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Subcutaneous daratumumab for RRMM: PAVO part 2
Table 3. Treatment-emergent adverse events.
Figure 2. Simulation of mean concentration-time profiles of daratumumab fol- lowing subcutaneous and intravenous dosing.a,b QW: weekly; Q2W: every 2 weeks; Q4W: every 4 weeks; SC: subcutaneous; IV: intravenous; DARA: daratu- mumab. aThe dosing schedule is once weekly in cycles 1 and 2, every 2 weeks in cycles 3 through 6, and every 4 weeks thereafter. bSimulations were conduct- ed based on a population pharmacokinetic (PK) model developed for daratu- mumab following SC and IV administration using scheduled dosing and estimat- ed individual PK parameters. Serum concentration-time data (from the PAVO, GEN501, and SIRIUS studies) were used for the population PK model develop- ment using a nonlinear mixed-effects modeling (NONMEM®, version 7.2) approach with the first-order conditional estimation with interaction method. The daratumumab SC model was based on a previous population PK model for dara- tumumab IV21 except for the absorption, which was described by a first-order process and a relative bioavailability parameter.
at month 2. At the clinical cutoff, the median progression- free survival was 12.0 (range, 5.6-16.6) months among all- treated patients and 11.7 (range, 2.8-13.8) months among patients refractory to both PI and IMiD.
Discussion
PAVO is the first clinical study to evaluate the safety, PK, and efficacy of SC administration of daratumumab in com- bination with rHuPH20. The results from this study demonstrate that daratumumab co-formulated with rHuPH20 is well tolerated, has an acceptable PK profile, and achieves deep and durable responses in patients with RRMM. In part 1 of the study, dose escalation of a first-gen- eration mix-and-deliver formulation of daratumumab and rHuPH20 (DARA-MD) showed that daratumumab SC administration is feasible in patients with RRMM.15 DARA- MD 1,800 mg had a PK profile and produced clinical responses that were consistent with those of IV infusion of daratumumab 16 mg/kg and was well tolerated, with a low rate of IRR. Based on the promising safety and efficacy observed with DARA-MD during part 1 of PAVO, a pre- mixed co-formulation of daratumumab 1,800 mg with rHuPH20 (DARA SC), which has a smaller injection volume and is administered over 3 to 5 min, was investigated in part 2 of the study.
Population PK and exposure-response analyses of daratu- mumab IV monotherapy in patients with MM revealed that the daratumumab maximum Ctrough is strongly related to ORR.21 In these studies, the maximum Ctrough occurred prior to daratumumab dosing on day 1 of cycle 3 with daratu- mumab monotherapy administered with the same dosing
All grades >10%
8 (32.0) 6 (24.0) 4 (16.0) 3 (12.0) 2 (8.0)
7 (28.0) 7 (28.0) 6 (24.0) 6 (24.0) 5 (20.0) 5 (20.0) 5 (20.0) 5 (20.0) 5 (20.0) 5 (20.0) 5 (20.0) 5 (20.0) 5 (20.0) 4 (16.0) 4 (16.0) 4 (16.0) 4 (16.0) 3 (12.0) 3 (12.0) 3 (12.0) 3 (12.0) 3 (12.0) 3 (12.0)
Grade 3 or 4 >1 patient
5 (20.0) 2 (8.0) 1 (4.0) 1 (4.0) 2 (8.0)
0
0
1 (4.0) 0
2 (8.0) 1 (4.0) 1 (4.0) 1 (4.0) 0
0
0
0
0
0
0
0
0
1 (4.0) 0
0
0
0
0
TEAE, n (%)
Hematologic Lymphopenia Thrombocytopenia Anemia Leukopenia Neutropenia
Non-hematologic Arthralgia
Back pain Diarrhea Nasopharyngitis Hypertension Fatigue Asthenia Insomnia Nausea Headache Upper RTI Pyrexia
Cough
Vomiting Constipation Musculoskeletal pain Oropharyngeal pain Bone pain
Chills
Peripheral edema Musculoskeletal chest pain Musculoskeletal discomfort Dyspnea
DARA SC 1,800 mg (n=25)
TEAE: treatment-emergent adverse event; DARA: daratumumab; SC: subcutaneous; RTI: respiratory tract infection.
schedule used in the PAVO study.22 Based on these findings, Ctrough at the end of weekly dosing (just prior to the dose on day 1 of cycle 3) was selected as the primary PK endpoint for the PAVO study. DARA SC 1,800 mg achieved similar or greater maximum Ctrough values compared with those of standard IV dosing (16 mg/kg) at day 1 of cycle 3 (i.e., at the end of weekly dosing). The mean C at day 1 of cycle 3
trough
(pre-dose) was 932 mg/mL after eight weekly doses of
DARA SC 1,800 mg compared with 617 mg/mL (GEN501 part 2) and 573 mg/mL (SIRIUS) after weekly dosing with IV daratumumab.16,22 Daratumumab serum concentrations were sustained from 48 h post-dose onwards until the end of the dosing interval. Although DARA SC is administered at a fixed dose, while IV daratumumab is administered by weight-based dosing, interpatient PK variability of the two dosing methods was comparable.23,24 Due to the small sam- ple size in part 2 of PAVO, the relationship between the PK of DARA SC and patients’ body weight could not be assessed. However, in a body-weight–based subgroup analysis of the phase III COLUMBA study (NCT03277105), DARA SC achieved adequate exposure that was consistent with that of IV daratumumab, regardless of body weight.25 In patients weighing ≤65 kg, the higher mean maximum Ctrough observed with DARA SC versus IV daratumumab did not have a clinically relevant effect on safety, and the ORR in all subgroups were consistent with the overall popula- tion. These results suggest that dose individualization of DARA SC on the basis of body weight is not necessary.
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