these patients. ⋯ Grade 3/4 elevations in hepatic transaminases occurred in 6% of the patients, which in most patients resolved with dose reduction. Ongoing studies will define the true utility of this drug in ALK-rearranged non-small-cell lung cancer patients and in patients with other tumors that also have ALK activation. Preliminary data suggest that the drug may also be active in tumors with an activated c-Met pathway.
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Standard whole-breast irradiation consisting of a dose of 45-50 Gy over 5 weeks with or without the addition of a boost to the tumor bed has equivalent survival to mastectomy and is considered to be the standard of care for most patients with early-stage breast cancer. Newer techniques have been developed to shorten the course of radiation or limit normal tissue exposure in an attempt to increase accessibility to and tolerance of radiation therapy. This article will review some of the newer regimens and techniques for treating early-stage breast cancer after breast-conserving surgery.
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Review
Ridaforolimus: a promising drug in the treatment of soft-tissue sarcoma and other malignancies.
Ridaforolimus (deforolimus; AP23573; MK-8669) is a novel sirolimus derivative manufactured by ARIAD Pharmaceuticals and acquired by Merck. It is a small-molecule kinase inhibitor of the mTOR in clinical development for the treatment of cancer. Both intravenous and oral formulations of the agent are being tested in cancer clinical trials. ⋯ With single-agent ridaforolimus, mucositis and myelosuppression were dose-limiting toxicities. In advanced soft-tissue sarcoma, single-agent ridaforolimus was associated with a 29% clinical benefit rate and 2% partial response rate. A Phase III trial has recently been reported to have met its primary end point.