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 July 24, 2015, carfilzomib (Kyprolis) was approved for use in combination with lenalidomide (Revlimid) and dexamethasone in the treatment of patients with relapsed multiple myeloma who have received one to three prior lines of therapy.1,2
Carfilzomib was previously approved as a single agent for treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib (Velcade) and an immunomodulatory agent and had disease progression within 60 days of completion of their last therapy. The revised labeling for carfilzomib includes a revised dose schedule and safety information for monotherapy in this setting, and new warnings/precautions have been added to the labeling.
Efficacy Data
The new approval was based on improved progression-free survival in a phase III open-label trial in which 792 patients with relapsed or refractory multiple myeloma after one to three lines of prior therapy were randomly assigned to receive lenalidomide plus low-dose dexamethasone with (n = 396) or without carfilzomib (n = 396) for 18 cycles.3 Lenalidomide and dexamethasone were continued thereafter until disease progression. There was no planned crossover from the control group to treatment with carfilzomib.
In the carfilzomib and control groups, median age was 64 and 65 years, 54% and 59% of patients were male, 95% in both groups were white, the number of prior regimens was one in 46% and 40% and two in 30% and 35%, 55% and 58% had undergone prior transplantation, and International Staging System disease stage was I in 42% and 39% and II in 37% and 38%. Testing for genetic mutations was performed in 53% of patients, with high-risk mutations identified in 12% and 13% of patients.
On independent review, median progression-free survival was 26.3 months (95% confidence interval [CI] = 23.3–30.5 months) in the carfilzomib group vs 17.6 months (95% CI = 15.0–20.6 months) in the control group (hazard ratio [HR] = 0.69, P = .0001). A treatment effect favoring carfilzomib was observed across all subgroups, but the magnitude of benefit was reduced in patients with higher tumor burden (improvement of 11 months for stage I, 8 months for stage II, and 2 months for stage III).
An interim analysis of overall survival performed at the time of progression-free survival analysis showed that the difference between groups did not reach the protocol-specified early stopping boundary. A partial response or better was observed in 87% vs 67% of patients.
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. The drug exhibits antiproliferative and proapoptotic activities in solid and hematologic tumor cells. It inhibits proteasome activity in blood and tissue and delays tumor growth in animal models of multiple myeloma, hematologic, and solid tumors.
How It Is Given
Carfilzomib is given as a 10-minute intravenous infusion on 2 consecutive days each week for 3 weeks followed by a 12-day rest period in each 28-day cycle. The recommended starting dose is 20 mg/m2 in cycle 1 on days 1 and 2. If tolerated, the dose can be escalated to a target dose of 27 mg/m2 on day 8 of cycle 1. From cycle 13, the doses on days 8 and 9 are omitted. Treatment is continued for up to 18 cycles or until disease progression or unacceptable toxicity.
Oral lenalidomide is given at 25 mg on days 1 to 21, and oral or intravenous dexamethasone at 40 mg on days 1, 8, 15, and 22 of each cycle. In patients on dialysis, carfilzomib should be administered after the procedure.
All patients should receive hydration prior to administration and, as needed, following administration. Patients should be premedicated with dexamethasone at the recommended dose prior to all cycle 1 doses and if infusion reactions occur or recur. Thromboprophylaxis is recommended, with the regimen based on assessment of the patient’s underlying risks. Antiviral prophylaxis should be considered to reduce risk of herpes zoster reactivation.
Treatment should be withheld or dose-reduced for absolute neutrophil count < 0.5 × 109/L; 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. One dose level reduction is from 27 to 20 mg/m2 or from 20 to 15 mg/m2.
Safety Profile
In the phase III trial, the most common adverse events of any grade occurring during the first 12 cycles of therapy in the carfilzomib group were anemia (35% vs 33% in the control group), neutropenia (32% vs 30%), diarrhea (29% vs 27%), fatigue (28% vs 27%), and thrombocytopenia (26% vs 19%). Grade ≥ 3 adverse events that occurred with an incidence > 2% higher in the carfilzomib group included neutropenia (27% vs 23%), thrombocytopenia (15% vs 10%), and hypokalemia (6% vs 3%).
Despite protocol-mandated use of thromboprophylaxis, venous thromboembolic events occurred in 13% of carfilzomib recipients vs 6% of the control group. The most common grade 3 or 4 laboratory abnormalities in the carfilzomib group were lymphopenia (46% vs 31%), neutropenia (39% vs 36%), hypophosphatemia (31% vs 27%), and thrombocytopenia (26% vs 15%). Serious adverse events occurred in 60% vs 54% of patients, with the most common in the carfilzomib group being pneumonia (14% vs 11%), respiratory tract infection (4% vs 1.5%), pyrexia (4% vs 2%), and pulmonary embolism (3% vs 2%).
Adverse events led to treatment discontinuation in 26% vs 25% of patients and to discontinuation of carfilzomib in 12%, with the most common reasons being pneumonia (1%), myocardial infarction (0.8%), and upper respiratory tract infection (0.8%). Deaths due to adverse events within 30 days of the last dose of any therapy occurred in 7% vs 7% of patients, with the most common causes being cardiac events (3% vs 2%), infection (2% vs 3%), renal events (0% vs < 1%), and other events (2% vs 3%).
Among patients receiving carfilzomib, the incidence of serious adverse events was 50% in patients aged ≤ 65 years, 70% in those aged 65 to 74 years, and 74% in those aged ≥ 75 years.
Carfilzomib carries warnings/precautions for cardiac toxicities, including cardiac failure and myocardial infarction with fatal outcome, and myocardial ischemia; 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 thrombocytopenic purpura/hemolytic uremic syndrome; posterior reversible encephalopathy syndrome; and embryofetal toxicity.
Patients should be monitored regularly for serum creatinine, blood pressure, platelet counts, and liver enzymes. If hypertension cannot be controlled, a risk-benefit decision on continued carfilzomib treatment is necessary.
Patients should be monitored for tumor lysis syndrome, including uric acid levels, and treated promptly. Patients should be monitored for signs and symptoms of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome.
If posterior reversible encephalopathy syndrome is suspected, neuro-radiologic imaging for onset of visual or neurologic symptoms should be considered. Females of reproductive potential should avoid becoming pregnant during treatment. ■
References
1. U.S. Food and Drug Administration: Carfilzomib. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm455873.htm. Accessed July 28, 2015.
2. Kyprolis (carfilzomib) for injection prescribing information, Onyx Pharmaceuticals, Inc, an Amgen Inc. subsidiary, July 2015. Available at http://www.accessdata.fda.gov/-drugsatfda_docs/label/2015/202714s009lbl.pdf. -Accessed July 28, 2015.
3. Stewart AK, Rajkumar SV, Dimopoulos MA, et al: Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 372:142-152, 2015.
Report Adverse Events
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (800-FDA-1088).
