Date: 2014-12-07
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition, being held December 6-9 in San Francisco, CA
Company: Celgene (USA - NJ)
Product: Revlimid® (lenalidomide) plus dexamethasone
Action mechanism:
Disease: multiple myeloma
Therapeutic area: Cancer - Oncology
Country:
Trial
details: In the FIRST (Frontline Investigation of REVLIMID + Dexamethasone Versus Standard Thalidomide) trial, 1,623 patients from 18 countries either ≥65 or < 65 years of age and ineligible for stem cell transplant were randomized 1:1:1 into three arms: REVLIMID plus low-dose dexamethasone in 28-day cycles until disease progression (continuous Rd); REVLIMID plus low-dose dexamethasone for 72 weeks (18 cycles, Rd18); or melphalan, prednisone and thalidomide in 42-day cycles for 72 weeks (12 cycles, MPT). The primary endpoint was a comparison of progression-free survival for continuous Rd versus MPT.
Latest
news: * On December 7, 2014, Celgene announced that results were presented from multiple post-hoc analyses of its pivotal phase III FIRST (MM-020/IFM 07-01) trial, comparing continuous Revlimid® (lenalidomide) plus low-dose dexamethasone (continuous Rd) to a fixed duration of 18 cycles of Rd (Rd18) or 12 cycles of melphalan, prednisone and thalidomide (MPT) for the treatment of newly diagnosed, transplant-ineligible multiple myeloma. The studies were presented during the 56th American Society of Hematology (ASH) annual meeting. As previously reported, the study met the primary endpoint of progression-free survival (PFS) in the intent-to-treat analysis of all randomized patients (Median PFS 21.2 months MPT vs 25.5 months Rd, Hazard Ratio (HR) 0.72, p < 0.01). In one analysis, the authors examined the impact of age (75 years or younger vs. over 75 years) on PFS and secondary endpoints. Overall, 35% of patients were over 75 years of age. PFS and overall survival (OS) outcomes favored continuous Rd over MPT and over Rd18 in both age groups. In addition, response rates were higher with continuous RD vs MPT and duration of response was longer in the continuous Rd arm compared to MPT in both age groups. Additionally, an analysis of patients with renal impairment (RI) was presented. In the study, 24% had normal renal function (creatinine clearance [CrCl] ≥ 80 mL/min), 44% presented with mild RI (CrCl ≥ 50 and < 80 mL/min), 23% had moderate RI (CrCl ≥ 30 and < 50 mL/min), and 9% had severe RI (CrCl < 30 mL/min). Patients requiring dialysis were excluded. The starting doses of lenalidomide (25 mg for pts with normal renal function or mild RI, 10 mg QD for moderate RI, and 15 mg every other day for severe RI) in the Rd arms and of melphalan (reduced by 50% in patients with moderate or severe RI) in the MPT arm were adjusted for patients with CrCl < 50 mL/min. Continuous Rd demonstrated a longer PFS compared with MPT in all groups of patients with renal impairment, in particular, in patients with normal renal function (HR = 0.71; P = 0.05), in patients with mild RI (HR = 0.74; P = 0.02), patients with moderate RI (HR = 0.66; P < 0.01) and in patients with severe RI (HR 0.76; P=0.31). A slight PFS benefit was also seen with continuous Rd compared to Rd18 (a secondary comparison) in patients with mild or moderate RI (P < 0.01 for both). An analysis of the impact of depth of response on PFS was also presented. In patients who achieved at least a very good partial response (VGPR), median PFS was significantly longer (not reached (NR) with continuous Rd compared with Rd18 (31.0 months; HR = 0.46; P < 0.01) or MPT (34.7 months; HR = 0.55; P < 001). A benefit of continuous Rd was observed compared with Rd18 or MPT in patients who achieved a complete response (CR), where the median PFS with continuous Rd was NR vs. 45.2 months with Rd18 (HR = 0.29; P < 0.01) and 44.6 months with MPT (HR = 0.28; P < 0.01). Safety results in the FIRST study (N Engl J Med 2014) showed that grade 3/4 adverse events that occurred in at least 8% of patients in the continuous Rd arm, Rd18 arm or MPT arm included neutropenia (28%, 26% and 45%, respectively), anemia (18%, 16% and 19%, respectively), thrombocytopenia (8%, 8% and 11%, respectively), febrile neutropenia (1%, 3% and 3%, respectively), leukopenia (5%, 6% and 10%, respectively), infection (29%, 22% and 17%, respectively), pneumonia (8%, 8% and 6%, respectively), deep-vein thrombosis and/or pulmonary embolism (8%, 6% and 5%, respectively), asthenia (8%, 6% and 6%, respectively), fatigue (7%, 9% and 6%, respectively), and peripheral sensory neuropathy (1%, < 1% and 9%, respectively). Rates of grade 3/4 cardiac disorders for patients in the continuous Rd, Rd18 and MPT arms were 12%, 7% and 9%, respectively. The incidence of invasive second primary malignancies was 3% in patients taking continuous Rd, 6% in patients taking Rd18 and 5% in patients taking MPT. The overall incidence of solid tumors was identical in the continuous Rd and MPT arms (3%) and 5% in the Rd18 arm. Celgene has submitted applications for approval of Revlimid® in combination with dexamethasone for the treatment of newly diagnosed multiple myeloma patients with the European Medicines Agency (EMA) in February 2014 and with the FDA in April 2014. The FDA has set a Prescription Drug User Fee Act (PDUFA) date of Feb. 22, 2015. * On September 4, 2014, Celgene Corporation announced that data from FIRST (MM-020/IFM 07-01)—an open-label phase III randomized study of continuous Revlimid® (lenalidomide) in combination with dexamethasone in patients newly diagnosed with multiple myeloma (NDMM) who are not candidates for stem cell transplant—have been published in the Sept. 4 issue of the New England Journal of Medicine. Initial findings, including that the trial had met its primary endpoint of progression free survival (PFS), were reported during the plenary session at the 55th American Society of Hematology annual meeting in December 2013. The findings, as published in the New England Journal of Medicine, demonstrated that at a median follow-up of 37 months among surviving patients, the median progression-free survival was 25.5 months with continuous oral lenalidomide plus low-dose dexamethasone (Rd), 20.7 months with a fixed course of oral lenalidomide plus low-dose dexamethasone (Rd18) and 21.2 months with melphalan, prednisone and thalidomide (MPT). This resulted in a 28% reduction in risk of progression or death for patients treated with continuous Rd compared with those treated with MPT (HR 0.72; 95% CI, 0.61 to 0.85; P<0.001) and a 30% reduction compared with Rd18 (HR 0.70; 95% CI, 0.60 to 0.82; P<0.001) in the study. The pre-planned interim analysis of overall survival demonstrated a 22% reduction in risk of death for continuous Rd vs. MPT (HR 0.78; 95% CI, 0.64 to 0.96; P=0.02), although the difference did not cross the pre-specified superiority boundary (P<0.0096). As of the time of the analysis (May 24, 2013), 121 of 535 (23%) patients in the continuous Rd arm were still on therapy. Additional secondary endpoints showed response rates were also significantly better with continuous Rd (75%) and with Rd18 (73%) than with MPT (62%; P Safety results showed that grade 3/4 adverse events that occurred in at least 8% of patients in the continuous Rd arm, Rd18 arm or MPT arm included neutropenia (28%, 26%, 45%, respectively), anemia (18%, 16%, 19%), thrombocytopenia (8%, 8%,11%), febrile neutropenia (1%, 3%, 3%), leukopenia (5%, 6%, 10%), infection (29%, 22%, 17%), pneumonia (8%, 8%, 6%), deep-vein thrombosis and/or pulmonary embolism (8%, 6%, 5%), asthenia (8%, 6%, 6%), fatigue (7%, 9%, 6%), and peripheral sensory neuropathy (1%, <1%, 9%). Rates of grade 3/4 cardiac disorders for patients in the continuous Rd, Rd18 and MPT arms were 12%, 7% and 9%, respectively. The incidence of invasive second primary malignancies was 3% in patients taking continuous Rd, 6% in patients taking Rd18 and 5% in those taking MPT; the overall incidence of solid tumors was identical in the continuous Rd and MPT arms (3%) and 5% in the Rd18 arm. Based on the results of the FIRST study, Celgene submitted Revlimid® in combination with dexamethasone for the treatment of newly diagnosed multiple myeloma patients with the European Medicines Agency (EMA) in February 2014 and with the FDA in April 2014.
