COMMENTARY

Brentuximab Approval First for Lymphoma in 30 Years

Bruce D. Cheson, MD

Disclosures

August 24, 2011

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Good afternoon, and welcome to Medscape Hematology. I am Bruce Cheson from Georgetown University Hospital, the Lombardi Comprehensive Cancer Center. Today I am talking to you about some really exciting news. The US Food and Drug Administration (FDA) has just approved SGN-35 (also called brentuximab vedotin), with the new trade name of Adcetris™ (Seattle Genetics, Bothell, WA), for 2 indications. The first is relapsed refractory Hodgkin lymphoma for patients having failed autologous stem cell transplant or 2 previous regimens, and who are not candidates for stem cell transplant; or anaplastic large cell lymphoma that is refractory or relapsed to first-line therapy.

What is this drug? This drug is probably the hottest new drug out there. It is a drug-antibody conjugate, in which a monoclonal antibody (in this case, anti-CD30) is linked to a poison (in this case monomethyl auristatin E [MMAE]), which is internalized into the cells and disrupts the microtubules.

We have an earlier example of this, which was Mylotarg® (Pfizer Inc., New York, NY), gemtuzumab ozogamicin, using calicheamicin as the poison, and a different antibody, for the treatment of acute myeloid leukemia. This drug has been removed from the market primarily because it lacked efficacy but was also associated with considerable toxicity, notably veno-occlusive disease of the liver and other hepatic incidents. The poison here is auristatin. It's different, as is the antibody anti-CD30.

Why are we so excited about this? There are 2 reasons. In Hodgkin lymphoma patients, the overall response rate was 73% including 32% complete remissions. For anaplastic large cell lymphoma, the response rate was 86% with more than 50% complete remissions. The median duration of response was 6.7 months for the Hodgkin lymphoma patients, and complete remission had a median duration of more than 20 months.

The anaplastic large cell data showed a complete remission rate of 57% with a median duration of 13.2 months. This drug is very active. It is also very well tolerated, with the major complications being neutropenia, thrombocytopenia, some usually reversible peripheral neuropathy, and a variety of other minor complaints.

We have here a biological drug that is associated with response rates higher than any chemotherapy regimen we have available for these patients. It is now being developed to use in treatment earlier in the course of the disease. However, it can be said, "Sure, relapse refractory Hodgkin's is a small niche, as is relapsed anaplastic large cell, which only accounts for a couple percent of lymphomas." Once a protocol is open for these patients, however, it is surprising how many of patients are out there. The compassionate-use protocol filled up rather quickly, as did the original clinical trials. Responses tend to occur rapidly, and symptoms disappear very quickly.

Of importance, not only is this a great drug, it is also a proof of concept. We now have demonstrated that you can take an antibody and link it strongly to a poison. It will get in the cells and kill them, without doing much damage to the rest of the body. This will be one of many to follow in its footsteps. A couple of non-Hodgkin lymphoma drugs are being studied. Gemtuzumab ozogamicin showed activity, and the Genentech molecule DCTD and a few others are currently being studied in phase 1 trials.

How these will best be combined or sequenced with chemotherapy remains to be seen, but I predict that this will change the way we treat Hodgkin lymphoma and large cell lymphoma. Some of the drugs that we are using now aren't great. We could incorporate this really exciting drug into a frontline combination and improve the outcome of the poor-risk patients; or we could salvage patients early on, without having to wait for transplant; or we could make patients transplant candidates who otherwise would not be available for this potentially life-saving procedure.

This news is going out all over the wires. It is really exciting for us lymphoma people, but it should be exciting for oncologists and hematologists all over the place because this form of drug will develop other second- and third-generation compounds that have the potential to really improve outcomes for patients -- not only with these unusual types of lymphomas, but for the more common types of lymphomas, and eventually perhaps solid tumors as well.

This is Bruce Cheson signing off for Medscape Hematology, and I hope when this drug gets on the market, you have patients who will benefit from it, and hopefully they will get it as soon as possible. The availability of this drug was made possible through patient participation in the clinical trials that led to its FDA approval. Thank you and have a great afternoon.

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