Two phase 3 trials led to Darzalex being granted a breakthrough therapy designation by the FDA.
Darzalex (daratumumab) was granted a breakthrough therapy designation by the U.S. Food and Drug Administration (FDA) for use in combination with Revlimid /dexamethasone or Velcade /dexamethasone for patients with multiple myeloma who have had at least one prior therapy, according to the developers of the CD38-targeted antibody, Janssen and Genmab.
The designation, which will expedite the development and review of the Darzalex regimens, is based on two phase 3 trials. The phase 3 POLLUX trial demonstrated that combining Darzalex with Revlimid (lenalidomide) and dexamethasone reduced the risk of disease progression by 63 percent versus Revlimid and dexamethasone alone in patients with relapsed/refractory multiple myeloma. In the phase 3 CASTOR trial, adding Darzalex to Velcade (bortezomib) and dexamethasone reduced the risk of progression or death by 61 percent in patients with recurrent or refractory multiple myeloma.
“Despite tremendous progress in the past 15 years, multiple myeloma remains a highly complex and difficult disease to treat, with most patients relapsing or becoming resistant to therapy,” POLLUX lead author Meletios A. Dimopoulos, department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Alexandra General Hospital, Athens, Greece, said in a statement. “Daratumumab has already shown pronounced activity as a monotherapy in heavily pretreated patients. This designation underscores the potential of daratumumab in combination with either a proteasome inhibitor or an immunomodulatory agent to provide much-needed benefit to patients with at least one prior therapy.”
The international, open-label POLLUX trial randomized 569 patients with relapsed/refractory multiple myeloma to Darzalex combined with Revlimid dexamethasone (286 patients) or Revlimid plus dexamethasone alone (283 patients). Darzalex was dosed at 16 mg/kg IV once weekly during cycles one and two, every two weeks during cycles three to six, and once only (on day one) of cycles seven onward. Oral Revlimid was administered at 25 mg daily for the first three weeks of each cycle and dexamethasone was dosed at 40 mg weekly (20 mg weekly in patients older than 75 or with a BMI less than 8.5). Treatment cycles for both study arms were 28 days. Patients were treated until progression or unacceptable toxicity.
The median patient age was 65 years. The median number of of prior treatment lines was one, with 19 percent of patients having received three or more lines of therapy. Eighty-six percent of patients had received a proteasome inhibitor; 55 percent had been treated with an immunomodulatory agent (IMiD), including 18 percent with Revlimid; and 44 percent had previously receiving both a proteasome inhibitor and an IMiD. Across the study population, 27 percent of patients were refractory to their most recent treatment and 18 percent were refractory to a proteasome inhibitor; however, no patients were refractory to Revlimid.
The primary endpoint of the study was progression-free survival (PFS), with secondary outcome measures including time to progression, overall response rate (ORR), overall survival and very good partial response (VGPR). At a preplanned interim analysis in May 2016, the study was unblinded after an independent panel determined the trial met its primary endpoint of improved PFS. Patients in the control arm were allowed to receive Darzalex at progression.
At a median follow-up of 13.5 months, the median PFS was not yet reached in the Darzalex arm versus 18.4 months with Revlimid /dexamethasone alone. The ORR was 93 percent versus 76 percent, respectively. The VGPR or better rate was 76 percent with Darzalex versus 44 percent in the control arm and the compete response rates were 43 percent and 19 percent, respectively.
The safety profile was consistent with previously reported adverse events (AEs) for single-agent Darzalex and the combination of Revlimid and dexamethasone. The most common all-grade AEs included neutropenia (59 percent with the Darzalex triplet vs 43 percent in the control arm), diarrhea (43 percent vs 25 percent), fatigue (35 percent vs 28 percent), upper respiratory tract infection (32 percent vs 21 percent), anemia (31 percent vs 35 percent), constipation (29 percent vs 25 percent), cough (29 percent vs 13 percent), thrombocytopenia (27 percent each) and muscle spasms (26 percent vs 19 percent).
Infusion reactions related to Darzalex were reported in 48 percent of patients and were mostly grade 1/2, with 5 percent experiencing grade 3. Ninety-two percent of these reactions occurred during the initial infusion.
The most common grade 3/4 AEs were neutropenia (52 percent in the Darzalex arm vs 37 percent in the control arm), thrombocytopenia (13 percent vs 14 percent) and anemia (12 percent vs 20 percent). Grade 3/4 infections occurred in 28 percent of patients receiving Darzalex compared with 23 percent of patients in the control arm. The most common grade 3/4 infection was pneumonia, which occurred in 8 percent of patients in each arm. Discontinuation rates due to AEs occurred in 7 percent and 8 percent of patients in the two arms, respectively.
The CASTOR trial included 498 patients were who were randomized one to one to receive eight cycles of Velcade/dexamethasone with or without 16 mg/kg of Darzalex. Velcade was administered subcutaneously at 1.3 mg/m2 on days one, four, eight and 11 of each 21-day cycle for a maximum of eight cycles. Patients received 20 mg of oral dexamethasone on days one, two, four, five, eight, nine, 11 and 12 of the first eight Velcade treatment cycles. Patients in the Darzalex group were administered an IV infusion of the antibody at 16 mg/kg weekly for the first three cycles, on day one of cycles four to nine, and then every four weeks. Treatment was administered until disease progression or unacceptable toxicity.
Patients in the trial had received a median of two prior lines of therapy (range, one to 10) and 66 percent had received prior Velcade, 76 percent has received prior IMiDs, and 48 percent had received prior proteasome inhibitors and IMiDs. Thirty-three percent were IMiD-refractory and 32 percent were refractory to last line of prior therapy.
The primary endpoint was PFS and secondary endpoints include time-to-progression, ORR, overall survival, and safety.
Median PFS was 7.2 months in the standard treatment arm and was not yet reached in the Darzalex arm. The ORR was 83 percent and 63 percent in the experimental and control arms, respectively. Nineteen percent of patients in the Darzalex arm had a complete response (CR) or better and 59 percent of patients had a VGPR or better compared with 9 percent of patients experiencing a CR and 29 percent experiencing a VGPR in the control arm.
The most common treatment-emergent AEs were thrombocytopenia, which occurred in 59 percent of patients in the Darzalex arm versus 44 percent in the Velcade/dexamethasone arm; sensory peripheral neuropathy, which occurred in 47 percent and 38 percent of patients in the experimental and control arms, respectively; diarrhea, which occurred in 32 percent and 22 percent of patients in each arm respectively and anemia, which occurred in 26 percent and 31 percent of patients in each arm, respectively.
Seven percent of patients in the Darzalex arm discontinued treatment due to AEs versus 9 percent of patients receiving Velcade/dexamethasone alone. Infusion-related reactions (IRRs) were experienced by 45 percent of patients in the study overall. Nine percent were grade 3, there were no grade 4 IRRs and 98 percent occurred during the first infusion.
Commenting on the breakthrough status, Craig L. Tendler, vice president, Late-Stage Development and Global Medical Affairs for Oncology, Hematology, and Supportive Care at Janssen, said, “This is an important recognition of the transformative potential of Darzalex and its possible benefit as a backbone therapy in combination with two of the most widely used regimens for multiple myeloma. We look forward to working closely with the FDA throughout the review process and remain committed to exploring the full clinical benefit of this promising compound for multiple myeloma patients who are eagerly awaiting new treatment options.”
In November 2015, the FDA granted an accelerated approval to Darzalex as a monotherapy for patients who have relapsed after three or more prior lines including a proteasome inhibitor and an IMiD or who are double-refractory to those therapies. In May 2016, the European Commission granted conditional marketing approval to Darzalex for the treatment of patients with relapsed/refractory multiple myeloma previously treated with a proteasome inhibitor and an IMiD who progressed on their last therapy.