ASH: Regeneron's bispecific banishes lymphoma—even in patients failed by CAR-T

Regeneron
Although CAR-T therapies have transformed the treatment of patients with diffuse large B-cell lymphoma and other blood cancers, there remains room for improvement. (Regeneron)

CAR-T therapies have been a game changer in certain blood cancers, but they aren't a complete solution. For starters, not all patients can get CAR-T treatment, while others see their cancer worsen despite receiving it.

But Regeneron’s bispecific antibody could be a new option for those patients. The drug beat cancer back in two kinds of lymphoma in a phase 1 study, eliminating tumors in 70% of patients with follicular lymphoma (FL) and in 21% of patients with diffuse large B-cell lymphoma (DLBCL) who had not tried a CAR-T therapy.

The study, presented virtually Sunday at the annual meeting of the American Society of Hematology, found the treatment, odronextamab, did even better in DLBCL patients who had never received CAR-T treatment, banishing tumors in 55% of those patients.

The study tested various dose levels of odronextamab, a bispecific antibody targeting CD3 and CD20, in 127 patients with various non-Hodgkin lymphomas. That included 71 patients with DLBCL and 37 patients with FL. The patients had tried a median of three other treatments, with some receiving as many as 11 prior treatments. Of the 71 patients with DLBCL, just over one-third had tried a CAR-T therapy, namely Novartis’ Kymriah or Gilead’s Yescarta. In addition to being approved for the treatment of DLBCL, Kymria and Yescarta are also in the hunt for nods in FL.

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Odronextamab’s effects were long-lasting, too. Of the 70% of FL patients whose tumors were cleared, 81% were still responding to treatment up to 41 months later. The numbers were similar in the DLBCL patients who hadn’t tried CAR-T therapy—of the 55% of patients who saw their tumors banished, 83% were still responding up to 21 months later.

The most common side effects were fever, affecting about three-quarters of the patients, and cytokine release syndrome (CRS), affecting 62% of patients. CRS is an inflammatory response that can happen after treatment with certain types of immunotherapies and is a common side effect of CAR-T therapies. Most of the cases of CRS seen in the study were mild or moderate, though, and no patients quit the study because of CRS.

“It is important to note that CRS occurs almost universally in the first one to two weeks,” said Andres Sirulnik, M.D., Ph.D., senior vice president of translational and clinical sciences, hematology at Regeneron. The company thinks its approach of stepping up patients’ doses in the first two weeks before hitting the target dose in Week 3 has helped it reduce the risk of severe CRS, he added.

Although CAR-T therapies have transformed the treatment of patients with DLBCL and other blood cancers, there remains room for improvement. The available CAR-T therapies are made from a patient’s own cells in a process that can be complicated and time-consuming.

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“CAR-Ts are excellent tools to combat this disease, but on the other hand, they’re not available to everybody and we even have patients now that are starting to show progression in spite of CAR-T therapies,” Sirulnik said. The need for new last-line treatments for these kinds of blood cancer remains, he added.

“The CAR-T therapies available to a subset of patients have already shown themselves to be long-lasting therapies,” Sirulnik said. With odronextamab, Regeneron hopes to deliver similarly long-lived responses that are easier to administer to patients and be available to more people.

One other advantage of an antibody over CAR-T is the ability to adjust treatment after it’s started. Doctors may tweak the dose of odronextamab, or stop giving the drug entirely, if the patient is suffering side effects—something that can’t be done with CAR-Ts.

Regeneron has already started a phase 2 study of odronextamab that it hopes to finish enrolling in the first half of 2021, Sirulnik said. If all goes well, the company plans to conduct phase 3 confirmatory studies in FL and DLBCL in earlier lines of treatment, including second-line DLBCL and first-line FL. Further down the line, Regeneron hopes to combine odronextamab with the next generation of bispecifics in its pipeline to see whether they can deliver better results together.