Isatuximab Nears European Approval for Relapsed/Refractory Myeloma

John Reed, MD, PhD

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended isatuximab (Sarclisa) in combination with pomalidomide (Pomalyst) and dexamethasone (Pd) for the treatment of adult patients with relapsed/refractory multiple myeloma who have received ≥2 prior therapies, including lenalidomide (Revlimid) and a proteasome inhibitor and have demonstrated disease progression on the last therapy.¹

The recommendation is based on results from the phase III ICARIA-MM trial, in which adding isatuximab to pomalidomide and low-dose dexamethasone led to a greater than 40% reduction in the risk of disease progression or death compared with Pd alone in patients with relapsed/refractory multiple myeloma.² Moreover, the objective response rates (ORRs) were 60.4% and 35.3%, respectively (P <.0001).

The European Commission will now review the CHMP recommendation and make a final decision in the next few months.

“Relapsed and refractory multiple myeloma is a complicated disease that continuously develops resistance to treatment, creating a significant need for continued innovation,” John Reed, MD, PhD, Sanofi’s Global Head of Research & Development, said in a press release. “This positive CHMP opinion for Sarclisa brings us closer to our ambition to deliver a new treatment option for patients in Europe with relapsed and refractory multiple myeloma.”

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

Patient characteristics were well balanced between the 2 arms. 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 PI, and 19.5% had high-risk disease cytogenetics.

In the isatuximab arm, 97.4% of patients were refractory to their last line of therapy compared to 98.7% of patients in the Pd arm. In the isatuximab group, 60.4% of patients were refractory to lenalidomide at their last line, compared to 57.5% of patients in the control arm.

Isatuximab was administered intravenously (IV) at 10 mg/kg once weekly for 4 weeks followed by bi-weekly for 28-day cycles in combination with standard pomalidomide and dexamethasone 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.

At a median follow-up of 11.6 months, the median progression-free survival (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). Overall survival data (OS) were not yet mature at the time of analysis but there was a trend toward a survival benefit for the isatuximab arm (HR, 0.687; 95% CI, 0.461-1.023). 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 PFS results per investigator assessment were similar to the independent review data. 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, 0.444-0.816; 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 PI (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).

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), PIs (56.7% vs 47.0%, respectively), IMiDs (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, 1.0-73.7) 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%), and back pain (2.0% vs 1.3%).

The FDA approved isatuximab for the same indication on March 2, 2020.

References

1. Sanofi receives positive CHMP opinion for Sarclisa® (isatuximab) for the treatment of relapsed and refractory multiple myeloma. Published online March 27, 2020. https://bit.ly/39mwmwF. Accessed March 27, 2020.
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; abstr 8004).