Proteasome inhibition as an anticancer target We read with interest the concise article by Irena Melnikova and James Golden on apoptosis-targeting therapies in the News and Analysis section of the November issue of Nature Reviews Drug Discovery1. We would like to correct what we view to be factual inaccuracies in regards to the authors' conclusions on proteasome inhibition as an emerging anticancer target. Melnikova and Golden state that “The effectiveness of bortezomib is based on response rates (the FDA reviewed bortezomib under the accelerated approval programme). There are no controlled trials demonstrating a clinical benefit, such as improvement in survival.”
On the contrary, bortezomib was determined to be an effective therapy for advanced multiple myeloma on data from a large multi-centre Phase II trial of 202 heavily pre-treated patients with relapsed and refractory multiple myeloma2 in which not only were the response rates (35%) encouraging; in addition, the time-to-disease progression (TTP) of patients while on bortezomib therapy (median 7 months) was superior to the TTP of the same patients (median 3 months) while receiving their last line of salvage therapy prior to study entry. Extensive clinical experience in patients with advanced-stage myeloma has shown that each line of salvage therapy is associated with progressive shortening of TTP. Therefore the ability of bortezomib to reverse that trend is a crucial feature of its efficacy in this disease. Furthermore, the overall survival (OS) among bortezomib-treated patients with a complete or partial response was superior to that of non-responders according to analyses of the Phase II trial data with the landmark method.
In regards to the notion that “There are no controlled trials demonstrating a clinical benefit, such as improvement in survival”, this is also not accurate — a large multi-centre (93 participating centres), international, randomized clinical trial in 669 advanced myeloma patients3 demonstrated that bortezomib treatment led to superior TTP and OS than high-dose dexamethasone, a standard salvage regimen for multiple myeloma. In fact, the independent Data Monitoring Committee for this trial recommended the early termination of the trial, after a formal protocol-specified interim analysis, and patients randomized to high-dose dexamethasone were allowed to receive bortezomib.
We appreciate the opportunity to bring this important information to the attention of your readers in order to avoid any misinterpretation of the existing evidence on the clinical activity of this important new class of anticancer agents.
Melnikova, I. & Golden, J. Apoptosis-targeting therapies. Nature Rev. Drug Discov. 3, 905–906 (2004).
Richardson, P. G. et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N. Engl. J. Med. 348, 2609–2617 (2003).
Richardson, P. et al. Bortezomib versus dexamethasone in relapsed multiple myeloma: a phase 3 randomized study. J. Clin. Oncol. 22 (Suppl. 14), 6511 (2004).