Carfilzomib Phase III ENDEAVOR Data Submitted for FDA Approval in Myeloma

Sean E. Harper, MD

Sean E. Harper, MD

According to Amgen, a supplemental new drug application (sNDA) was recently submitted for carfilzomib (Kyprolis) in combination with dexamethasone for patients who have relapsed multiple myeloma, following previous treatment with at least one therapy.

The application for carfilzomib is based on findings from the phase III ENDEAVOR trial, which were presented at the 2015 ASCO Annual Meeting. In the study, the median progression-free survival (PFS) with carfilzomib was 18.7 versus 9.4 months with bortezomib (HR = 0.53, 95% CI, 0.44—0.65;P<.0001), representing a 47% reduction in the risk of progression. The FDA is scheduled to review the application within 60 days, at which point the agency will assign a decision deadline under the Prescription Drug User Fee Act.

"Submission of this new sNDA for Kyprolis is important because if approved, it will mean more treatment options for patients with this serious disease," Sean E. Harper, MD, executive vice president of Research and Development at Amgen, said in a statement. "The ENDEAVOR study showed that patients who had failed at least one prior therapy were half as likely to see their disease worsen if they received Kyprolis. This is yet another data set that illustrates Kyprolis' potential to extend the time patients live without their disease progressing and improve the depth and duration of a response."

In the phase III study, 929 patients were randomized to receive carfilzomib as a 30-minute infusion along with dexamethasone (n = 464) or bortezomib and dexamethasone (n = 465). Carfilzomib was administered at a starting dose of 20 mg/m²on days 1 and 2 of cycle 1. If tolerated, the dose was escalated to 56 mg/m²on day 8 of cycle 1. After this point, the 56 mg/m²dose was maintained on days 9, 15, and 16 and throughout subsequent cycles. In the control arm, patients received bortezomib at 1.3 mg/m². The majority of patients received bortezomib subcutaneously (75%).

The median age of patients enrolled in the trial was 65 years. All but 7% of patients had ECOG PS of 0 or 1 (about 50% ECOG 0), and about 20% of the patients had high-risk cytogenetic by fluorescence in situ hybridization. The primary endpoint was PFS, with overall survival (OS), objective response rate (ORR), duration of response, and safety as secondary measures.

The advantage in PFS seen with carfilzomib was consistent across subgroups. The median OS was 24.3 months in the bortezomib arm but had not yet been reached in the carfilzomib arm (HR = 0.79;P= .066). However, at the time of the primary analysis, survival data were not yet mature.

The ORR was 77% with carfilzomib versus 29% with bortezomib. The complete response rate with carfilzomib was 13% versus 6% with bortezomib. The rate of very good partial response or better with carfilzomib was 54% compared with 29% with bortezomib.

Grade 3 adverse events (AEs) occurred more frequently in the carfilzomib arm compared with bortezomib (73% vs 67%). Additionally, serious AEs were more common with carfilzomib (48% vs 36%). However, dose reductions associated with AEs were more frequent with bortezomib versus carfilzomib (48% vs 23%). Treatment discontinuation due to AEs and on-study deaths were comparable between the two arms.

Grade &ge;3 hematologic adverse events occurred in a similar proportion of patients in both groups, including anemia, thrombocytopenia, neutropenia, upper respiratory infection, and pneumonia. However, there was an increase in the incidence of hypertension and dyspnea with carfilzomib versus bortezomib. The most frequent non-hematologic grade &ge;3 AEs were diarrhea, fatigue, dyspnea, pyrexia, constipation, and insomnia.

Peripheral neuropathy occurred in 5% of patients treated with bortezomib and 1.3% of those in the carfilzomib arm. The proportion of patients with grade &ge;2 peripheral neuropathy was significantly higher with bortezomib (32% versus 6%;P<.0001).

&ldquo;The combination of carfilzomib and dexamethasone was superior to bortezomib and dexamethasone regardless of age or prior bortezomib exposure and represents a new standard of care,&rdquo; lead investigator Meletios A. Dimopoulos, MD, chair of clinical therapeutics at the University of Athens in Greece, said when the data were presented. &ldquo;Although patients treated with carfilzomib and dexamethasone remained on study treatment longer, treatment discontinuation due to adverse events and on-study deaths due to adverse events were comparable between groups.&rdquo;

Carfilzomib is currently approved as a treatment for patients with multiple myeloma who have received at least two prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of the completion of the last therapy. The treatment continues to be explored across a number of settings.

The FDA is currently considering a separate sNDA for carfilzomib in combination with lenalidomide and low-dose dexamethasone for patients with relapsed multiple myeloma. This application was based on the phase III ASPIRE trial, which demonstrated a 31% reduction in the risk of disease progression with the triplet compared with lenalidomide and low-dose dexamethasone alone.

A decision based on the ASPIRE data is expected by July 26, 2015.