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FDA Reviewing Isatuximab BLA in Relapsed/Refractory Multiple Myeloma

Lisa Astor
Published Online:6:30 PM, Wed July 10, 2019
The FDA has accepted and is reviewing a Biologics License Application (BLA) for isatuximab as a potential treatment for patients with relapsed or refractory multiple myeloma. A target action date of April 30, 2020 has been set by the agency.1

Data from the pivotal phase III ICARIA-MM, as presented at the 2019 ASCO Annual Meeting, acts as the basis for the BLA. The trial investigated the combination of isatuximab with pomalidomide (Pomalyst) and low-dose dexamethasone compared with pomalidomide and dexamethasone alone (Pd), and the trial showed a 5-month increase in progression-free survival (PFS) with the addition of isatuximab as well as a trend toward improved overall survival (OS).

This was the first randomized phase III trial to show positive results for the use of an antibody in combination with pomalidomide and dexamethasone in patients with multiple myeloma.

The open-label multicenter ICARIA-MM trial enrolled 307 patients with relapsed/refractory multiple myeloma who had received ≥2 prior lines of treatment, including lenalidomide (Revlimid) and a proteasome inhibitor.

The median patient age was 67 years (range, 36-86) and patients had received a median of 3 (range, 2-11) prior lines of therapy. Overall, 92.5% of patients were lenalidomide refractory, 75.9% were refractory to a proteasome inhibitor, and 19.5% had high-risk disease cytogenetics.

Isatuximab was administered intravenously at 10 mg/kg once weekly for 4 weeks followed by bi-weekly for 28-day cycles in combination with standard Pd for the duration of therapy. There were 154 patients on the isatuximab arm and 153 patients on the control arm of Pd alone. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint was PFS. Key secondary endpoints included overall response rate (ORR) and OS.

The median PFS per independent review was 11.53 months with the isatuximab regimen compared with 6.47 months with Pd alone (HR, 0.596; 95% CI, 0.44-0.81; P = .001). The investigator data showed a median PFS of 11.14 months with the isatuximab triplet compared with 6.54 months for the Pd-alone group (HR, 0.602; 95% CI, 0.44-0.82; P = .0009).

The PFS benefit held up across multiple patient subgroups, including patients with high cytogenetic risk (HR, 0.66; 95% CI, 0.33-1.28); patients refractory to lenalidomide (HR, 0.59; 95% CI, 0.43-0.82); patients refractory to lenalidomide at their last previous line (HR, 0.50; 95% CI, 0.34-0.76); patients refractory to a proteasome inhibitor (HR, 0.58; 95% CI, 0.41-0.82); and patients refractory to lenalidomide and a proteasome inhibitor (HR, 0.58; 95% CI, 0.40-0.84).

At the time of the data cutoff before the ASCO presentation, OS data were not yet mature, but there was a trend toward a survival benefit for the isatuximab arm (HR, 0.687; 95% CI, 0.46-1.02). The median OS was not reached in either arm. The 1-year OS rate was 72% with the isatuximab triplet compared with 63% with Pd alone.

The ORR was 60.4% in the isatuximab arm compared with 35.3% in the Pd-alone arm (P <.0001). The ORR in the isatuximab group comprised a complete response (CR)/stringent CR rate of 4.5%, a very good partial response rate of 27.3%, and a partial response rate of 28.6%. The corresponding numbers for the control arm were 2.0%, 6.5%, and 26.8%, respectively.

The median time to first response was 35 days with the isatuximab triplet compared to 58 days with Pd alone. The MRD negativity rate was 5.2% versus 0% with isatuximab versus Pd-alone, respectively.

The median time to next therapy was not reached in the isatuximab arm compared with 9.1 months in the control arm (HR, 0.538; 95% CI, 0.382-0.758). Sixty patients in the isatuximab group and 83 patients in the Pd-alone group received subsequent antimyeloma therapy. These treatments included alkylating agents (66.7% of patients in the isatuximab arm vs 39.8% of patients in the Pd-alone arm), proteasome inhibitors (56.7% vs 47.0%, respectively, immunomodulatory drugs (23.3% vs 22.9%), and daratumumab (10.0% vs 54.2%).

The median duration of treatment was 41.0 weeks (range, 1.3-76.7) in the isatuximab arm compared to 24.0 weeks (range, 1.0-73.4) in the control arm. In the isatuximab arm, 56.5% of patients discontinued treatment compared to 74.5% of patients in the Pd-alone arm. Progressive disease was the primary reason for discontinuation in both arms.

Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 86.8% of the isatuximab arm compared with 70.5% of the control arm. The rates of serious TEAEs were 61.8% versus 53.7%, respectively.

The rate of TEAE-related discontinuations was 7.2% with the isatuximab triplet compared with 12.8% in the control arm. Deaths related to TEAEs occurred in 7.9% and 9.4% of the 2 arms respectively.

Grade 4 pneumonia occurred in 1.3% of patients in each arm. The most common grade 3 TEAEs in the isatuximab arm were pneumonia (15.1% vs 13.4% in the Pd-alone arm), fatigue (3.9% vs 0%, respectively), dyspnea (3.9% vs 1.3%), upper respiratory tract infection (3.3% vs 0.7%), asthenia (3.3% vs 2.7%) bronchitis (3.3% vs 0.7%), diarrhea (2.0% vs 0.7%), back pain (2.0% vs 1.3%).

Isatuximab has received an orphan drug designation from the FDA and the European Medicines Agency for the treatment of patients with relapsed/refractory multiple myeloma.

The agent is continuing to be investigated in additional phase III trials for both newly diagnosed and relapsed/refractory patients with multiple myeloma.
  1. 1) FDA to review isatuximab as a potential treatment for relapsed/refractory multiple myeloma [press release]. Paris: Sanofi; July 10, 2019. https://bit.ly/2JrKs63. Accessed July 10, 2019.
  2. 2) Richardson PG, Attal M, S. Rajkumar V, et al. A phase III randomized, open label, multicenter study comparing isatuximab, pomalidomide, and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2019;37(suppl 15; abstr 8004).

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