Sarclisa Extends Survival in RRMM, Long-term Phase 3 Trial Data Shows

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by Steve Bryson, PhD |

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The therapy Sarclisa (isatuximab) extended survival by nearly seven months in relapsed/refractory multiple myeloma patients also given Pomalyst (pomalidomide) and dexamethasone as standard treatment, according to updated three-year data from the ICARIA-MM Phase 3 trial.

The data, “Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): follow-up analysis of a randomised, phase 3 study,” were published in The Lancet Oncology.

Sarclisa is an antibody-based therapy that blocks the activity of CD38, a protein receptor found on the surface of multiple myeloma cells. Similar to other CD38 inhibitors, it’s designed to prevent cancer cell growth.

Sarclisa, developed by Sanofi, is approved in the U.S. and Europe in combination with Pomalyst, an oral immunomodulatory medicine, and the corticosteroid dexamethasone to treat adults with myeloma who failed to respond to at least two prior lines of therapy and whose disease progressed on their most recent treatment.

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Sarclisa’s approval was based on data from ICARIA-MM (NCT02990338), an ongoing Phase 3 clinical trial that enrolled 307 patients to compare the triple combination therapy against the standard treatment, Pomalyst and dexamethasone. Participants included those who had at least two prior lines of treatment, including Revlimid (lenalidomide) and a proteasome inhibitor.

Initial data showed adding Sarclisa extended progression-free survival — the time patients lived without disease worsening — from 6.5 to 11.5 months, a nearly 40% reduction. It also increased the percentage of patients who responded from 35% to 60%.

Researchers at the Dana Farber Cancer Institute, Harvard Medical School, Massachusetts, collaborating with investigators at Sanofi and trial sites worldwide, provided a pre-specified update on overall survival at 24 months (two years) after the initial analysis.

“This study provides the first evidence, to our knowledge, of the long-term efficacy of [Sarclisa] in combination with [Pomalyst] and dexamethasone in patients with relapsed and refractory multiple myeloma,” the researchers wrote.

At the time of this analysis, 18% of patients initially assigned the Sarclisa combination group versus 8% of the standard group remained on treatment.

After a median follow-up of 35.3 months (almost three years), the median progression-free survival was significantly longer among patients who received Sarclisa combination therapy instead of standard treatment — 11.1 vs. 5.9 months. A total of 60% of those in the triple combination group had died, compared to 69% in the standard therapy group.

The median overall survival was 24.6 months in the Sarclisa group and 17.7 months in the standard group — an increase of 6.9 months.

Overall, 60% of the Sarclisa group and 72% of the standard group proceeded to a different therapy after progression. Median progression-free survival on subsequent therapy was 17.5 months for the Sarclisa group and 12.9 months for the standard group.

The outcomes of those who moved on to another anti-CD38 therapy after progression were also investigated.

“Important questions in the myeloma field are the sequencing of different anti-CD38 monoclonal antibodies and whether a tumor progressing on one anti-CD38 agent might be responsive to another anti-CD38 agent,” the researchers wrote.

Among patients who first received Sarclisa, 24% proceeded to the anti-CD38 therapy Darzalex (daratumumab) and 58% in the standard group. The median overall survival of Sarclisa-treated patients who then received Darzalex was 24.6 months compared to 19.9 months in the standard therapy group who received Darzalex, and 17.4 months for patients with no further Darzalex therapy.

The overall response rate with Darzalex as a subsequent anti-myeloma treatment was lower for patients in the Sarclisa group than in the control group. This difference was not seen when Darzalex was used alongside a proteasome inhibitor or immunomodulatory agent, “raising the question of whether becoming refractory to anti-CD38 therapy can be overcome with additional therapies,” the scientists wrote.

Median progression-free survival was similar between the Sarclisa and standard therapy groups who subsequently received a non-Darzalex regimen (4.2 vs. 5.0 months). In comparison, the median progression-free survival of those who received Darzalex as first-line therapy after Sarclisa was lower than patients in the standard group (2.2 vs. 5.1 months).

The team reported no new safety concerns with the Sarclisa triple combination with longer follow-up. The most frequent severe treatment-emergent side effects in the Sarclisa group versus the standard group were neutropenia, or low neutrophil counts (50% vs. 35%), pneumonia (23% vs. 21%), and low platelet counts (13% vs. 12%).

The most frequent serious side effect was pneumonia, reported in 23% of Sarclisa-treated patients and 21% of the standard treatment group. Definitive treatment discontinuations due to treatment-emergent side effects occurred at a similar rate in both treatment groups (12% vs. 14%).

“In summary, the updated results of this large, international, [multi-center] study solidify the position of [Sarclisa–Pomalyst–dexamethasone] combination therapy as an efficacious and well tolerated standard of care for patients with relapsed or refractory multiple myeloma,” the investigators said.

“Our analysis of other secondary outcomes, including overall response rates to subsequent [Darzalex]-based therapies, could inform the important clinical question of whether benefit can be gained from an alternate anti-CD38 antibody after the patient has not responded to another in an earlier line of treatment,” they added.