September 14, 2017
On September 14, 2017, the U.S. Food and Drug Administration granted accelerated approval to copanlisib (Aliqopa™, Bayer HealthCare Pharmaceuticals Inc.) for the treatment of adult patients with relapsed follicular lymphoma who have received at least two prior systemic therapies.
Approval was based on efficacy results in 104 patients with relapsed follicular lymphoma enrolled in an open-label, single-arm, multicenter, phase 2 trial. Patients received 0.8 mg/kg or 60 mg of copanlisib by intravenous infusion on days 1, 8, and 15 of a 28-day treatment cycle. The objective response rate was 58.7% (95% CI: 48.6%-68.2%) with an estimated median response duration of 12.2 months (range, 0+ to 22.6 months). The complete response rate was 14.4% and partial response rate was 44.2%. The safety population included 168 patients with follicular lymphoma and other hematologic malignancies treated with the recommended copanlisib dosing regimen.
Common adverse reactions in greater than 20% of patients include hyperglycemia, diarrhea, fatigue, hypertension, leukopenia, neutropenia, nausea, lower respiratory tract infections, and thrombocytopenia. The most common grade 3-4 adverse reactions include hyperglycemia, leukopenia, hypertension, neutropenia, and lower respiratory tract infections. Serious non-infectious pneumonitis occurred in 6% of patients.
The recommended copanlisib dose is 60 mg administered as a 1-hour intravenous infusion on days 1, 8, and 15 of a 28-day treatment cycle on an intermittent schedule (three weeks on and one week off).
Full dosing information is available at:
FDA previously granted orphan drug and fast track designation for copanlisib. As a condition of accelerated approval, a randomized controlled trial will be required to verify the clinical benefit of copanlisib. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at:
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and 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) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
Pharmacist’s Applications to Practice
Copanlisib (Aliqopa) for Relapsed Follicular Lymphoma
Author: Kathryn Maples, PharmD
Clinical Pharmacy Specialist, Lymphoma/Myeloma
Memorial Sloan Kettering Cancer Center
New York, NY
What is the potential role for copanlisib in the treatment of follicular lymphoma?1-4
- Copanlisib is an intravenous (IV) pan-class 1 phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant activity against the PI3K-α and PI3K-δ isoforms that was recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior lines of systemic therapy.
- Copanlisib was approved on the basis of data from the phase 2 CHRONOS-1 trial, which included 104 patients with FL who had relapsed following at least two prior therapies. All included patients had received prior rituximab and alkylating agents, which are the first-line standard of care for these patients, and 43% of patients included in this trial were refractory to rituximab plus an alkylating agent.
- The objective response rate (ORR) in FL patients was 59%, with 14% achieving a complete response. The median progression-free survival was 11.2 months, and the median overall survival had not yet been reached.
- The National Comprehensive Cancer Network (NCCN) guidelines have recently been updated to include copanlisib as a subsequent treatment regimen for FL. Currently copanlisib is a Category 2A recommendation for patients who are refractory to two prior therapies and is listed behind chemoimmunotherapy, rituximab, lenalidomide with or without rituximab, bendamustine plus obinutuzumab, radioimmunotherapy, and idelalisib, in order of the NCCN panel’s preference.
- The only other FDA-approved PI3K inhibitor is idelalisib, which is an oral selective PI3K-δ inhibitor that carries indications for relapsed chronic lymphocytic leukemia (CLL), relapsed FL, and relapsed small lymphocytic lymphoma (SLL). Idelalisib and copanlisib demonstrated similar ORRs (56% vs. 59%, respectively) and similar durations of response (10.8 months vs. 12.2 months, respectively) in relapsed FL; however, because of the selective inhibition of the PI3K-δ isoform with idelalisib, alternative isoforms may become upregulated over time and contribute to resistance mechanisms, thus supporting a pan-class inhibition.
What role can the pharmacist play in the management of patients on copanlisib?1-4
- Copanlisib is administered as a flat dose of 60 mg intravenous (IV) over 1 hour on days 1, 8, and 15 of a 28-day treatment cycle, continuing until the disease progresses or an unacceptable level of toxicity is reached.
- The dose should be reduced to 45 mg if concomitant strong CYP3A4 inhibitors cannot be avoided.
- IV therapy may lead to improved adherence versus oral therapy because the patient must come to the site for treatment.
- The side-effect profile of copanlisib differs from that of idelalisib. Idelalisib carries boxed warnings for hepatotoxicity, colitis, pneumonitis, infections, and intestinal perforation, but copanlisib currently does not have any boxed warnings. In the phase 2 trial with copanlisib, the most common grade 3 or 4 adverse events were hyperglycemia (41%), hypertension (24%), neutropenia (24%), and lung infection (15%). The grade 3 noninfectious pneumonitis rate with copanlisib was noted to be 1% versus 4% with idelalisib. Similarly, the severe infection rate was lower with copanlisib at 19% versus 21%–36% with idelalisib.
- Dose reductions should be applied for various grade 3 or 4 toxicities, including neutropenia, hyperglycemia, hypertension, and dermatologic toxicity.
- Pharmacologic intervention to help manage the hyperglycemia or hypertension may be required.
- Copanlisib should be held for a fasting blood glucose (BG) of 160 mg/dl or greater, a random BG of 200 mg/dl or greater, or blood pressure of 150/90 mmHg or greater; multiple occurrences require dose reductions.
- Aliqopa Resource Connections offers a patient assistance program that will provide Aliqopa at no cost to eligible uninsured or underinsured patients.5
- For the currently available PI3K inhibitors, copanlisib is administered IV; idelalisib is administered as an oral tablet with or without food.
- Copanlisib should be reconstituted and diluted only with normal saline.
- Pregnancy testing should be conducted prior to therapy, and highly effective contraception is recommended in women of reproductive potential for at least 1 month after the last dose.
- Copanlisib is currently being studied in other indolent lymphomas, peripheral T-cell lymphoma, diffuse large B-cell lymphoma, and cholangiocarcinoma, as well as in endometrial, breast, and head and neck cancers.
- Aliqopa (copanlisib) for injection [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc; September 2017.
- Dreyling M, Santoro A, Mollica L, et al. Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. J Clin Oncol. 2017; 10;35(35):3898-3905. https://www.ncbi.nlm.nih.gov/pubmed/28976790. doi: 10.1200/JCO.2017.75.4648 [Epub ahead of print].
- Lexi-Drugs Online. Copanlisib. Hudson, OH: Lexi-Comp, Inc.; 2013. Accessed November 16, 2017.
- B-Cell Lymphomas. Version 6.2017. National Comprehensive Cancer Network. Available at: https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Accessed November 16, 2017.
- Aliqopa (copanlisib): Patient Access and Reimbursement Support for Aliqopa. https://www.hcp.aliqopa-us.com/access-and-reimbursement/arc-program/. Accessed November 27, 2017.
- ClinicalTrials.gov Registry. National Institutes of Health. Copanlisib. www.ClinicalTrials.gov. Accessed November 16, 2017.