In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

On January 21, 2016, carfilzomib (Kyprolis) was approved for use in combination with dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.¹ In July 2015, carfilzomib was approved for use in combination with lenalidomide (Revlimid) and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy. It is also approved as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received at least one line of therapy.

Supporting Efficacy Data

The current approval is based on findings in an open-label phase III trial (ENDEAVOR) in which 929 patients were randomly assigned to receive carfilzomib/dexamethasone (n = 464) or bortezomib (Velcade)/dexamethasone (n = 465).^1,2 Carfilzomib was given at 20 mg/m² on days 1 and 2 of cycle 1 and 56 mg/m² thereafter via 30-minute intravenous infusion on days 1, 2, 8, 9, 15, and 16, with dexamethasone at 20 mg orally or via intravenous infusion on days 1, 2, 8, 9, 15, 16, 22, and 23 of 28-day cycles. Bortezomib was given at 1.3 mg/m² via intravenous bolus or subcutaneous injection on days 1, 4, 8, and 11, with dexamethasone at 20 mg orally or via intravenous infusion on days 1, 2, 4, 5, 8, 9, 11, and 12 of 21-day cycles. 

Concurrent use of thromboprophylaxis was optional; prophylaxis with an antiviral agent and a proton pump inhibitor was required. Of 465 patients in the bortezomib group, 381 received subcutaneous bortezomib. 

Median progression-free survival was 18.7 months (95% confidence interval [CI] = 15.6 months to not reached) in the carfilzomib group vs 9.4 months (95% CI = 8.4–10.4 months) in the bortezomib group (hazard ratio = 0.53, P < .0001). The objective response rates were 77% vs 63% (P < .0001). 

How It Works 

Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. Carfilzomib exhibits antiproliferative and proapoptotic activities in solid and hematologic tumor cells and inhibits proteasome activity in blood and tissue. It also delays tumor growth in animal models of multiple myeloma and hematologic and solid tumors. 

How It Is Given 

For the combination regimen with dexamethasone, carfilzomib should be given intravenously via 30-minute infusion on 2 consecutive days each week for 3 weeks followed by a 12-day rest period. Each 28-day period is considered one treatment cycle. The recommended starting dose is 20 mg/m² in cycle 1 on days 1 and 2. If tolerated, the dose should be escalated to 56 mg/m² on day 8 of cycle 1, with this dose used thereafter during treatment. Dexamethasone 20 mg is given orally or intravenously on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle, with administration at 30 minutes to 4 hours before carfilzomib administration. Treatment may be continued until disease progression or unacceptable toxicity.  

Adequate hydration is required prior to dosing in cycle 1, particularly in patients at high risk of tumor lysis syndrome or renal toxicity. Oral and/or intravenous hydration, as needed, should be continued in subsequent cycles and should be adjusted to individual patient needs, especially in patients with or at risk for cardiac failure. Thromboprophylaxis is recommended, with the regimen based on assessment of underlying risk in each patient. Antiviral prophylaxis should be considered to decrease the risk of herpes zoster reactivation.

Stepwise dose reductions for carfilzomib are made from 56 to 45, 36, and 27 mg/m². Treatment should be withheld or dose-reduced for absolute neutrophil count < 0.5 × 10⁹/L; febrile neutropenia; platelets < 10 × 10⁹/L or evidence of bleeding with thrombocytopenia; serum creatinine ≥ 2 × baseline or creatinine clearance < 15 mL/min, creatinine clearance reduction to ≤ 50% of baseline, or need for dialysis; or any severe or life-threatening nonhematologic toxicity.  

Safety Profile

In the phase III trial, the most common adverse events of any grade in the carfilzomib group were anemia (35% vs 25% in the bortezomib group), thrombocytopenia (27% vs 25%), and dyspnea (27% vs 15%). The most common grade ≥ 3 adverse events included anemia (12% vs 9%), thrombocytopenia (10% vs 14%), hypertension (6% vs 3%), and dyspnea (5% vs 2%). Grade ≥ 2 peripheral neuropathy occurred in 6% vs 32% of patients. The most common grade 3 or 4 lab abnormalities were decreased lymphocytes (54% vs 40%), increased uric acid (53% vs 43%); grade 3 or 4 decreased creatinine clearance occurred in 14% vs 11%, and grade 3 or 4 increased potassium occurred in 12% vs 5%. 

Serious adverse events occurred in 48% vs 36% of patients, with the most common being pneumonia (6% vs 9%). Adverse events led to discontinuation of treatment in 20% vs 21%, with the most common causes being cardiac failure in the carfilzomib group (1.3%) and peripheral neuropathy in the bortezomib group (4.2%). Death due to adverse events within 30 days of last study treatment occurred in 5% vs 5% of patients; causes included cardiac events (2% vs 1%), infection (1% vs 2%), disease progression (1% vs 1%), and pulmonary events (1% vs < 1%). 

Carfilzomib carries warnings/precautions for cardiac toxicities; acute renal failure; tumor lysis syndrome; pulmonary toxicity, including acute respiratory distress syndrome, acute respiratory failure, and acute diffuse infiltrative pulmonary disease; pulmonary hypertension; dyspnea; hypertension, including hypertensive crisis; venous thrombosis; infusion reactions; thrombocytopenia; hepatic toxicity and hepatic failure; thrombotic microangiopathy; posterior reversible encephalopathy syndrome; and embryofetal toxicity.  

Patients should be monitored regularly for signs/symptoms of cardiac failure and ischemia, signs/symptoms of thrombotic microangiopathy, serum creatinine, blood pressure, platelet counts, and liver enzymes. Patients should also be monitored for tumor lysis syndrome, including monitoring of uric acid levels. Neuroradiologic imaging should be considered for onset of visual or neurologic symptoms. Women of reproductive potential should avoid becoming pregnant during treatment. ■ 

References 

1. Kyprolis (carfilzomib) for injection prescribing information, Onyx Pharmaceuticals, January 2016. Available at pi.amgen.com/united_states/kyprolis/kyprolis_pi.pdf. Accessed February 23, 2016. 

2. Dimopoulos MA, Moreau P, Palumbo A, et al: Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): A randomised, phase 3, open-label, multicentre study. Lancet Oncol 17:27-38, 2016.