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Amgen Submits Application for Cancer Drug Kyprolis (Carfilzomib)

Company seeks expanded indication

Amgen and its subsidiary Onyx Pharmaceuticals, Inc., have announced the submission of a supplemental new drug application (sNDA) to the FDA for Kyprolis (carfilzomib) injection to seek approval for the treatment of patients with relapsed multiple myeloma who have received at least one prior therapy.

The sNDA is designed to support the conversion of accelerated approval to full approval and to expand the current approved indication.

The sNDA was based on data from the phase III ASPIRE (CArfilzomib, Lenalidomide, and DexamethaSone Versus Lenalidomide and Dexamethasone for the Treatment of PatIents With Relapsed Multiple MyEloma) trial and other relevant data.

The ASPIRE study evaluated carfilzomib in combination with lenalidomide and low-dose dexamethasone (KRd) compared with lenalidomide and low-dose dexamethasone alone (Rd) in patients with relapsed multiple myeloma after treatment with one to three prior regimens. The study’s primary endpoint was progression-free survival (PFS), defined as the time from treatment initiation to disease progression or death. Secondary endpoints included overall survival (OS), the overall response rate (ORR), the duration of response (DOR), the disease control rate, health-related quality of life (QoL), and safety.

The patients were randomly assigned to receive carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1 only, escalating to 27 mg/m2 on days 8, 9, 15, and 16 of cycle 1 and continuing on days 1, 2, 8, 9, 15, and 16 of subsequent cycles) in addition to a standard dosing schedule of lenalidomide (25 mg per day for 21 days on, 7 days off) and low-dose dexamethasone (40 mg per week in 4-week cycles) compared with lenalidomide and low-dose dexamethasone alone. The study included 792 patients at sites in North America, Europe, and Israel.

Interim results were reported in December 2014 at the 56th American Society of Hematology (ASH) annual meeting and exposition, held in San Francisco, California.

At the time of the prespecified interim analysis, the study met its primary endpoint for PFS, with a longer duration of median PFS in the KRd group compared with the Rd group (26.3 months vs. 17.6 months, respectively; P < 0.0001).

Median OS was not reached in either group; however, there was a trend toward longer OS with KRd compared with Rd (P = 0.018), which did not meet the prespecified statistical boundary at the interim analysis of survival (P = 0.005). The Kaplan-Meier OS event-free rates at 24 months were 73.3% and 65.0% for the two treatment groups, respectively.

The ORRs were 87.4% with KRd and 66.9% with Rd, with median DORs of 28.6 months and 21.2 months, respectively.

In the KRd and Rd groups, 31.8% and 9.4%, respectively, achieved a stringent complete response or a complete response, and 70.4% and 40.7% achieved a “very good” partial response or better.

Treatment with KRd consistently improved the global health status or QoL compared with Rd during 18 cycles of treatment (P = 0.0001).

Treatment discontinuation due to an adverse event (AE) occurred in 15.2% (KRd) and 17.4% (Rd) of patients. In each group, 7.7% and 8.5% of patients died during study treatment or within 30 days of receiving the last dose of study treatment. The most common hematologic treatment-emergent AEs (TEAEs) (greater than or equal to grade 3) included neutropenia (29.6% vs. 26.5%), anemia (17.9% vs. 17.2%), and thrombocytopenia (16.6% vs. 12.3%). The most common nonhematologic TEAEs (all grades) included diarrhea (42.3% vs. 33.7%), fatigue (32.9% vs. 30.6%), and cough (28.8% vs. 17.2%). The most common nonhematologic TEAEs (greater than or equal to grade 3) included pneumonia (12.5% vs. 10.5%), hypokalemia (9.4% vs. 4.9%), and hypophosphatemia (8.4% vs. 4.6%).

Important warnings and precautions associated with the use of carfilzomib include cardiac arrest, congestive heart failure, myocardial ischemia, pulmonary hypertension, pulmonary complications, infusion reactions, tumor lysis syndrome, thrombocytopenia, hepatic toxicity, and embryo-fetal toxicity.

Multiple myeloma is the second most common hematologic cancer and results from an abnormality of plasma cells, usually in the bone marrow. Worldwide, nearly 230,000 people have the disease. In 2014, the estimated number of new cases in the U.S. was 24,000, and the estimated number of deaths was 11,000.

Sources: Amgen; January 27, 2015; and ASH Abstract; December 7, 2014.

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