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September 27, 2004

Expanding Radioimmunotherapy
By David Surface
Radiology Today
Vol. 5 No. 20 Page 10

Zevalin and Bexxar are the only FDA-approved therapeutic compounds; they target certain non-Hodgkin’s lymphomas. Researchers and clinicians are looking to broaden their indications—and the use of radioimmunotherapy in general.

On July 1 of this year, Corixa Corporation, the makers of the radioimmunotherapy drug Bexxar (tositumomab and iodine I 131 tositumomab), filed a supplemental application with the FDA requesting accelerated approval for expanded use of Bexxar. This marks the latest chapter in the rivalry between the makers of Bexxar and its closest competitor, Zevalin (ibritumomab tiuxetan), the two FDA-approved radioimmunotherapy drugs.

The approved indications for both drugs are practically identical, with one critical difference. While each is approved for the treatment of patients with CD20 positive, follicular, non-Hodgkin’s lymphoma, with and without transformation, who have failed at least one scheme of chemotherapy, Bexxar carries an additional indication: Patients must also have failed the drug Rituxan.

Leveling the Field
Because the indication for Zevalin does not mention Rituxan, Zevalin enjoys a broader approval than Bexxar—a situation that the makers of Bexxar are working to change. Besides the July filing, researchers are also investigating Bexxar as a first-line therapy for non-Hodgkin’s lymphoma. Initial clinical research presented at the 40th annual meeting of the American Society of Clinical Oncology reported that 72% of patients who received initial sequential therapy with fludarabine and Bexxar and achieved a complete response remained disease-free after a median follow-up of nearly 41/2 years.

In a second study, the chemotherapy regimen CVP (cyclophosphamide, vincristine, and prednisolone) followed by Bexxar produced a complete response rate of 80%, with 77% continuing in response after a median follow-up of 2.3 years.

“These data contribute to our growing picture of the utility of Bexxar in the treatment of non-Hodgkin’s lymphoma, particularly its ability to produce durable remissions in some patients with advanced disease,” said John P. Leonard, MD, clinical director, Center for Lymphoma and Myeloma at Weill Medical College of Cornell University.

What’s ironic about watching Bexxar play “catch-up” with Zevalin is the fact that almost everyone expected Bexxar to be approved first.

“Bexxar was first out of the chute,” remembers Roger Macklis, MD, professor and chair of the department of radiation oncology at the Cleveland Clinic Foundation. “The first good paper showing large clinical trials with clinical success came out about Bexxar. There was work done by Oliver Press, MD, PhD, in Seattle and Mark Kaminski, MD, at the University of Michigan. People thought Bexxar would be the first approved.”

But the FDA took a different view. “Instead of comparing Bexxar to the standard of care, Corixa had compared Bexxar to whatever regimen of chemotherapy these patients had undergone,” Macklis recalls. “The FDA said, ‘That’s not a true standardized trial—go back and do it over.’”

Meanwhile, Idec, the company that made Zevalin, was doing its own trials.
Zevalin’s indication does not mention Rituxan for one simple and unique reason: Zevalin contains Rituxan because both drugs are made by Idex.

Very Similar Uses
“Bexxar and Zevalin are both for essentially the same indications,” says Macklis. “To get an indication for Zevalin, they were already getting the Rituxan in the mix. The question was: Would the radiolabeled form of the parent antibody used to design Rituxan be better than Rituxan alone? And it was. The results showed approximately a 50% response rate for Rituxan vs. an 80% response rate for Zevalin. And they got approved.”

For Maxim, the lesson of the Zevalin approval is not just one of good science but of bureaucratic savvy. “The interesting story is that the guys who made Zevalin aced out the guys who made Bexxar because they understood better what the FDA wanted.”

As expected, the makers of Bexxar were not happy with the FDA’s decision. “The Bexxar people were screaming, ‘A trial against their own drug is not fair,’” says Macklis, “but it was too late.”

“When Bexxar was presented to the FDA, the study they used to obtain approval was in patients who failed chemotherapy and Rituxan—88% of the patients met the definition of Rituxan refractory,” says Andres Forero, MD, medical director of the clinical studies unit at the University of Alabama Comprehensive Cancer Center. “It was not approved directly after first chemotherapy failure. That’s the work they presented. It’s very restrictive—only for those who are resistant to Rituxan. What they are applying for now is approval not only for patients resistant to Rituxan but for every patient who has failed at least one course of chemotherapy. They are looking for the same indication that Zevalin received.”

Radioimmunotherapy drugs have had a difficult time finding their way from the laboratory to the marketplace. “The first radioimmunotherapy antibodies were developed in the 1940s but didn’t take off until the 1970s, with the development of monoclonal antibodies,” says Macklis. “Even so, it took another 30 years for this idea to get its first approved radioimmunotherapy drug.”

Slow Approval
Why does it take so long for radioimmunotherapy drugs to get approval? “You had to show that these compounds were substantially better than other standards of care,” explains Macklis. “It’s fairly complex. People have had radioimmunotherapy antibodies in the lab for decades, but it took a while to have a commercializable product. You can make a lot of products in the lab that don’t necessarily pass good manufacturing processes.”

“When you are using radioactivity, the FDA is very conservative in their approach to evaluating those compounds,” says Forero. “It’s difficult to run trials because in order to protect humans, there are restrictions that prolong time for clinical evaluation. Of course, in many cases they have a good reason because the most important point is safety. If I have a new radioimmunoconjugate, it takes a lot of time to run the phase 1 and phase 2 trials.”

The Toxicity Question
One factor in Bexxar’s and Zevalin’s effort to reach the marketplace has been concerns about their reported toxicity. Forero believes those concerns are overrated. “The feeling of both companies is that it’s a concern, but no more than in standard chemotherapies,” he says. “The first time myelodysplastic syndrome was described was in patients who’d received chemotherapy. When we started evaluating Zevalin and Bexxar, we found the same. When we analyze the percentage of patients who develop myelodysplastic syndrome, it’s not different from the percentage of those with chemotherapy. The risk is similar, and it’s quite low—less than 3%.”

Forero also believes it’s questionable whether or not Zevalin and Bexxar actually play a direct role in patients developing myelodysplastic syndrome. “Also, remember that patients who’ve been treated with Zevalin and Bexxar have also received a lot of chemotherapy, since that’s the indication,” says Forero. “So we don’t really know what the real cause is.”

Based on the preliminary data, Forero believes that Bexxar will almost certainly receive the approval they are seeking for expanded use. “If you review the data, it is hard to imagine that it won’t be approved,” says Forero. “You will have two products on the market, and that will be a good thing.”

In the meantime, what the FDA required was for the manufacturers to run a trial in which Bexxar will be evaluated head to head with Zevalin. Again, Forero is positive about the eventual outcome of the trial. “My feeling is that the effectiveness will be about the same.”

Broadening RIT
Macklis, for one, believes in the need to see beyond the competitive nature of the pharmaceutical market and focus on a more worthy consideration: the patients’ needs.

“The question is not which drug is better, though that in itself is an interesting question which might takes years to answer,” says Macklis. “The real question is: How can we make the whole field of radioimmunotherapy more broadly applicable? Right now, less than 3,000 patients are treated with radioimmunotherapy of every sort combined every year. It should be four or five times that in my estimation.”

Macklis explains the reasons radioimmunotherapy is being underused. “There are all sorts of reasons,” says Macklis. “For one, instead of one doctor, you have to have a whole team from various specialities, and that adds layers of complexity. As a patient advocate, I believe we should be using much more radioimmunotherapy. Right now we have no data suggesting that either Bexxar or Zevalin is better than the other. We do have data that suggests we aren’t doing as much radioimmunotherapy as we should.”

— David Surface is a freelance writer based in Brooklyn, N.Y. He is a frequent contributor to Radiology Today.

Treating More Types of Lymphomas
Today, there are no radioimmunotherapy drugs approved for the treatment of certain types of lymphomas. Andres Forero, MD, medical director of the clinical studies unit at the University of Alabama Comprehensive Cancer Center, is working to change that.

“Both Bexxar and Zevalin are used to target specific markers expressed by the B cells (CD20) of the non-Hodgkin’s lymphomas. Eighty percent of the lymphomas that we have now are CD20 positive. So you can use, in theory, both drugs in multiple types of lymphomas.”

The two CD20 positive lymphomas Forero is investigating are mantle cell lymphoma and diffuse large B-cell lymphoma, an intermediate-grade lymphoma.

“If you review the data published in the field of radioimmunotherapy, you’ll find some studies investigating them in these lymphomas,” says Forero. “But the really important studies [phase 3 and randomized trials] have not been published yet—that’s what we’re investigating now.”

Forero explains the protocol: “We’re treating the patients with ‘standard of care.’ In addition, they are receiving radioimmunotherapy sometimes before, sometimes after standard chemotherapy. The question is: Does the addition of one of the radioimmunoconjugates improve outcome?”

Forero knows he’s in for the long haul. “These phase 3 and randomized trials for large B-cell and mantle cell lymphomas are long studies. It’ll be four or five years before we’ll know results that can change the standard of care. It’s a long run.”

— DS

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