FDA Approves Daratumumab With Hyaluronidase-fihj in AL Amyloidosis

The FDA has granted accelerated approval to the subcutaneous formulation of daratumumab (Darzalex Faspro) with hyaluronidase-fihj as treatment of patients with light chain (AL) amyloidosis, announced Genmab A/S in a press release.1

Approval was granted to the combination based on results from the phase 3 ANDROMEDA clinical trial (NCT03201965) for which results were recently presented during the 2020 American Society of Hematology (ASH) Annual Meeting.

“AL amyloidosis is a devastating and potentially fatal blood disorder that, until now, did not have any U.S. FDA-approved therapies. This makes today’s approval of Darzalex FASPRO a critical step forward for patients in the U.S. in dire need of treatment options,” said Jan van de Winkel, PhD, chief executive officer, Genmab A/B, in a statement.

ANDROMEDA randomized patients 1:1 to receive bortezomib (Velcade), cyclophosphamide, and dexamethasone (VCd) on a weekly basis for 6 cycles in combination with subcutaneous daratumumab 1800 mg for 2 weekly cycles, followed by another 3 to 6 cycles given every 2 weeks, which was followed by subcutaneous daratumumab 1800 mg every 4 weeks. Treatment was continued until major organ deterioration–progression-free survival (MOD-PFS) or until patients reached a maximum of 24 cycles, or weekly VCd for 6 cycles.2

Median follow-up time in the study was 15.7 months (range, 0.0-24.1), and the median duration of treatment was 15.8 months (range, 0.1-24.1) in patients who received D-VCd compared with 5.3 months (range, 0.03-7.3) in the VCd arm. Patients were evaluated for the primary end point of complete response (CR) rate as well as secondary end points including PFS, objective response rate, disease control rate, safety, and quality of life.

Daratumumab plus hyaluronidase-fihj achieved hematologic CR rate of 53% in 195 patients compared with 18% in patients who received VCd, odds ratio [OR], 5.1; 95% CI, 3.2-8.2; P < .0001).

The addition of daratumumab to VCd (D-VCd) also achieved higher rates of best hematologic response at any time in the study. Specifically, the rates observed in the D-VCd arm versus the VCd arm were 56.9% versus 18.7%, (OR, 5.68; 95% CI, 3.58-9.00; P <.0001. In the subset of patients with a free light chain (FLC) 20 mg/L or lower, the best hematologic response rate for the D-VCd arm was 71.3% compared with 20.2% in the VCd alone arm (OR, 9.8; 95% CI, 6.1-15.7; P <.0001). Notably, the patients who demonstrated a difference between involved and uninvolved FLC of less than 10 mg/L, the best hematologic response rate was 65.6% for the daratumumab combination arm versus 30.6% for the VCd alone arm (OR, 4.3; 95% CI, 2.8-6.6; P <.0001). In addition, patients who had International Society of Amyloidosis criteria showed a best hematologic response rate of 49.2% when treated with D-VCd versus 23.3% when treated with VCd alone (OR, 3.25; 95% CI, 2.09-5.06; P < 0001).

Treatment with the daratumumab combination also induced a significantly prolonged MOD-PFS compared with VCd alone. In particular, MOD-PFS events were seen in 17.4% of patients on D-VCd versus 27.5% of patients who received VCd alone (HR, 0.58; 95% CI, 0.36-0.93; P = .0211).

At the time of the ASH presentation, safety was reported as being consistent with prior studies. No new safety signals were observed. Investigator noted, however, that the D-VCd arm had a higher rate of cardiac and renal responses at 6 months (42%) when compared with the VCd alone arm (22%) for cardiac, and renal was 54% versus 27%, respectively.

Adverse reaction related to D-VCd reportedly occur in ≥20% of patients. The most commonly observed adverse reaction include upper respiratory tract infection, diarrhea, peripheral edema, constipation, fatigue, peripheral sensory neuropathy, nausea, insomnia, dyspnea, and cough. In addition, serious adverse reactions can occur, which commonly include pneumonia (9%), cardiac failure (8%), and sepsis (5%). Adverse reaction with the combination can be fatal in about 11% of patients. The adverse reaction that may lead to death included cardiac arrest (4%), sudden death (3%), cardiac failure (3%) and sepsis (1%).

ANDROMEDA is an open-label, active-controlled, randomized protocol study. Patients were eligible to enroll is they had AL amyloidosis with at least 1 organ impacted, no prior therapy for AL amyloidosis or multiple myeloma, cardiac stage I to IIIA disease, and an estimated glomerular filtration rate of at least 20 mL/min

_References:

_{Genmab Announces that Janssen has been granted U.S. FDA approval for DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) for patients with newly diagnosed light-chain (al) amyloidosis. News release. January 15, 2020. Accessed January 15, 2020. https://bit.ly/2XMq4mF}

_{Comenzo RL, Kastritis E, Minnema MC, et al. Reduction in absolute involved free light chain and difference between involved and uninvolved free light chain is associated with prolonged major organ deterioration progression-free survival in patients with newly diagnosed AL amyloidosis receiving bortezomib, cyclophosphamide, and dexamethasone with or without daratumumab: results from ANDROMEDA. Presented at: 2020 ASH Annual Meeting & Exposition; December 5-8, 2020; virtual. Abstract 552.}