Pharmacotherapeutic Group: Antineoplastic agents, monoclonal antibodies. ATC Code: L01XC24.
Pharmacology: Pharmacodynamics: Mechanism of action: Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to the CD38 protein expressed at a high level on the surface of multiple myeloma tumour cells, as well as other cell types and tissues at various levels. CD38 protein has multiple functions such as receptor mediated adhesion, signalling and enzymatic activity.
Daratumumab has been shown to potently inhibit the in vivo growth of CD38-expressing tumour cells. Based on in vitro studies, daratumumab may utilise multiple effector functions, resulting in immune mediated tumour cell death. These studies suggest that daratumumab can induce tumour cell lysis through complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis in malignancies expressing CD38. A subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+Tregs) and B cells (CD38+Bregs) are decreased by daratumumab mediated cell lysis. T cells (CD3+, CD4+, and CD8+) are also known to express CD38 depending on the stage of development and the level of activation. Significant increases in CD4+ and CD8+ T cell absolute counts, and percentages of lymphocytes, were observed with daratumumab treatment in peripheral whole blood and bone marrow. In addition, T-cell receptor DNA sequencing verified that T-cell clonality was increased with daratumumab treatment, indicating immune modulatory effects that may contribute to clinical response.
Daratumumab induced apoptosis in vitro after Fc mediated cross-linking. In addition, daratumumab modulated CD38 enzymatic activity, inhibiting the cyclase enzyme activity and stimulating the hydrolase activity. The significance of these in vitro effects in a clinical setting, and the implications on tumour growth, are not well understood.
Pharmacodynamic effects: Natural killer (NK) cell and T-cell count: NK cells are known to express high levels of CD38 and are susceptible to daratumumab mediated cell lysis. Decreases in absolute counts and percentages of total NK cells (CD16+CD56+) and activated (CD16+CD56dim) NK cells in peripheral whole blood and bone marrow were observed with daratumumab treatment. However, baseline levels of NK cells did not show an association with clinical response.
Immunogenicity: Patients treated with daratumumab monotherapy (n = 199) and combination therapy (n = 299) were evaluated for anti-therapeutic antibody responses to daratumumab at multiple time points during treatment and up to 8 weeks following the end of treatment. Following the start of daratumumab treatment, none of the monotherapy patients and 2 (0.7%) of the combination therapy patients tested positive for anti-daratumumab antibodies; 1 of the combination therapy patients developed transient neutralizing antibodies against daratumumab.
However, the employed assay has limitations in detecting anti-daratumumab antibodies in the presence of high concentrations of daratumumab. Therefore, the incidence of antibody development might not have been reliably determined.
Clinical efficacy and safety: Monotherapy: The clinical efficacy and safety of DARZALEX monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who had demonstrated disease progression on the last therapy, was demonstrated in two open-label studies.
In study MMY2002, 106 patients with relapsed and refractory multiple myeloma received 16 mg/kg DARZALEX until disease progression. The median patient age was 63.5 years (range, 31 to 84 years), 11% of patients were ≥75 years of age, 49% were male and 79% were Caucasian. Patients had received a median of 5 prior lines of therapy. Eighty percent of patients had received prior autologous stem cell transplantation (ASCT). Prior therapies included bortezomib (99%), lenalidomide (99%), pomalidomide (63%) and carfilzomib (50%). At baseline, 97% of patients were refractory to the last line of treatment, 95% were refractory to both, a proteasome inhibitor (PI) and immunomodulatory agent (IMiD), 77% were refractory to alkylating agents, 63% were refractory to pomalidomide and 48% of patients were refractory to carfilzomib.
Efficacy results of the pre-planned interim analysis based on Independent Review Committee (IRC) assessment are presented in Table 1 as follows. (SeeTable 1.)
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Overall response rate (ORR) in MMY2002 was similar regardless of type of prior anti-myeloma therapy.
At a survival update with a median duration of follow up of 14.7 months, median Overall Survival (OS) was 17.5 months (95% CI:13.7, not estimable).
In Study GEN501, 42 patients with relapsed and refractory multiple myeloma received 16 mg/kg DARZALEX until disease progression. The median patient age was 64 years (range, 44 to 76 years), 64% were male and 76% were Caucasian. Patients in the study had received a median of 4 prior lines of therapy. Seventy-four percent of patients had received prior ASCT. Prior therapies included bortezomib (100%), lenalidomide (95%), pomalidomide (36%) and carfilzomib (19%). At baseline, 76% of patients were refractory to the last line of treatment, 64% were refractory to both a PI and IMiD, 60% were refractory to alkylating agents, 36% were refractory to pomalidomide and 17% were refractory to carfilzomib.
Pre-planned interim analysis showed that treatment with daratumumab at 16 mg/kg led to a 36% ORR with 5% CR and 5% VGPR. The median time to response was 1 (range: 0.5 to 3.2) month. The median duration of response was not reached (95% CI: 5.6 months, not estimable).
At a survival update with a median duration of follow up of 15.2 months, median OS was not reached (95% CI: 19.9 months, not estimable), with 74% of subjects still alive.
Combination treatment with lenalidomide: Study MMY3003, an open-label, randomised, active-controlled Phase III trial, compared treatment with DARZALEX 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with relapsed or refractory multiple myeloma who had received at least one prior therapy. Lenalidomide (25 mg once daily orally on Days 1-21 of repeated 28-day [4-week] cycles) was given with low dose dexamethasone at 40 mg/week (or a reduced dose of 20 mg/week for patients >75 years or body mass index [BMI] <18.5). On DARZALEX infusion days, 20 mg of the dexamethasone dose was given as a pre-infusion medication and the remainder given the day after the infusion. Treatment was continued in both arms until disease progression or unacceptable toxicity.
A total of 569 patients were randomised; 286 to the DRd arm and 283 to the Rd arm. The baseline demographic and disease characteristics were similar between the DARZALEX and the control arm. The median patient age was 65 years (range 34 to 89 years) and 11% were ≥75 years. The majority of patients (86%) received a prior PI, 55% of patients had received a prior IMiD, including 18% of patients who had received prior lenalidomide; and 44% of patients had received both a prior PI and IMiD. At baseline, 27% of patients were refractory to the last line of treatment. Eighteen percent (18%) of patients were refractory to a PI only, and 21% were refractory to bortezomib. Patients refractory to lenalidomide were excluded from the study.
Study MMY3003 demonstrated an improvement in Progression Free Survival (PFS) in the DRd arm as compared to the Rd arm; the median PFS had not been reached in the DRd arm and was 18.4 months in the Rd arm (hazard ratio [HR]=0.37; 95% CI: 0.27, 0.52; p <0.0001), representing 63% reduction in the risk of disease progression or death in patients treated with DRd (see Figure 1).
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Additional efficacy results from Study MMY3003 are presented in Table 2 as follows.
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Median OS was not reached for either treatment group. With an overall median follow-up of 13.5 months, the hazard ratio for OS was 0.64 (95% CI: 0.40, 1.01; p = 0.0534).
Combination treatment with bortezomib: Study MMY3004, an open-label, randomised, active-controlled Phase III trial, compared treatment with DARZALEX 16 mg/kg in combination with bortezomib and dexamethasone (DVd), to treatment with bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma who had received at least one prior therapy. Bortezomib was administered by SC injection or IV infusion at a dose of 1.3 mg/m2 body surface area twice weekly for two weeks (Days 1, 4, 8, and 11) of repeated 21 day (3-week) treatment cycles, for a total of 8 cycles. Dexamethasone was administered orally at a dose of 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each of the 8 bortezomib cycles (80 mg/week for two out of three weeks of the bortezomib cycle) or a reduced dose of 20 mg/week for patients >75 years, BMI <18.5, poorly controlled diabetes mellitus or prior intolerance to steroid therapy. On the days of DARZALEX infusion, 20 mg of the dexamethasone dose was administered as a pre-infusion medication. DARZALEX treatment was continued until disease progression or unacceptable toxicity.
A total of 498 patients were randomized; 251 to the DVd arm and 247 to the Vd arm. The baseline demographic and disease characteristics were similar between the DARZALEX and the control arm. The median patient age was 64 years (range 30 to 88 years) and 12% were ≥75 years. Sixty-nine percent (69%) of patients had received a prior PI (66% received bortezomib) and 76% of patients received an IMiD (42% received lenalidomide). At baseline, 32% of patients were refractory to the last line of treatment. Thirty-three percent (33%) of patients were refractory to an IMiD only, and 28% were refractory to lenalidomide. Patients refractory to bortezomib were excluded from the study.
Study MMY3004 demonstrated an improvement in PFS in the DVd arm as compared to the Vd arm; the median PFS had not been reached in the DVd arm and was 7.2 months in the Vd arm (HR [95% CI]: 0.39 [0.28, 0.53]; p-value <0.0001), representing a 61% reduction in the risk of disease progression or death for patients treated with DVd versus Vd (see Figure 2).
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Additional efficacy results from Study MMY3004 are presented in Table 3 as follows. (See Table 3.)
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Median OS was not reached for either treatment group.
With an overall median follow-up of 7.4 months (95% CI: 0.0, 14.9), the hazard ratio for OS was 0.77 (95% CI: 0.47, 1.26; p = 0.2975).
Cardiac electrophysiology: Daratumumab as a large protein has a low likelihood of direct ion channel interactions. The effect of daratumumab on the QTc interval was evaluated in an open label study for 83 patients (Study GEN501) with relapsed and refractory multiple myeloma following daratumumab infusions (4 to 24 mg/kg). Linear mixed PK PD analyses indicated no large increase in mean QTcF interval (i.e., greater than 20ms) at daratumumab Cmax.
Paediatric population: The European Medicines Agency has waived the obligation to submit the results of studies with DARZALEX in all subsets of the paediatric population in multiple myeloma (see DOSAGE & ADMINISTRATION for information on paediatric use).
Pharmacokinetics: The pharmacokinetics (PK) of daratumumab following intravenous administration of daratumumab monotherapy were evaluated in patients with relapsed and refractory multiple myeloma at dose levels from 0.1 mg/kg to 24 mg/kg. A population PK model of daratumumab was developed to describe the PK characteristics of daratumumab and to evaluate the influence of covariates on the disposition of daratumumab in patients with multiple myeloma. The population PK analysis included 223 patients receiving DARZALEX monotherapy in two clinical trials (150 subjects received 16 mg/kg).
In the 1- to 24 mg/kg cohorts, peak serum concentrations (Cmax) after the first dose increased in approximate proportion to dose and volume of distribution was consistent with initial distribution into the plasma compartment. Following the last weekly infusion, Cmax increased in a greater than dose-proportional manner, consistent with target mediated drug disposition. Increases in AUC were more than dose proportional and clearance (CL) decreased with increasing dose. These observations suggest CD38 may become saturated at higher doses, after which the impact of target binding clearance is minimised and the clearance of daratumumab approximates the linear clearance of endogenous IgG1. Clearance also decreased with multiple doses, which may be related to tumour burden decreases.
Terminal half-life increases with increasing dose and with repeated dosing. The mean (standard deviation [SD]) estimated terminal half-life of daratumumab following the first 16 mg/kg dose was 9 (4.3) days. The estimated terminal half-life of daratumumab following the last 16 mg/kg dose increased, but there are insufficient data for a reliable estimation. Based on population PK analysis, the mean (SD) half life associated with non-specific linear elimination was approximately 18 (9) days; this is the terminal half-life that can be expected upon complete saturation of target mediated clearance and repeat dosing of daratumumab.
At the end of weekly dosing for the recommended monotherapy schedule and dose of 16 mg/kg, the mean (SD) serum Cmax value was 915 (410.3) micrograms/mL, approximately 2.9 fold higher than following the first infusion. The mean (SD) predose (trough) serum concentration at the end of weekly dosing was 573 (331.5) micrograms/mL.
Based on the population PK analysis of daratumumab monotherapy, daratumumab steady state is achieved approximately 5 months into the every 4 week dosing period (by the 21st infusion), and the mean (SD) ratio of Cmax at steady state to Cmax after the first dose was 1.6 (0.5). The mean (SD) central volume of distribution is 56.98 (18.07) mL/kg.
An additional population PK analysis was conducted in patients with multiple myeloma that received daratumumab in various combination therapies from four clinical trials (694 patients of which 684 received daratumumab at 16 mg/kg). Daratumumab concentration-time profiles were similar following the monotherapy and combination therapies. The mean (SD) estimated terminal half-life associated with linear clearance in combination therapy was approximately 23 (12) days.
Based on population PK analysis body weight was identified as a statistically significant covariate for daratumumab clearance. Therefore, body weight based dosing is an appropriate dosing strategy for the multiple myeloma patients.
Special populations: Age and gender: Based on population PK analysis in patients receiving daratumumab monotherapy, age (range: 31 84 years) had no clinically important effect on the PK of daratumumab, and the exposure of daratumumab was similar between younger (aged <65 years, n = 127) and older (aged ≥65 years, n = 96; aged ≥75 years, n = 18; aged ≥85 years, n = 0) patients. Similar to monotherapy, no clinically important influence of age on the exposure to daratumumab was observed in the population PK analyses in patients receiving combination therapies. The difference in exposure was within 6% between younger (age <65 years, n = 352; or age <75 years, n = 630) and older subjects (age ≥65 years, n = 342; or age ≥75 years, n = 64).
Gender did not affect exposure of daratumumab to a clinically relevant degree in both population PK analyses.
Renal impairment: No formal studies of daratumumab in patients with renal impairment have been conducted. A population PK analysis was performed based on pre-existing renal function data in patients receiving daratumumab monotherapy, including 71 with normal renal function (creatinine clearance [CRCL] ≥90 mL/min), 78 with mild renal impairment (CRCL <90 and ≥60 mL/min), 68 with moderate renal impairment (CRCL <60 and ≥30 mL/min), and 6 with severe renal impairment or end stage renal disease (CRCL<30 mL/min). No clinically important differences in exposure to daratumumab were observed between patients with renal impairment and those with normal renal function. Additional population PK analyses in patients receiving combination treatments also demonstrated no clinically important differences in exposure to daratumumab between patients with renal impairment (mild, n = 264; moderate, n = 166; severe, n = 12) and those with normal renal function (n = 251).
Hepatic impairment: No formal studies of daratumumab in patients with hepatic impairment have been conducted. Changes in hepatic function are unlikely to have any effect on the elimination of daratumumab since IgG1 molecules such as daratumumab are not metabolised through hepatic pathways.
The population PK analysis of patients treated with daratumumab monotherapy included 189 patients with normal hepatic function (total bilirubin [TB] and aspartate aminotransferase [AST] ≤ upper limit of normal [ULN]) and 34 with mild hepatic impairment (TB 1.0 x to 1.5 xULN or AST > ULN). No clinically important differences in exposure to daratumumab were observed between patients with mild hepatic impairment and those with normal hepatic function. An additional population PK analysis of patients with multiple myeloma that received daratumumab in various combination therapies included 598 patients with normal hepatic function, 83 patients with mild hepatic impairment and 5 patients with moderate (TB >1.5 x to 3.0 x ULN), or severe (TB >3.0 x ULN) hepatic impairment. No clinically important differences in the exposure to daratumumab were observed between patients with hepatic impairment and those with normal hepatic function.
Race: Based on the population PK analysis of daratumumab monotherapy, the exposure to daratumumab was similar between white (n=197) and non white (n=26) subjects. In an additional population PK analysis in multiple myeloma patients that received daratumumab with various combination therapies, the exposure to daratumumab was also similar between white (n = 558) and non white (n = 136) subjects.
Toxicology: Preclinical safety data: Toxicology data have been derived from studies with daratumumab in chimpanzees and with a surrogate anti-CD38 antibody in cynomolgus monkeys. No chronic toxicity testing has been conducted.
Carcinogenicity and mutagenicity: No animal studies have been performed to establish the carcinogenic potential of daratumumab.
Reproductive toxicology: No animal studies have been performed to evaluate the potential effects of daratumumab on reproduction or development.
Fertility: No animal studies have been performed to determine potential effects on fertility in males or females.