Daratumumab given positive opinion by the EMA CHMP for use in the treatment of MM patients who have received at least one prior therapy

On February 24th 2017, the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) gave a positive opinion for daratumumab to be used in combination with either lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with Multiple Myeloma (MM) who have received at least one prior therapy. This recommendation broadens the current EMA treatment indication for daratumumab, which is currently approved for use as a monotherapy in RRMM patients whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy.

Daratumumab) is a high-affinity monoclonal antibody against CD38, which is highly expressed on the surface of MM cells. High affinity binding of daratumumab to tumor cells drives complement-dependent cell death, as well several immune-related responses.

Genmab A/S (Nasdaq Copenhagen: GEN) received this Positive Opinion based on Phase III clinical trial data from two major clinical trials: CASTOR - which assessed the efficacy of daratumumab in combination with bortezomib and dexamethasone, and POLLUX - which assessed the efficacy of daratumumab in combination with lenalidomide and dexamethasone, both in relapsed and refractory (RR) MM patients. 

The CASTOR study included 498 patients with RRMM, randomized to receive daratumumab in combination with bortezomib and dexamethasone or bortezomib and dexamethasone alone:

• Patients treated with daratumumab, in combination with bortezomib and dexamethasone, had a 61% reduction in the risk of disease progression (Hazard Ratio (HR) = 0.39, 95% CI 0.28-0.53, p<0.0001)
• ORR = 83% daratumumab vs. 63% placebo p<0.0001
• CR = 19% daratumumab vs. 9% placebo 
• VGPR or better = 59% daratumumab vs. 29% placebo
• Minimal residual disease (MRD) negative status at the 10^-4 threshold (one tumor cell in 10,000 white cells) = 13.5% daratumumab vs 2.8% placebo (p<0.000006)
• Common grade 3 or 4 AEs (daratumumab vs. placebo):
  • thrombocytopenia: 45% vs 33%
  • anemia: 14% vs 16%
  • neutropenia: 13% vs 4%
  • Overall safety profile was consistent with that of daratumumab monotherapy or combination therapy of bortezomib and dexamethasone

The POLLUX study included 569 patients with RRMM, randomized to receive either daratumumab combined with lenalidomide and dexamethasone, or lenalidomide and dexamethasone alone:

• Patients treated with daratumumab, in combination with lenalidomide and dexamethasone had a 63% reduction in risk of their disease progressing, compared to those who did not receive daratumumab (Hazard Ratio (HR) = 0.37; 95% CI 0.27-0.52; p<0.0001)
• Median PFS for patients treated with daratumumab in combination with lenalidomide and dexamethasone has not been reached, compared to an estimated median PFS of 18.4 months for patients who received lenalidomide and dexamethasone alone.
• ORR = 93% daratumumab vs. 76% placebo (p<0.0001)
• CR or better = 43% daratumumab vs. 19% placebo
• VGPR or better = 76% daratumumab vs. 44% placebo
• MRD negative status = 29% daratumumab vs 7.8% placebo (p<0.000001)
• Common grade 3 or 4 AEs (daratumumab vs. placebo):  
  • neutropenia = 52% vs. 37%
  • thrombocytopenia = 13% vs. 14%
  • anemia = 12% vs. 20%
  • Safety profile was consistent with known toxicities of either daratumumab monotherapy or combination therapy of lenalidomide and dexamethasone.