On May 14, 2020, pomalidomide was granted accelerated approval to treat adult patients with AIDS-related Kaposi sarcoma after failure of highly active antiretroviral therapy and for Kaposi sarcoma in adult patients who are HIV-negative.^1,2 Pomalidomide is available only through the restricted Pomalyst REMS program.

Supporting Efficacy Data

Approval was based on findings in the single-center phase I/II Study 12-C-0047 (ClinicalTrials.gov identifier NCT01495598),^2,3 conducted at the National Cancer Institute. In the trial, 28 participants, including 18 HIV-positive and 10 HIV-negative patients, received oral pomalidomide, 5 mg once daily, on days 1 through 21 of 28-day cycles until disease progression or unacceptable toxicity. All HIV-positive patients continued receiving highly active antiretroviral therapy. Patients received deep-vein thrombosis prophylaxis with daily low-dose aspirin. The main efficacy outcome measure was investigator-assessed overall response rate according to the AIDS Clinical Trial Group Oncology Committee response criteria for Kaposi sarcoma.

Among all 28 patients, response was observed in 20 (71%, 95% confidence interval [CI] = 51%–87%), with complete response in 4 (14%). Median response duration was 12.1 months (95% CI = 7.6–16.8 months), with response duration of more than 12 months in 50% and less than 24 months in 20%. Among the 18 HIV-positive patients, response was observed in 12 (67%, 95% CI = 41%–87%), including complete response in 3 (17%). Median response duration was 12.5 months (95% CI = 6.5–24.9 months), with response duration of more than 12 months in 58% and less than 24 months in 17%. Among the 10 HIV-negative patients, response was observed in 8 (80%, 95% CI = 44%–98%), including complete response in 1 (10%). Median response duration was 10.5 months (95% CI = 3.9–24.2 months), with response duration of more than 12 months in 38% and less than 24 months in 25%. Median time to first response was 1.8 months.

How It Works

Pomalidomide is an analog of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. Cellular activities of pomalidomide are mediated through its target cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex.

In the presence of the drug in vitro, substrate proteins are targeted for ubiquitination and subsequent degradation, leading to direct cytotoxic and immunomodulatory effects. In in vitro cellular assays, pomalidomide inhibited proliferation and induced apoptosis of hematopoietic tumor cells. Pomalidomide also inhibited the proliferation of lenalidomide-resistant multiple myeloma cell lines and acted synergistically with dexamethasone in both lenalidomide-sensitive and lenalidomide-resistant cell lines to induce tumor cell apoptosis. Pomalidomide enhanced T cell– and natural killer cell–mediated immunity and inhibited production of proinflammatory cytokines by monocytes. Pomalidomide demonstrated antiangiogenic activity in a mouse tumor model and in the in vitro umbilical cord model.

How It Is Used

Women of reproductive potential must have negative pregnancy testing and use contraception before initiating treatment with pomalidomide.

The recommended dosage in the current indication is 5 mg once daily on days 1 through 21 of each 28-day cycle until disease progression or unacceptable toxicity. Highly active antiretroviral therapy should be continued in patients with AIDS-related Kaposi sarcoma. Recommended dosages are 4 mg once daily in patients with severe renal impairment requiring dialysis and 3 mg once daily in patients with mild or moderate hepatic impairment.

Pomalidomide prescribing information provides instructions on dosage modification, including dose reduction, and withholding and discontinuation of treatment for hematologic adverse reactions including neutropenia, febrile neutropenia, and thrombocytopenia as well as nonhematologic adverse reactions including angioedema, anaphylaxis, grade 4 rash, skin exfoliation, bullae, any other severe dermatologic reactions, and other grade 3 or 4 adverse reactions.

Concomitant administration with strong CYP1A2 inhibitors should be avoided; if such use cannot be avoided, the pomalidomide dose should be reduced to 2 mg daily.

Safety Profile

Among the 28 patients in Study 12-C-0047, 75% were exposed to pomalidomide for at least 6 months and 25% for more than 1 year. The most common adverse events of any grade including laboratory abnormalities (at least 30% of patients) were decreased absolute neutrophil count (96%), decreased white blood cells (79%), elevated creatinine (86%), rash (71%), constipation (71%), fatigue (68%), elevated glucose (57%), decreased hemoglobin (54%), decreased platelets (54%), decreased phosphate (54%), decreased albumin (54%), decreased calcium (50%), increased alanine transaminase (32%), nausea (36%), and diarrhea (32%). The most common grade 3 or 4 adverse events included rash, diarrhea, and peripheral edema (3.6% each). The most common grade 3 or 4 laboratory abnormalities were decreased neutrophil count (50%), decreased phosphate (25%), and elevated creatine kinase (7%).

Serious adverse events occurred in five patients (18%). Adverse events led to treatment interruption in four patients (14%) and to dose reduction in one patient (due to gout). Three patients (11%) permanently discontinued treatment due to adverse events.

Pomalidomide has boxed warnings for embryofetal toxicity and venous and arterial thromboembolism. Pomalidomide is an analog of thalidomide, a known human teratogen that causes severe life-threatening birth defects. For females of reproductive potential, pregnancy must be ruled out before start of treatment and prevented during therapy by the use of two reliable methods of contraception. Deep-venous thrombosis, pulmonary embolism, myocardial infarction, and stroke have occurred in patients with multiple myeloma receiving pomalidomide; antithrombotic prophylaxis is recommended.

Pomalidomide also has warnings/precautions for increased mortality, hematologic toxicity, hepatotoxicity, severe cutaneous reactions, tumor-lysis syndrome, and hypersensitivity. Increased mortality has been observed in patients with multiple myeloma when pembrolizumab was added to dexamethasone and a thalidomide analog. Patients should be monitored for hematologic toxicities, and liver function tests should be monitored monthly.

Patients at risk of tumor-lysis syndrome should be monitored and appropriate precautions taken. Patients should be monitored for potential hypersensitivity, and treatment should be discontinued for angioedema or anaphylaxis. Contraindications to pomalidomide treatment consist of pregnancy and hypersensitivity. Patients should be advised not to breastfeed while taking pomalidomide. 

REFERENCES

1. U.S. Food and Drug Administration: FDA grants accelerated approval to pomalidomide for Kaposi sarcoma. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pomalidomide-kaposi-sarcoma. Accessed May 29, 2020.

2. U.S. Food and Drug Administration: Highlights of prescribing information for Pomalyst (pomalidomide) capsules. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/204026s024lbl.pdf. Accessed May 29, 2020.

3. Polizzotto MN, et al: Pomalidomide for symptomatic Kaposi’s sarcoma in people with and without HIV infection. J Clin Oncol 34:4125-4131, 2016.