An advisory panel at the FDA has unanimously recommended an investigational drug, brentuximab vedotin, for accelerated approval for the treatment of refractory cases of two types of lymphoma.

Brentuximab vedotin, developed by Seattle Genomics, a biotech company headquartered in Bothell, WA, USA, is an antibody-drug conjugate with a novel mechanism of action. It consists of a chimeric monoclonal antibody, brenduximab, which targets the tumour necrosis factor receptor protein CD30, bound to a small molecule, vedotin.

The antibody directs the drug to tumour cells; vedotin, which is also known as monomethyl auristatin E, prevents cell division by inhibiting tubulin polymerisation. It is only effective in a conjugate with an antibody.

The drug has been recommended for approval for treating certain patients with Hodgkin's lymphoma and systemic anaplastic large cell lymphoma based on results of two pivotal Phase II clinical trials. Both these trials were presented as abstracts at the American Society of Haematology meeting in 2010. They were open label, single arm trials in patient groups who had failed previous therapies.

Hodgkin's lymphoma, previously known as Hodgkin's disease, is one of the more common types of lymphoma. It is characterised by the presence of Hodgkin Reed-Sternberg cells, which express the CD30 receptor that is the target for brentuximab. The clinical trial that formed the basis for approval of brentuximab vedotin for this indication was led by Robert Chen of City of Hope National Medical Center, California, USA [1].

Chen and his colleagues recruited 102 patients diagnosed with Hodgkin's lymphoma who had previously failed an autologous stem cell transplant to 26 study centres across the US. Each patient was treated with up to 16 three-weekly cycles of brentuximab vedotin by intravenous infusion, and the primary end point was the overall response rate. The researchers reported an overall response rate of 75% in this patient group, with 34% achieving complete remission; only 3% had progressive disease. Adverse events, mainly peripheral neuropathy, fatigue and nausea, were generally manageable.

Systemic anaplastic large cell lymphoma (sALCL) is a rarer disease, accounting for only 2-3% of cases of non-Hodgkin's lymphoma; lymphoma cells in patients with this disease also express the CD30 receptor. The trial that led to approval of brentuximab vedotin for sALCL had a similar design to that in Hodgkin's lymphoma, but was smaller, involving 58 patients, all of whom had failed at least one previous treatment [2].

It was led by Andrei Shustov of Fred Hutchinson Cancer Research Center, University of Washington Medical Center, Seattle, Washington, USA. Again, all participants were treated with up to 16 three-weekly cycles of the drug by intravenous infusion. In this relatively small group of patients, the overall response rate was 86% and the complete response rate was 57%. Again, all adverse events were manageable.

Current options for patients with either of these lymphomas who fail first line treatments are limited, and no new drugs for Hodgkin's lymphoma have been approved since 1977. The FDA is not required to follow the recommendations of its committees, but it very often does so; this recommendation, therefore, represents a hopeful sign that options for these patients will soon increase. Before the drug can be fully approved, however, it must undergo further trials for safety and efficacy.

References:

[1] Chen, R., Gopal, A.K., Smith, S.E. and 9 others (2010). Results of a pivotal phase 2 study of brentuximab vedotin (SGN-35) in patients with relapsed or refractory Hodgkin lymphoma. American Society for Haematology 2010; Abstract 283.

[2] Shustov, A.R., Advani, R., Brice, P. and 11 others (2010). 961 complete remissions with brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large cell lymphoma. American Society for Haematology 2010; Abstract 312.