EHA 2018 | Phase Ib study of isatuximab in combination with pomalidomide and dexamethasone

The 23^rd Congress of the European Hematology Association (EHA) took place in Stockholm from 14-17 June 2018. On Saturday 16 June, an oral session took place during which, Joseph Mikhael from the Mayo Clinic, Phoenix, USA and the International Myeloma Foundation, Los Angeles, US, presented the results of a phase Ib clinical trial of isatuximab (ISA) with pomalidomide (pom) and dexamethasone (dex) in relapsed/refractory multiple myeloma (RRMM) patients who had received at least two prior treatments. The primary endpoint of the study was to determine the recommended dose of ISA in combination with pom and dex.

Isatuximab is an IgG1 monoclonal antibody which targets CD38 and has multiple modes of action: it inhibits CD38 through direct apoptotic activity and also has immunomodulatory properties. Preclinical data showed that isatuximab’s activity was enhanced when combined with immunomodulatory drugs (IMiDs) such as lenalidomide or pomalidomide, providing the rationale for further evaluation of this treatment regimen.

Study Design:                                                                                                             

• Total number of patients (pts) = 45
• Pts had received at least two prior treatments, including lenalidomide and a proteasome inhibitor (PI)
• Median prior lines of treatment = 3 (range, 2–10)
• Secondary end points: Determine efficacy (IMWG criteria), safety, and pharmacokinetics (PK)
• Standard dose escalation (3 + 3 design)
• Three different ISA concentrations were administered in 4 weekly [QW] doses, then every 2 weeks per 28-day cycle:
  • 5 mg/kg (n = 8 pts)
  • 10 mg/kg ISA (n = 9 pts)
  • 20 mg/kg ISA (n= 6 pts)
• Pom = 4 mg (days: 1-21)
• Dex = 40 mg on days: 1, 8, 15, and 22; 20 mg if aged > 75 years
• Based on efficacy, safety, and PK data, 10 mg/kg was chosen for the expansion cohort (n = 22 pts)

Key Data:

• Median age (years) = 67.0 (42–82)
• Ongoing treatment = 19 pts (42%)
• Most common treatment emergent adverse events (TEAEs) = fatigue = 28 pts (62%); Infusion-related reaction (IRR) = 19 pts (42%); upper respiratory tract infection = 19 pts (42%); dyspnea, 18 pts (40%)
• Discontinued treatment due to AEs = 2 pts (4%); one AE = grade 5: perforated bowel leading to death; not related to treatment, and one AE = grade 3: IRR (ISA: 10 mg/kg)
• Median infusion duration (ISA: 10 mg/kg): first infusion = 3.4 hr; subsequent infusions, = 2.9 hr (at infusion rate of 175 mg/hr)
• Neutropenia of grade > 3 = 37 pts (84%); all cases of neutropenia were manageable with dose modification and/or G-CSF support and did not cause any treatment discontinuations or withdrawals
• Very good partial response (VGPR) or better (≥ VGPR) = 26.6 % of all pts
• ORR: in all pts = 65%; via subgroups: High risk cytogenetics = 33%; IMiD refractory = 57%; PI refractory = 63%
• Median duration of response = 18.7 months;
• Median time to first response = 0.9 months
• Median duration of follow-up = 8.6 months
• Median PFS = 17.6 months (95% CI, 6.8–20.5 months)
• Median OS = not reached
• ISA PK was unaffected by co-administration of pom, and conversely, pom PK was not affected by co-administration with ISA/dex

Conclusion

Results of the phase Ib trial show that isatuximab, in combination with pomalidomide and dexamethasone, has a meaningful clinical activity and a manageable safety profile. This study addresses the needs of heavily pre-treated myeloma patients, who are faced with a limited number of treatment options. It has also established the optimal dose of isatuximab for future phase III clinical trials, in which this monoclonal antibody is being used in combination with different IMiDs and PIs to treat myeloma patients.