FDA Grants Priority Review to Carfilzomib for Relapsed Multiple Myeloma

Sean E. Harper, MD

Sean E. Harper, MD

Carfilzomib (Kyprolis) in combination with dexamethasone, was recently granted a priority review designation by the FDA for patients who have relapsed multiple myeloma, following prior treatment with at least one therapy, based on results from the phase III ENDEAVOR trial.

In the study, carfilzomib and dexamethasone reduced the risk of progression by 47%, compared with bortezomib and dexamethasone. 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).¹Under the priority review program, the FDA will make a decision by January 22, 2016.

"Clinicians need a range of options and robust clinical data to make informed choices that can ideally extend the time patients live without their cancer progressing," said Sean E. Harper, MD, executive vice president of Research and Development at Amgen, the company developing the drug, in a statement. "The acceptance of this submission is an important next step toward providing more options for patients with relapsed multiple myeloma and we look forward to working with the FDA over the coming months."

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 increased to 56 mg/m²on day 8 of cycle 1. After this point, the 56 mg/m²dose was maintained on days 9, 15, and 16, as well as 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; said lead investigator Meletios A. Dimopoulos, MD, chair of clinical therapeutics at the University of Athens in Greece, 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 was initially granted an accelerated approval in July 2012 as a treatment for patients with multiple myeloma following at least two therapies, including bortezomib and an immunomodulatory agent. In July 2015, the FDA transitioned this to a full approval and expanded the indication to included the treatment of patients with relapsed multiple myeloma who have received at least one to three prior lines of therapy, based on results from the phase III ASPIRE trial.²

In the pivotal ASPIRE trial, the combination of carfilzomib, lenalidomide, and low-dose dexamethasone reduced the risk of progression by 31% compared with lenalidomide and low-dose dexamethasone alone in patients with relapsed multiple myeloma. The median PFS with carfilzomib was 26.3 months compared with 17.6 months without the proteasome inhibitor (HR, 0.69; 95% CI, 0.57-0.83;P<.0001).

1. Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd) in patients (pts) with relapsed multiple myeloma (RMM): results from the phase III study ENDEAVOR. J Clin Oncol. 2015;(suppl; abstr 8509).
2. Stewart KA, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone vs lenalidomide and dexamethasone in patients with relapsed multiple myeloma: interim results from ASPIRE, a randomized, open-label, multicenter phase 3 study. Presented at: 2014 ASH Annual Meeting; December 6-9, 2014, San Francisco, CA. Abstract: 79.