Darzalex Faspro (Page 6 of 8)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity or genotoxicity studies have been conducted with daratumumab. No animal studies have been performed to evaluate the potential effects of daratumumab on reproduction or development, or to determine potential effects on fertility in males or females.

No carcinogenicity, genotoxicity, or fertility studies were conducted for recombinant human hyaluronidase. There were no effects on reproductive tissues and function and no systemic exposure of hyaluronidase in monkeys given 22,000 U/kg/week subcutaneously (12 times higher than the human dose) for 39 weeks. As hyaluronidase is a recombinant form of the endogenous human hyaluronidase, no carcinogenicity, mutagenesis, or effects on fertility are expected.

14 CLINICAL STUDIES

14.1 Newly Diagnosed Multiple Myeloma

In Combination with Bortezomib, Melphalan and Prednisone

The efficacy of DARZALEX FASPRO with bortezomib, melphalan and prednisone was evaluated in a single-arm cohort of PLEIADES (NCT03412565), a multi-cohort, open-label trial. Eligible patients were required to have newly diagnosed multiple myeloma who are ineligible for transplant. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks 1 to 6, once every 3 weeks from weeks 7 to 54 and once every 4 weeks starting with week 55 until disease progression or unacceptable toxicity; bortezomib 1.3 mg/m2 subcutaneously twice weekly on Weeks 1, 2, 4 and 5 for the first 6-week cycle (Cycle 1; 8 doses), followed by once weekly on Weeks 1, 2, 4 and 5 for eight more 6-week cycles (Cycles 2–9; 4 doses per cycle); and melphalan 9 mg/m2 and prednisone 60 mg/m2 orally on Days 1 to 4 of the nine 6-week cycles (Cycles 1–9). The major efficacy outcome measure was overall response rate (ORR).

A total of 67 patients received DARZALEX FASPRO with VMP. The median age was 75 years (range: 66 to 86 years); 46% were male; 69% were White, 8% Asian, and 2% Black or African American; and 33% had ISS Stage I, 45% had ISS Stage II, and 22% had ISS Stage III disease.

Efficacy results are summarized in Table 19. The median duration of follow-up for patients was 6.9 months.

Table 19: Efficacy Results from PLEIADES in Patients Who Received DARZALEX FASPRO-VMP
DARZALEX FASPRO-VMP(N=67)
CI=confidence interval
*
Based on treated patients
Overall response rate (sCR+CR+VGPR+PR), n (%)* 59 (88%)
95% CI (%) (78%, 95%)
Stringent complete response (sCR) 5 (8%)
Complete response (CR) 7 (10%)
Very good partial response (VGPR) 31 (46%)
Partial response (PR) 16 (24%)

14.2 Relapsed/Refractory Multiple Myeloma

In Combination with Lenalidomide and Dexamethasone

The efficacy of DARZALEX FASPRO with lenalidomide and dexamethasone (DARZALEX FASPRO-Rd) was evaluated in a single-arm cohort of PLEIADES (NCT03412565), a multi-cohort, open-label trial. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity with lenalidomide 25 mg once daily orally on Days 1–21 of each 28-day cycle; and dexamethasone 40 mg per week (or a reduced dose of 20 mg per week for patients >75 years or BMI <18.5). The major efficacy outcome measure was ORR.

A total of 65 patients received DARZALEX FASPRO with Rd. The median age was 69 years (range: 33 to 82 years); 69% were male; 69% were White, and 3% Black or African American; and 42% had ISS Stage I, 30% had ISS Stage II, and 28% had ISS Stage III disease. Patients had received a median of 1 prior line of therapy. A total of 52% of patients had a prior ASCT; 95% of patients received a prior PI; 59% received a prior immunomodulatory agent, including 22% who received prior lenalidomide; and 54% of patients received both a prior PI and immunomodulatory agent.

Efficacy results are summarized in Table 20. The median duration of follow-up for patients was 7.1 months.

Table 20: Efficacy Results from PLEIADES in Patients Who Received DARZALEX FASPRO-Rd
DARZALEX FASPRO-Rd(N=65)
CI=confidence interval
*
Based on treated patients
Overall response rate (sCR+CR+VGPR+PR), n (%)* 59 (91%)
95% CI (%) (81%, 97%)
Stringent complete response (sCR) 4 (6%)
Complete response (CR) 8 (12%)
Very good partial response (VGPR) 30 (46%)
Partial response (PR) 17 (26%)

In Combination with Pomalidomide and Dexamethasone

The efficacy of DARZALEX FASPRO with pomalidomide and dexamethasone (DARZALEX FASPRO-Pd) versus pomalidomide and dexamethasone (Pd) alone was evaluated in APOLLO (NCT03180736), an open-label, randomized, active-controlled trial. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity with pomalidomide 4 mg once daily orally on Days 1–21 of each 28-day cycle; and dexamethasone 40 mg per week (or a reduced dose of 20 mg per week for patients >75 years). The major efficacy outcome measure was progression-free survival (PFS).

A total of 304 patients were randomized: 151 to the DARZALEX FASPRO-Pd arm and 153 to the Pd arm. The median age was 67 years (range: 35 to 90); 53% were male and 89% were White, <1% were Black or African American, and <1% were Asian, and 45% had ISS Stage I, 33% had ISS Stage II, and 22% had ISS Stage III disease. Patients had received a median of 2 prior lines of therapy (range 1–5), with 11% of patients having received 1 prior line of therapy and 75% of patients having received 2–3 prior lines of therapy. All patients received a prior treatment with a PI and lenalidomide, and 56% of patients received prior ASCT. The majority of patients were refractory to lenalidomide (80%), a PI (48%), or both an immunomodulatory agent and a PI (42%).

APOLLO demonstrated an improvement in PFS in the DARZALEX FASPRO-Pd treatment group as compared to the Pd treatment group; the median PFS was 12.4 months in the DARZALEX FASPRO-Pd treatment group and 6.9 months in the Pd treatment group (HR [95% CI]: 0.63 [0.47, 0.85]; p-value = 0.0018), representing a 37% reduction in the risk of disease progression or death for patients treated with DARZALEX FASPRO-Pd versus Pd.

Figure 1: Kaplan-Meier Curve of PFS in APOLLO

Figure 1
(click image for full-size original)

Additional efficacy results from APOLLO are presented in Table 21.

Table 21: Efficacy results from APOLLO *
DARZALEX FASPRO-Pd (n=151)Pd (n=153)
Pd=pomalidomide-dexamethasone; MRD=minimal residual disease; CI=confidence interval
*
Based on intent-to-treat population
p-value from Cochran Mantel-Haenszel Chi-Squared test adjusted for stratification factors
Based on the intent-to-treat population
§
Based on threshold of 10-5 using a next-generation sequencing assay (clonoSEQ).
p-value from Fisher’s exact test.
Overall response (sCR+CR+VGPR+PR) n (%)*104 (68.9%)71 (46.4%)
P-value <0.0001
Stringent complete response (sCR)14 (9.3%)2 (1.3%)
Complete response (CR)23 (15.2%)4 (2.6%)
Very good partial response (VGPR)40 (26.5%)24 (15.7%)
Partial response (PR)27 (17.9%)41 (26.8%)
MRD negativity rate , § n (%)13 (8.6%)3 (2.0%)
95% CI (%)(4.7%, 14.3%)(0.4%, 5.6%)
P-value 0.0102
MRD negativity rate in patients with CR or better §
Number of patients with CR or betterN=37 N=6
MRD negativity rate n (%)13 (35.1%)3 (50.0%)
95% CI (%)(20.2%, 52.5%)(11.8%, 88.2%)

In responders, the median time to response was 1 month (range: 0.9 to 9.1 months) in the DARZALEX FASPRO-Pd group and 1.9 months (range: 0.9 to 17.3 months) in the Pd group. The median duration of response had not been reached in the DARZALEX FASPRO-Pd group (range: 1 to 34.9+ months) and was 15.9 months (range: 1+ to 24.8 months) in the Pd group.

With a median follow-up of 16.9 months, 99 deaths were observed; 48 in the DARZALEX FASPRO-Pd group and 51 in the Pd group. Median OS was not reached for either treatment group.

In Combination with Carfilzomib and Dexamethasone

The efficacy of DARZALEX FASPRO with carfilzomib and dexamethasone (DARZALEX FASPRO-Kd) was evaluated in a single-arm cohort of PLEIADES (NCT03412565), a multi-cohort, open-label trial. This cohort enrolled patients with relapsed or refractory multiple myeloma excluding patients with left ventricular ejection fraction (LVEF) less than 40%, myocardial infarction within 6 months, uncontrolled cardiac arrhythmia, or uncontrolled hypertension (systolic blood pressure >159 mmHg or diastolic >99 mmHg despite optimal treatment). Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from Weeks 1 to 8, once every 2 weeks from Weeks 9 to 24 and once every 4 weeks starting with Week 25 until disease progression or unacceptable toxicity with carfilzomib administered by IV infusion at a dose of 20 mg/m2 on Cycle 1 Day 1 and if a dose of 20 mg/m2 was tolerated, carfilzomib was administered at a dose of 70 mg/m2 as a 30-minute IV infusion, on Cycle 1 Day 8 and Day 15, and then Day 1, 8 and 15 of each cycle and dexamethasone 40 mg per week (or a reduced dose of 20 mg per week for patients ≥75 years or BMI <18.5). The major efficacy outcome measure was ORR.

A total of 66 patients received DARZALEX FASPRO with Kd. The median age was 61 years (range: 42 to 84); 52% were male; 73% were White and 3% Black or African American; and 68% had ISS Stage I, 18% had ISS Stage II, and 14% had ISS Stage III disease. A total of 79% of patients had a prior ASCT; 91% of patients received a prior PI. All patients received 1 prior line of therapy with exposure to lenalidomide and 62% of patients were refractory to lenalidomide.

Efficacy results are summarized in Table 22. At a median follow-up of 9.2 months, the median duration of response had not been reached and an estimated 85.2% (95% CI: 72.5, 92.3) maintained response for at least 6 months and 82.5% (95% CI: 68.9, 90.6) maintained response for at least 9 months.

Table 22: Efficacy Results from PLEIADES in Patients Who Received DARZALEX FASPRO-Kd
DARZALEX FASPRO-Kd (N=66)
CI=confidence interval
*
Based on treated patients
Overall response rate (sCR+CR+VGPR+PR), n (%)* 56 (84.8%)
95% CI (%) (73.9%, 92.5%)
Stringent complete response (sCR) 11 (16.7%)
Complete response (CR) 14 (21.2%)
Very good partial response (VGPR) 26 (39.4%)
Partial response (PR) 5 (7.6%)

Monotherapy

The efficacy of DARZALEX FASPRO as monotherapy was evaluated in COLUMBA (NCT03277105), an open-label, randomized, non-inferiority study. Eligible patients were required to have relapsed or refractory multiple myeloma who had received at least 3 prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who were double-refractory to a proteasome inhibitor and an immunomodulatory agent. Patients were randomized to receive DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously or daratumumab 16 mg/kg administered intravenously; each administered once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until unacceptable toxicity or disease progression. The major efficacy outcome measures were ORR by the IMWG response criteria and maximum Ctrough at pre-dose Cycle 3 Day 1 [see Clinical Pharmacology (12.3)]. Randomization was stratified by body weight, myeloma type, and number of prior lines of therapy.

A total of 522 patients were randomized: 263 to the DARZALEX FASPRO arm and 259 to the intravenous daratumumab arm. The median age was 67 years (range: 33 to 92 years); 55% were male; and 78% were White, 14% Asian, and 3% Black or African American. The median weight was 73 kg (range: 29 to 138). Patients had received a median of 4 prior lines of therapy. A total of 51% of patients had a prior ASCT; 100% of patients received both a PI and an immunomodulatory agent. Forty-nine percent of patients were refractory both a PI and an immunomodulatory agent. Eighty-two percent of patients were refractory to their last line of prior systemic therapy.

The results show that DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously is non-inferior to daratumumab 16 mg/kg administered intravenously in terms of ORR and maximum trough concentration [see Clinical Pharmacology (12.3)]. Median progression-free survival was 5.6 months in the DARZALEX FASPRO arm and 6.1 months in the intravenous daratumumab arm. ORR results are provided in Table 23.

Table 23: Efficacy Results from COLUMBA
DARZALEX FASPRO (N=263) Intravenous Daratumumab(N=259)
*
Based on intent-to-treat population.
Overall response (sCR+CR+VGPR+PR), n (%)* 108 (41%) 96 (37%)
95% CI (%) (35%, 47%) (31%, 43%)
Ratio of response rates (95% CI) 1.11 (0.89, 1.37)
CR or better, n (%) 5 (1.9%) 7 (2.7%)
Very good partial response (VGPR) 45 (17%) 37 (14%)
Partial response (PR) 58 (22%) 52 (20%)

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