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.
Indication
On February 8, 2013, the immunomodulatory agent pomalidomide (Pomalyst) was granted accelerated approval for the treatment of patients with multiple myeloma who have received at least two prior therapies including lenalidomide (Revlimid) and bortezomib (Velcade) and who showed disease progression within 60 days of completion of their last therapy.1 Approval was based on response rate. Improvement in survival or symptoms with pomalidomide treatment has not yet been verified. Due to embryo-fetal risk associated with pomalidomide treatment, the drug is available only through a restricted distribution program.
The approval was based on the results of a multicenter, randomized, open-label study (CC-4047-MM-002) in which 221 patients with relapsed/refractory multiple myeloma who had previously received lenalidomide and bortezomib and who were refractory to the last myeloma therapy were randomized to pomalidomide alone (n = 108) alone or pomalidomide plus low-dose dexamethasone (n = 113).2 Dexamethasone was added to treatment in 61 patients in the pomalidomide-alone group. Due to risk of venous thromboembolism with pomalidomide, all patients were required to receive prophylaxis or antithrombotic treatment.
For the pomalidomide and pomalidomide-plus-dexamethasone groups, respectively, median ages were 61 years (40% ≥ 65 years) and 64 years (47% ≥ 65 years), 53% and 55% were male, 80% and 81% were white, 88% and 88% had ECOG performance status of 0 or 1, median number of prior therapies was 5 and 5, 76% and 74% had prior transplantation, and 59% and 61% were refractory to bortezomib and lenalidomide.
The overall response rate was 7% with pomalidomide alone and 29% with pomalidomide plus low-dose dexamethasone, with one complete response observed in the latter group. Median duration of response was not reached in the pomalidomide group and was 7.4 months among patients receiving pomalidomide plus low-dose dexamethasone.
As a condition of the accelerated approval, FDA requires submission of the results of a randomized clinical trial (CC-4047-MM-007) of pomalidomide added to bortezomib and low-dose dexamethasone compared to bortezomib plus low-dose dexamethasone in previously treated multiple myeloma.
How It Works
Pomalidomide, which is an analog of thalidomide, is an immunomodulatory agent with antineoplastic activity. The agent enhances T cell– and natural killer cell–mediated immunity and inhibits monocyte production of proinflammatory cytokines (eg, tumor necrosis factor-alpha and interleukin-6). It has shown antiangiogenic activity in animal tumor models and in vitro in the umbilical cord model. In cellular assays, pomalidomide inhibits proliferation and induces apoptosis of hematopoietic tumor cells. It has been found to inhibit proliferation of lenalidomide-resistant multiple myeloma cell lines and to exhibit synergistic activity in inducing apoptosis when combined with dexamethasone in both lenalidomide-sensitive and lenalidomide-resistant cell lines.
How It Is Given
The recommended starting dose of pomalidomide is 4 mg once daily orally on days 1 to 21 of 28-day cycles repeated until disease progression. It may be given in combination with dexamethasone. It should be taken without food.
No cycle of pomalidomide should be started in patients with a neutrophil count less than 500/µL or platelet count less than 50,000/µL. For neutropenia and thrombocytopenia, pomalidomide treatment should be interrupted and reinitiated at 3 mg upon resolution for the first episode and at 1 mg lower than the preceding dose for any subsequent episodes. For other grade 3 or 4 toxicities, treatment should be interrupted until recovery and then resumed at a dose 1 mg lower than the preceding dose.
REMS
Thalidomide (Thalomid) is a known human teratogen that causes severe birth defects or embryo-fetal death. Due to embryo-fetal risk with pomalidomide, it is available only through a restricted program under a risk evaluation and mitigation strategy called POMALYST REMS. Prescribers and pharmacies dispensing the drug must be certified with this program, and patients must sign a patient-prescriber agreement form in order to receive pomalidomide. (Information about the POMALYST REMS program is available at celgeneriskmanagement.com or at 1-888-423-5436.)
Pomalidomide is contraindicated in pregnant women, and women of reproductive potential must avoid pregnancy while taking the drug and for at least 4 weeks after completing therapy. Women of reproductive potential must use two reliable methods of contraception starting 4 weeks before treatment and continuing through 4 weeks after final discontinuation of treatment. Two negative pregnancy tests must be obtained prior to initiating therapy.
Since pomalidomide is present in semen, men must always use a latex or synthetic condom during any sexual contact with women of reproductive potential while taking pomalidomide and for up to 28 days after discontinuing treatment, even if they have undergone a successful vasectomy. Patients receiving pomalidomide must not donate blood during treatment or for 1 month following treatment.
How It Is Metabolized
Pomalidomide is primarily metabolized by CYP1A2 and CYP3A, and it is a substrate for P-glycoprotein. Coadministration of pomalidomide with strong inhibitors of CYP1A2 (eg, ciprofloxacin, enoxacin, fluvoxamine), CYP3A (eg, clarithromycin, ketoconazole, grapefruit juice), or P-glycoprotein (eg, azithromycin, amiodarone, itraconazole) could increase pomalidomide exposure and should be avoided. Likewise, strong inducers of CYP1A2 (eg, broccoli, modafinil, nafcillin), CYP3A (eg, carbamazepine, phenytoin, rifampin), or P-glycoprotein (eg, avasimibe, rifampin, St. John’s wort) could decrease pomalidomide exposure and should be avoided. Cigarette smoking may reduce pomalidomide exposure via CYP1A2 induction, and patients should be advised that smoking may thus reduce the efficacy of pomalidomide.
Safety Profile
Patients in the clinical trial received a median of five cycles of treatment. Overall, the most common adverse events of any grade were fatigue and asthenia, neutropenia, anemia, constipation, nausea, diarrhea, dyspnea, upper respiratory tract infection, back pain, and pyrexia.
The most common grade 3 or 4 adverse events in the pomalidomide-alone and pomalidomide-plus-dexamethasone groups were neutropenia (47% and 38%), anemia (22% and 21%), thrombocytopenia (22% and 19%), pneumonia (16% and 23%), fatigue and asthenia (11% and 13%), back pain (12% and 9%), and dyspnea (7% and 13%).
Serious adverse events occurred in 67% of the pomalidomide-alone group and 62% of the pomalidomide-plus-dexamethasone group, with the most common being pneumonia (14% and 19%), renal failure (8% and 6%), and dyspnea (5% and 6%). Overall, dose interruption and dose reduction of either drug due to adverse events occurred in 63% and 37% of patients, respectively, and discontinuation of treatment due to treatment-related adverse events occurred in 3%.
Among adverse events of particular interest with pomalidomide, deep-vein thrombosis or pulmonary embolism occurred in 3% of patients, dizziness occurred in 18% of patients (grade 3/4 in 1%) and confusional state in 12% (grade 3/4 in 3%), and neuropathy occurred in 18% (all grade 1/2), including peripheral neuropathy in 9%.
Pomalidomide carries boxed warnings for embryo-fetal toxicity, use only through the POMALYST REMS program, and venous thromboembolism. It also has warnings/precautions for hematologic toxicity, hypersensitivity reactions, dizziness and confusional state, neuropathy, and risk of second primary malignancies. Cases of acute myelogenous leukemia have been reported in patients receiving pomalidomide as investigational therapy outside the setting of multiple myeloma. ■
References
1. U.S. Food and Drug Administration: Pomalidomide. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm339286.htm. Accessed February 20, 2013.
2. POMALYST® (pomalidomide) capsules prescribing information, Celgene Corporation, February 2013. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204026lbl.pdf.
Accessed February 20, 2013.
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 http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
