BY MARK FUERST
The recent announcement that GlaxoSmithKline (GSK) will discontinue the manufacture and sale of the Bexxar therapeutic regimen (tositumomab and iodine I 131 tositumomab) was met with dismay and resignation among those in the oncology community who believe this safe, effective therapy had been under-prescribed.
“Bexxar is an agent that clearly has activity in recurrent, indolent, transformed B-cell lymphoma. It would be nice to still have it available,” said John P. Leonard, MD, the Richard T. Silver Distinguished Professor of Hematology and Medical Oncology and Associate Dean for Clinical Research at Weill Cornell Medical College. “I certainly had a number of patients with durable, long-term remissions on Bexxar. But it couldn’t establish a place in the range of therapies.”
“It’s a shame to see an effective treatment be pulled off the shelves because of a lack of interest of prescribing it by oncologists,” said Anas Younes, MD, Chief of the Lymphoma Service at Memorial Sloan-Kettering Cancer Center. “It’s not just Bexxar, but radioimmunotherapy [RIT] as a class, including Zevalin, although Zevalin is a little easier to give than Bexxar. Both compounds were not appropriately positioned early on to help guide oncologists for the best indication.”
The GSK announcement to discontinue Bexxar as of February 20, 2014 stated: “The decision to discontinue Bexxar involved a thoughtful and careful evaluation of patient needs and the clinical use of the therapy, which was approved for use in the U.S. in 2003 and in Canada in 2005. The use of Bexxar has been extremely limited and is projected to continue to decline.”
‘Fewer than 75 Patients in the U.S. Received Bexxar Last Year’
GSK spokesperson Sarah Alspach told OT that “since its peak in 2006, there has been an average 30 percent annual decline in patient utilization for Bexxar, with fewer than 75 patients treated in the U.S. in 2012. In Canada, 18 patients have received Bexxar since 2008.”
In 2010 GSK had announced that it was moving to a pre-set manufacturing schedule for Bexxar. The change was effective November 1, 2010. “Our goal in establishing a predetermined production schedule was to find ways to manufacture Bexxar more efficiently and reduce the substantial waste that occurs through weekly production,” Alspach said. “At the time, our intention was to keep Bexxar on the market. However, we continued to see a progressive decline in Bexxar use, and there are other available treatment options for patients with non-Hodgkin’s lymphoma [NHL].”
Bexxar is indicated for the treatment of patients with CD20-positive relapsed or refractory, low-grade, follicular, or transformed NHL whose disease has progressed during or after rituximab therapy, including patients with rituximab-refractory NHL.
“It’s unfortunate that Bexxar was not used very commonly,” said Leonard, who is also a member of the American Society of Hematology Committee on Government Affairs. “Oncologists didn’t clearly see a patient population who could benefit the most from Bexxar, which is a highly active agent. They tended to use other, more straight-forward drugs that they were more familiar with. When bendamustine came along, it was a significantly active drug in follicular lymphoma. Oncologists saw they had an alternative agent.”
He noted that Zevalin is still available as a RIT, and other new agents are coming along, including lenalidomide, kinase inhibitors, novel antibody conjugates, and novel anti-CD20 agents. “We will go from one agent to another, as we need to.”
Younes called the discontinuation of Bexxar “a classic example of how a successful drug fails. Lack of data doesn’t cause a drug to fail, even lack of clinical data about survival. It was a mixture of confused marketing, lack of focused drug development, and poor sales.”
He noted that Bexxar had good single-agent activity with a response rate of more than 65 percent. “Although the duration of response was not that long, few drugs give more than one-year progression-free survival. And it was not a toxic drug. Just one course of treatment leads to no hair loss and little nausea and vomiting.”
Randomized, controlled trials failed to show a survival benefit of Bexxar over chemotherapy plus immunotherapy, he added. “But there are a lot of widely used drugs that have no scientific evidence of improved survival.”
Multiple, Small Company-Sponsored Trials Outside the Original Indication May Have Been Too Confusing
He said that he believes that multiple, small company-sponsored clinical trials outside the original indication confused oncologists about the best way to use Bexxar. “The intention was to allow single investigators to combine Bexxar with several regimens or combinations of new compounds. This was unfocused and did not advance the field or lead to other indications,” Younes said.
“At one point, there were only a few patients who needed Bexxar therapy who couldn’t get into one of the different clinical trials in the U.S.”
Leonard said that “Bexxar did not clearly prove to be a better therapy. If it had, oncologists would have used it more. Studies did not clearly establish its superiority, and people acted accordingly.”
The GSK statement noted that “additionally, there are other treatment options available for patients with relapsed NHL. Over the next six months, GSK will continue to provide support services for patients and treatment centers.”
Most oncologists now use bendamustine, said Younes, and clinical trials show it is effective as a single agent or combined with chemotherapy. A third-wave of active agents, including ibrutinib and PI3K inhibitors, will be used widely, he predicted.
Leukemia and Lymphoma Society
“Appropriate treatment for any given follicular lymphoma patient is highly individualized,” Clare Karten, Senior Director of Mission Education for the Leukemia & Lymphoma Society (LLS), told OT. “For the patient and the oncologist, it’s a personalized evaluation, taking into account the patient’s age and other medical conditions, symptoms, previous treatment, how advanced the disease is, other clinical signs, and the patient’s preferences.
With all these variables, it’s great that there are several treatment options for follicular lymphoma.”
She said that for certain patients, including the elderly or patients with substantial co-morbid conditions that make them poor candidates for chemotherapy, and others, RIT is considered an ideal choice by a number of lymphoma specialists because it causes relatively few side effects and can result in long periods of remission. LLS has started a dialogue with several clinical advisors about what the discontinuance of Bexxar means for patients.
“Our concerns go beyond any one therapy,” Karten continued.” It’s important that there are multiple treatment options in order to serve the individual needs of a diverse patient population, and further, that personalized, therapeutic decisions can be made between patients and physicians.”
Wanted to Give Adequate Notice
GSK said it announced its decision now to give treatment centers in the U.S. and Canada currently offering Bexxar adequate time to consider and, if appropriate, transition to other therapies.
Both Leonard and Younes agree that the discontinuation of Bexxar was a corporate decision, and that GSK accepted the reality that oncologists stopped using it. “It was good that GSK kept it going as long as it did,” said Leonard. “Still, it’s unfortunate that Bexxar won’t be available. Clearly, there are patients who used it in the past and could use it in the future. I hope that novel agents coming into use in follicular lymphoma and related lymphomas will step into the void.”
GSK Making the Cell Line Available
GlaxoSmithKline spokesperson Sarah Alspach said that “in keeping with GSK’s focus on transparency and collaboration, the company plans to make available, for legitimate research purposes, the cell line that secretes the anti-CD20 antibody used to make Bexxar. Access to the cell line will require that the user first enter a material transfer and other appropriate agreements. Because GSK will provide such access to the cell line, GSK does not plan to replenish the antibody supply.”
Bexxar is a therapy that involves very complicated manufacturing and supply chain processes, she noted. “The cell line is but one component of the product. It is used to produce the antibody for that product. It would be the responsibility of the user to assess the utility of the cell line in the manufacture of a biosimilar in any country, or for research or other purposes, and to obtain any licenses required for any contemplated use, for example, intellectual property or regulatory licenses.”
The cell line will be available through next August. Researchers interested in the cell line for legitimate research purposes can contact GSK at 888-825-5249.