In 13 March 2014 issue of the New England Journal of Medicine, Dr Ajay Gopal of the Division of Medical Oncology, University of Washington School of Medicine, Seattle Cancer Care Alliance, USA and colleagues reported results from an international non-randomised phase II study of idelalisib monotherapy in patients with indolent non-Hodgkin's lymphoma. The overall response rate was impressive 57%, with a median progression-free survival of 11 months, values suggesting that the efficacy of idelalisib is similar or superior to those of other active treatment options in relapsed or refractory indolent non-Hodgkin's lymphoma. The toxic effects were acceptable with common adverse events including diarrhoea and aminotransferase elevations that were mostly reversible on dose discontinuation or reduction.
Indolent cases constitute approximately one third of all patient with non-Hodgkin's lymphoma and include follicular lymphoma, small lymphocytic lymphoma, marginal-zone lymphoma, and lymphoplasmacytic lymphoma with or without Waldenström's macroglobulinemia.
An unmet need for new treatments with novel mechanisms of action in patients with rituximab- and chemotherapy-refractory disease
The mainstay of treatment for indolent non-Hodgkin's lymphoma is an anti-CD20 antibody rituximab in combination with chemotherapy consisting of alkylating agents, anthracyclines, antimitotic agents, or purine analogues. Although the current treatments are initially effective in inducing responses in most patients, they are not curative and show decreasing efficacy with repeated administrations. In addition, chemotherapy-based regimens are associated with long-term toxic effects, including cumulative myelosuppression, neuropathy, cardiac toxicity, and secondary cancers.
The most recent chemotherapeutic agent that has been approved for use in patients with rituximab-refractory indolent non-Hodgkin's lymphoma is the alkylating agent bendamustine, but it is not currative. Radioimmunotherapies can be active, but owing to the potential for haematologic toxic effects, their use has been limited to patients with adequate marrow function and limited marrow involvement by tumour.
The use of these agents is further constrained by the complex procedures for their administration. For these reasons, 90Y-ibritumomab is used infrequently, and 131I-tositumomab has been withdrawn from the market.
PI3K is a lipid kinase that has a catalytic subunit with four different isoforms: α, β, γ, and δ. The α and β isoforms are widely expressed in many tissues, whereas the γ and δ isoforms are highly restricted to haematopoietic cells. PI3Kδ signaling pathways are frequently hyperactive in B-cell malignancies, making inhibition of PI3Kδ a promising target.
Impressive response rate
Idelalisib is a potent, oral, small-molecule inhibitor of PI3Kδ that is highly selective for the δ isoform. Phase I study in patients with haematologic malignancies showed that idelalisib had an acceptable safety profile and promising antitumour activity.
In this single-arm, open-label, phase II study, 125 patients with indolent non-Hodgkin's lymphomas who had not had a response to rituximab and an alkylating agent or had had a relapse within 6 months after receipt of those therapies were administered idelalisib, until the disease progressed or the patient withdrew from the study. The primary endpoint was the overall rate of response; secondary endpoints included the duration of response, progression-free survival, and safety.
The median age of the patients was 64 years (range, 33 to 87). Patients had received a median of four prior therapy lines (range, 2 to 12). Subtypes of indolent non-Hodgkin's lymphoma included follicular lymphoma (72 patients), small lymphocytic lymphoma (28), marginal-zone lymphoma (15), and lymphoplasmacytic lymphoma with or without Waldenström's macroglobulinemia (10).
The response rate was 57%, with 6% meeting the criteria for a complete response. The median time to a response was 1.9 months, the median duration of response was 12.5 months, and the median progression-free survival was 11 months. Similar response rates were observed across all subtypes of indolent non-Hodgkin's lymphoma, though the numbers were small for some categories.
The most common adverse events of grade 3 or higher were neutropenia (in 27% of the patients), elevations in aminotransferase levels (in 13%), diarrhoea (in 13%), and pnaeumonia (in 7%).
Biology explains efficacy and side effects of idelalisib
Along with ibrutinib, which targets Bruton's tyrosine kinase (BTK), idelalisib represents a new class of agents that target signal transduction downstream of the B-cell receptor (BCR) in malignant B cells. BCR signaling activates PI3K to produce the second messenger PIP3, which recruits other proteins to the membrane. BTK is a key PI3K effector in B cells. PI3K and BTK are also activated downstream of numerous other receptors on B cells.
Idelalisib and ibrutinib do not produce durable responses in all patients. Identifying and overcoming resistance mechanisms will be crucial for the most effective use of these agents. Since the two agents have acceptable side effect profiles, it makes sense to test their combination.
Although most clinical trials with PI3K inhibitors have focused on solid tumorus with PI3K mutations or PTEN loss, and giving the results achieved in phase III trial with idelalisib and rituximab in relapsed chronic lymphocytic leukaemia, it is likely that the first approval of a PI3K inhibitor will be in a disease in which neither PI3K nor PTEN is mutated, wrote in an accompanied editorial article David Fruman of the University of California, Irvine and Lewis Cantley of the Weill Cornell Medical College, New York.
The study of idelalisib in relapsed indolent lymphoma was sponsored by Gilead Sciences and Calistoga Pharmaceuticals (which was acquired by Gilead Sciences in 2011), Fred Hutchinson Cancer Research Center, University of Washington Cancer Consortium Cancer Center Support Grant of the National Institutes of Health (P30 CA015704), and by philanthropic gifts from Frank and Betty Vandermeer. Dr Gopal is a Scholar in Clinical Research for the Leukemia and Lymphoma Society.
Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ Inhibition by Idelalisib in Patients with Relapsed Indolent Lymphoma. N Engl J Med 2014; 370(11):1008-1018.
Fruman DA, Cantley LC. Idelalisib — A PI3Kδ Inhibitor for B-Cell Cancers. N Engl J Med 2014; 370(11):1061-1062.