FDA, EMA Approval Sought for Subcutaneous Daratumumab Plus Pomalidomide/Dexamethasone in Relapsed/Refractory Myeloma

November 12, 2020 - Regulatory applications have been submitted to the FDA and the European Medicines Agency (EMA) for subcutaneous daratumumab (Darzalex Faspro, daratumumab and hyaluronidase-fihj; Darzalex SC) for use in combination with pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma who have received at least 1 previous therapy.¹

The supplemental biologics application and the Type II variation application are based on data yielded from the phase 3 APOLLO trial (MMY3013; NCT03180736), which showed that the triplet resulted in an improvement in progression-free survival (PFS) compared with pomalidomide/dexamethasone (Pd) alone in patients with relapsed/refractory multiple myeloma who had previously been treated with lenalidomide (Revlimid) and a proteasome inhibitor (PI).²

Full findings from the trial will be shared during an oral presentation at the 2020 ASH Annual Meeting, according to The Janssen Pharmaceutical Companies of Johnson & Johnson.

“The intravenous [IV] formulation of [daratumumab], which is approved in combination with pomalidomide and dexamethasone, is an important option for patients with multiple myeloma. We are excited to pursue the subcutaneous formulation of [daratumumab] for this indication as we look to reduce administration time from hours to minutes compared with the IV formulation,” Craig Tendler, MD, vice president of Late Development and Global Medical Affairs, Oncology, of Janssen Research & Development, LLC, stated in a press release. “Today’s regulatory milestones represent our continued commitment to advance innovative treatments for people living with multiple myeloma.”

Subcutaneous daratumumab can be delivered much more rapidly than the IV formulation; the former can be given within 3-5 minutes, while the latter typically takes several hours.

In June 2017, IV daratumumab plus Pd was approved by the FDA for the treatment of patients with multiple myeloma who had received at least 2 previous therapies, including a PI and lenalidomide based on data from the phase 1 EQUULEUS (MMY1001) trial, which demonstrated an ORR of 59% (95% CI, 49.1%-68.8%) with the triplet in this population.³ This triplet is not approved by the EMA for use in Europe.

In the multicenter, randomized, open-label, phase 3 APOLLO trial, daratumumab plus Pd was compared with Pd alone in patients with relapsed/refractory disease who previously received and progressed on at least 1 prior therapy comprised of both lenalidomide and a PI.⁴

To be eligible for inclusion, patients had to be at least 18 years of age, had to have an ECOG performance status of 0 to 2, and a creatinine clearance of 30 mL/min or more.⁵ Patients who had received only 1 previous therapy must have experienced disease progression at 60 days or less following treatment with the lenalidomide-based regimen. Patients could not have received prior anti-CD38 therapy or pomalidomide.

A total of 304 patients were enrolled to the trial. Participants were randomized in a 1:1 fashion to receive the daratumumab triplet or Pd. Patients in the investigational arm were given a 16 mg/kg dose of IV daratumumab or an 1800-mg subcutaneous dose of the agent at weekly intervals for 8 weeks, then every 2 weeks, for an additional 16 weeks, then every 4 weeks thereafter. Oral pomalidomide was administered at a dose of 4 mg on days 1 through 21, of each 28-day cycle, and oral dexamethasone was given at a once-daily dose of 40 mg on days 1, 8, 15, and 22, of each 28-day cycle. Patients in the control arm received Pd on the same schedule as the experimental arm.

The primary end point of the trial was PFS, while secondary end points comprised overall response rate (ORR), very good partial response (VGPR) or better rate, a complete response (CR) or better rate, and duration of response (DOR).

“Despite strong progress in multiple myeloma over the past decade, it remains a disease with significant unmet need,” Catherine Taylor, MD, vice president of Medical Affairs Therapeutic Area Strategy, Europe, Middle East and Africa, of Johnson & Johnson Middle East FZ-LLC, added in the release. “We are pleased to pursue this important [daratumumab]-based combination regimen, which was in the first study showing a significant increase in PFS of a subcutaneous anti-CD38 in combination with Pd in patients with previously treated multiple myeloma.”

In November 2015, IV daratumumab was first approved by the FDA for use in patients with multiple myeloma who had received at least 3 previous lines of treatment, including a PI and an IMiD agent, or who are double refractory to a PI and an IMiD agent based on data reported from the phase 2 SIRIUS trial (MMY2002), in which the CD38-directed monoclonal antibody elicited an ORR of 29.2% (95% CI, 20.8%-38.9%) in patients who received a median of 5 previous lines of treatment.⁶

More recently, in May 2020, the FDA gave the green light to daratumumab and hyaluronidase-fihj for the treatment of adult patients with newly diagnosed or relapsed/refractory multiple myeloma based on findings from the phase 3 COLUMBA trial (MMY3012). Here, the subcutaneous formulation of the agent showed noninferiority to the IV formulation with regard to efficacy.^7,8 Moreover, the subcutaneous approach also resulted in a reduction in treatment burden versus the standard. The regulatory decision was also supported by data from the ongoing, phase 2 PLEIADES trial (MMY2040; NCT03412565).

References

1. Janssen submits applications in the US and EU seeking approval of Darzalex Faspro (daratumumab and hyaluronidase-fihj)/Darzalex (daratumumab) subcutaneous (SC) formulation in combination with pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. November 12, 2020. Accessed November 12, 2020. https://prn.to/32GGwrw.

2. Genmab announces European Myeloma Network and Janssen achieve positive topline results from phase 3 APOLLO study of daratumumab in combination with pomalidomide and dexamethasone in relapsed or refractory multiple myeloma. News release. Genmab. July 31, 2020. Accessed November 12, 2020. https://bit.ly/31ddLBd.

3. Genmab announces US FDA approval of Darzalex (daratumumab) in combination with pomalidomide and dexamethasone for relapsed or refractory multiple myeloma. News release. Genmab. June 16, 2017. Accessed November 12, 2020. https://bit.ly/3ndtXvm.

4. Comparison of pomalidomide and dexamethasone with or without daratumumab in subjects with relapsed or refractory multiple myeloma previously treated with lenalidomide and a proteasome inhibitor daratumumab/pomalidomide/dexamethasone vs pomalidomide/dexamethasone (EMN14). ClinicalTrials.gov. Updated July 22, 2020. Accessed November 12, 2020. https://clinicaltrials.gov/ct2/show/NCT03180736​

5. Sonneveld P, Terpos E, Dimopoulos MA, et al. Pomalidomide and dexamethasone (pom-dex) with or without daratumumab (dara) in patients (pts) with relapsed or refractory multiple myeloma (RRMM): a multicenter, randomized, phase 3 study (APOLLO). J Clin Oncol. 2018;36(suppl 15):TPS8059. doi:10.1200/JCO.2018.36.15_suppl.TPS8059

6. Darzalex (daratumumab) approved by US FDA: first human anti-CD38 monoclonal antibody available for the treatment of multiple myeloma. News release. Janssen Biotech, Inc. November 16, 2015. Accessed November 12, 2020. https://bit.ly/38Ck2LS.

7. FDA approves daratumumab and hyaluronidase-fihj for multiple myeloma. News release. FDA. May 1, 2020. Accessed November 12, 2020. https://bit.ly/2zJvs0Y.

8. Genmab announces U.S. FDA approval of subcutaneous formulation of daratumumab, DARZALEX FASPRO (daratumumab and hyaluronidase-fihj), for the treatment of patients with multiple myeloma. News release. Genmab. May 1, 2020. Accessed November 12, 2020. https://bit.ly/3fbZ9YY.