On September 14, 2017, copanlisib (Aliqopa) was granted accelerated approval for treatment of adult patients with relapsed follicular lymphoma who have received at least two prior systemic therapies.1,2
Supporting Efficacy Data
Approval was based on durable responses observed in a multicenter phase II study (CHRONOS-1) in which 104 patients with follicular B-cell non-Hodgkin lymphoma who had relapsed following at least 2 prior treatments received copanlisib at 0.8 mg/ kg or 60 mg via intravenous (IV) infusion on days 1, 8, and 15 of 28-day treatment cycles.2 Patients had to have received rituximab (Rituxan) and an alkylating agent. The median age of patients was 62 years (range = 25–81 years), 83% were white, 52% were male, and the median number of prior therapies was 3 (range = 2–8). The most common prior systemic therapies were chemotherapy in combination with anti-CD20 immunotherapy (89%), chemotherapy alone (41%), and anti-CD20 immunotherapy alone (37%).
The objective response rate was 58.7% (95% confidence interval = 48.6%–68.2%), including a complete response in 14.4%. The estimated median response duration was 12.2 months (range = 0+ to 22.6 months). The median time to response was 1.7 months (range = 1.3–9.7 months).
How It Works
Copanlisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K), with inhibitory activity predominantly against PI3K-α and PI3K-δ isoforms expressed in malignant B cells. Copanlisib has been shown to induce tumor cell death by apoptosis and inhibition of proliferation of primary malignant B-cell lines. The agent inhibits several important cell signaling pathways, including B-cell receptor signaling, CXCR12-mediated chemotaxis of malignant B cells, and NFκB signaling in lymphoma cell lines.
How It Is Used
The recommended dose of copanlisib is 60 mg, given as a 1-hour IV infusion on days 1, 8, and 15 of a 28-day treatment cycle, with treatment continuing until disease progression or unacceptable toxicity.
Product labeling provides specific dosage modifications, including stepwise dose reductions to 45 mg and 30 mg, for grade ≥ 3 infection or suspected Pneumocystis jirovecii pneumonia infection of any grade; hyperglycemia; hypertension; grade 2 and ≥ 3 noninfectious pneumonitis; neutropenia; severe cutaneous reactions; thrombocytopenia; and other grade 3 toxicities. Each infusion should be started only when optimal blood glucose control is achieved. Treatment should be withheld until both systolic blood pressure is less than 150 mm Hg and diastolic pressure is less than 90 mm Hg. For neutropenia, treatment should be withheld until the absolute neutrophil count is ≥ 0.5 103 cells/mm3. Treatment should be withheld for grade ≥ 3 infections until resolution. Treatment should be permanently discontinued for persistent hypertension despite antihypertensive treatment after dose reductions, recurrent grade 2 or any grade ≥ 3 noninfectious pneumonitis, life-threatening cutaneous reactions, persistent thrombocytopenia after dose reductions, and any other life-threatening copanlisib-related toxicity.
Concomitant use of copanlisib with strong CYP3A inhibitors (eg, boceprevir [Victrelis], clarithromycin, conivaptan [Vaprisol], diltiazem, grapefruit juice, ketoconazole, nefazodone) should be avoided. If concomitant use cannot be avoided, the copanlisib dose should be reduced to 45 mg. Concomitant use of copanlisib with strong CYP3A inducers (eg, carbamazepine, enzalutamide (Xtandi), mitotane (Lysodren), phenytoin, rifampin, St. John’s wort) should be avoided.
Safety data are from 168 patients with follicular lymphoma and other hematologic malignancies treated with the recommended copanlisib dosing regimen. The most common adverse events of any grade were hyperglycemia (54%), diarrhea (36%), fatigue/asthenia (36%), leukopenia (36%), hypertension (35%), and neutropenia including febrile neutropenia (32%). The most common grade ≥ 3 adverse events were hyperglycemia (39%), hypertension (27%), leukopenia (27%), neutropenia (25%), and lower respiratory tract infections (14%). The most common grade 3 or 4 laboratory abnormalities were hyperglycemia (48%), decreased lymphocytes (29%), decreased neutrophils (27%), hyperuricemia (25%), decreased white blood cell count (20%), and hypophosphatemia (15%).
Copanlisib has warnings/precautions for infections, hyperglycemia, hypertension, noninfectious pneumonitis, neutropenia, severe cutaneous reactions, and embryofetal toxicity.
Serious adverse events occurred in 26%, with the most common being pneumonia (8%), pneumonitis (5%), and hyperglycemia (5%). Adverse events led to dose reduction in 21%, with the most common reasons being hyperglycemia (7%), neutropenia (5%), and hypertension (5%), and to treatment discontinuation in 16%, with the most common reasons being pneumonitis (2%) and hyperglycemia (2%).
Copanlisib has warnings/precautions for infections, hyperglycemia, hypertension, noninfectious pneumonitis, neutropenia, severe cutaneous reactions, and embryofetal toxicity. Women should be advised not to breastfeed while receiving copanlisib. Blood cell counts should be monitored at least weekly during treatment. Blood pressure and blood glucose must be monitored frequently. ■
1. U.S. Food and Drug Administration: FDA grants accelerated approval to copanlisib for relapsed follicular lymphoma. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm576098.htm. Accessed November 7, 2017.
2. Aliqopa (copanlisib) injection prescribing information, Bayer HealthCare Pharmaceuticals Inc, September 2017. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2017/209936s000lbl.pdf. Accessed November 7, 2017.