ASCO: Sanofi's anti-CD38 combo boosts responses, extends lives in advanced multiple myeloma

“Myeloma patients go through a journey where they get treated, they go into remission, and then they relapse, get treated and go into remission,” Sanofi R&D head John Reed told FierceBiotech. Sanofi is working on isatuximab as an agent that can boost the efficacy of multiple myeloma treatments at various stages of the disease. (Sanofi)

CHICAGO—Sanofi’s anti-CD38 antibody isatuximab added to the standard of care for relapsed multiple myeloma extended patients’ lives and nearly doubled the number of patients for whom the standard of care worked. The phase 3 data, presented Sunday at the annual meeting of the American Society of Clinical Oncology, showed that the isatuximab combination shrank tumors in 60% of patients compared to 35% of patients taking the standard of care alone. 

The standard of care is a combination of Celgene’s Pomalyst (pomalidomide) and the corticosteroid dexamethasone—dubbed pom-dex—which is usually given to patients who have relapsed after undergoing multiple treatments. 

“Myeloma patients go through a journey where they get treated, they go into remission, and then they relapse, get treated and go into remission,” Sanofi R&D head John Reed told FierceBiotech. “[Pom-dex] is usually the third line, when they’ve already been through this a couple times—by the time the third relapse occurs, there’s not much to offer patients.” 

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Frontline treatments succeed in the majority of patients, but multiple myeloma is still considered incurable—“everybody eventually relapses,” Reed said. Sanofi is working on isatuximab as an agent that can boost the efficacy of multiple myeloma treatments at various stages of the disease. 

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The phase 3 study enrolled 307 patients in 24 countries with relapsed or refractory multiple myeloma who had received at least two prior therapies. They received either pom-dex alone or pom-dex in tandem with isatuximab. 

The isatuximab combo kept cancer at bay for a median of 11.5 months, a five-month improvement over the 6.5 months for pom-dex alone. It also increased the number of patients for whom pom-dex worked—the combo shrank tumors in 60% of patients, compared to 35% for the standard of care alone. What’s more, of the patients who responded to treatment, the isatuximab combo worked faster, taking a median of 35 days to get a response versus 58 days for pom-dex alone.

“Isatuximab in combination with pomalidomide and dexamethasone resulted in an impressive 40% reduction in the risk of progression or death compared to pomalidomide and dexamethasone alone,” said the study’s principal investigator, Paul Richardson, M.D., in a statement. “This outcome is noteworthy because this trial included a particularly difficult-to-treat, relapsed and refractory patient population that was, in my view, highly reflective of real-world practice.”

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An analysis showed that the isatuximab combo performed similarly in different subgroups, including the elderly and people with poor kidney function.

“It gives you real confidence in the robustness of the data that every subgroup we looked at, you saw that adding isatuximab provided additional benefit,” Reed said. “When you see data sets where some groups benefit and others don’t, you wonder how strong are these data?”

Isatuximab showed early promise as a single agent, but Sanofi felt it would be best used to improve existing cancer treatments. It is testing it alongside earlier-line treatments such as Takeda’s Velcade and Amgen’s Kyprolis and is thinking about combining it with experimental treatments like the bispecific antibody it’s working on with Regeneron, Reed said.

Sanofi has filed isatuximab for approval in the U.S. and Europe and doesn’t expect any hiccups with the regulators, Reed said.

“We should be a player in myeloma pretty soon—that gives us an anchor point around which to build. Certainly, building vertically within myeloma—going to first-, second- and third-line therapy—[will involve] bringing in novel combination partners, so there will be a quite robust effort there.”

Isatuximab, like Johnson & Johnson’s blockbuster Darzalex (daratumumab) targets the CD38 receptor found on multiple myeloma cells to attack the cancer. Sanofi thinks it could one-up its rival thanks to a different different mechanism.

“Isatuximab binds to a different epitope on the CD38 target than daratumumab and in the laboratory, you can show mechanistic differences and how that affects the attack on the tumor,” Reed said.

“Isatuximab … induces a direct cell suicide signal in the myeloma cell, which is something daratumumab doesn’t do,” he said. “Also, CD38 is an enzyme and has what is called ecto-enzyme activity, where the enzyme activity is on the surface of the cell, not the interior of the cell.” Isatuximab blocks this activity strongly while Darzalex does so weakly, Reed said. Sanofi believes this combats the production of metabolites by the cell that tamp down the immune system in the tumor microenvironment.

Of course, Reed said, it isn't an apples-to-apples comparison and Sanofi will need to replicate the success of isatuximab in the lab into patients in the clinic. But if it works, it will be a success story for Sanofi’s efforts to build more of its pipeline from internal research rather than through partnerships.

Editor's note: This story has been edited to attribute the statements in the penultimate paragraph to John Reed and Sanofi. The comparison of the effect of isatuximab and Darzalex on ecto-enzyme activity was previously unattributed.

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