Page 228 - 2021_06-Haematologica-web

J. San-Miguel et al.
A
Figure 3. Responses to DARA SC 1,800 mg. (A) Summary of responses. Responses were evaluated in the all-treated pop- ulation, which included all patients who received at least one dose of the study drug. (B) Swim lane plot of responders. White text indicates the first response and pink text indi- cates the best response. ‘X’ indicates disease progression. DARA: daratumumab; SC: sub-
cutaneous; ORR:
response rate; CR: complete response; VGPR: very good par- tial response; PR: partial response.
overall
B
There was a low incidence of anti-daratumumab anti- bodies with DARA SC, indicating a low risk of daratumum- ab immunogenicity following SC administration. Few patients (16%) were positive for treatment-emergent or treatment-induced anti-rHuPH20 antibodies; this rate is consistent with the immunogenicity rates reported for other rHuPH20-containing treatments (SC rituximab [9%], trastuzumab [20%], and immune globulin infusion HYQVIA [18%]).26-28
The safety profile of DARA SC was consistent with the known profile of IV daratumumab; however, the frequency of IRR was lower with the SC administration than with the IV administration. The IRR rate with DARA SC was 16%, while IRR rates for IV administration of daratumumab range from 45% to 56% in monotherapy and combination regi- mens for RRMM.29-34 The majority of IRR occurred on day 1 of cycle 1. Only two patients experienced grade 3 IRR, and no cases of grade 4 IRR were reported. There were no dis- continuations due to IRR or other TEAE. DARA SC injec- tions in the periumbilical area were well tolerated; few injec- tion-site TEAE were observed, and all objectively measured cases of erythema and induration were fully reversible and resolved within 1 h after the end of the injection.
Durable clinical responses were observed with DARA SC during this study, with a median duration of response of 15.7 months. Over time, the ORR improved, increasing from 44% to 52% after a median follow-up of 4.617 versus 14.2 months, respectively, and responses deepened, with one patient achieving a complete response with longer fol- low-up. Despite the sample size of 25 patients, the median progression-free survival was 12.0 months among all-treat-
ed patients and 11.7 months among patients refractory to both PI and IMiD. An ORR of 52% is noteworthy in this population, with patients having received a median of three (range, 2-9) prior lines of therapy and 56% of patients being refractory to both PI and IMiD and 76% of patients being refractory to their last line of therapy. Clinical response rates achieved with DARA SC 1,800 mg were comparable to those achieved with daratumumab 16 mg/kg IV.16,35 In a pooled analysis of 148 patients with RRMM who received daratumumab 16 mg/kg IV in the monotherapy studies GEN501 and SIRIUS, the ORR was 31%, with 14% of patients achieving a very good partial response or better and 5% achieving a complete response or better.31 After a median follow-up of 20.7 months, the median progression- free survival was 4.0 months.31 The pooled patient popula- tion received a median of five (range, 2-14) prior lines of therapy, 87% were considered double refractory to a PI and an IMiD, and 91% were considered refractory to the last line of therapy.
In part 1 of PAVO, DARA-MD was administered by means of an infusion pump over a period of approximate- ly 20 to 30 min.15 Compared with DARA-MD, the DARA SC formulation contains a higher concentration of daratu- mumab in a smaller injection volume (15 mL), thus enabling drug delivery through a single SC injection with a handheld syringe and needle by manual push into the abdominal wall over 3 to 5 min. As the median durations of the first, second, and subsequent daratumumab IV infusions in clinical studies were 7.0, 4.3, and 3.4 hours, respectively,8 DARA SC substantially shortens the dura- tion of administration, thereby reducing the treatment
1730
haematologica | 2021; 106(6)