What is copanlisib?
Copanlisib is a phosphatidylinositol-3-kinase (PI3K) inhibitor with predominant activity against PI3K-alpha and PI3K-delta isoforms in malignant B cells.
How does copanlisib work?
The PI3K pathway plays an important role in the development and function of B cells. In malignant B-cell lymphomas, the PI3K pathway can be overactive, leading to aberrant cell survival (Front Immunol 2012;3(224):1-20). Copanlisib causes tumor cell death through apoptosis, inhibition of B-cell proliferation, and cell-signaling pathways.
What is this approved for?
Copanlisib is approved for the treatment of adult patients with relapsed follicular lymphoma (FL) who have previously received at least two prior systemic therapies.
What is the basis for this approval?
Copanlisib was granted accelerated approval in September 2017 based on results of a phase II, single-arm, open-label study of 142 patients with relapsed/refractory indolent B-cell lymphoma after at least two prior lines of therapy (including rituximab and an alkylating agent). Copanlisib 60 mg on days 1, 8, and 15 of a 28-day cycle was given until disease progression or unacceptable toxicity. The primary endpoint was objective tumor response rate (ORR) [complete response (CR) or partial response]. Median age was 63 years and 73 percent (n=104) had FL. ORR for all patients was 59 percent (12% CR) as well as FL patients (14% CR). Median duration of response and progression-free survival were 22.6 months (95% CI 7.4-22.6) and 11.2 months (95% CI 8.1-24), respectively. Median overall survival was not reached. Dose delays occurred in 74 percent of patients with 91 percent due to adverse events (transient hyperglycemia and hypertension, and neutropenia). Other pertinent adverse events include diarrhea, fatigue, fever, and lung infection (J Clin Oncol 2017;35:3898-3905).
How do you administer this drug?
Copanlisib is a 60 mg infusion over 60 minutes on days 1, 8, and 15 of a 28-day cycle (3 weeks on and 1 week off) continued until disease progression or unacceptable toxicity.
Are there any premedications needed for copanlisib?
None required.
What are the common side effects associated with copanlisib (> or =10%)?
Common toxicities of any grade included diarrhea, fatigue/weakness, nausea, stomatitis, vomiting, and rash. The most common grade 3/4 toxicities included hyperglycemia, hypertension, lung infections, leukopenia, decreased absolute lymphocyte count (ALC), and neutropenia.
What are the uncommon side effects associated with copanlisib (less than 10%?)
Less common toxicities include non-infectious pneumonitis (9%), mucosal inflammation (8%), and paresthesia/dysesthesia (7%).
Are there any important drug interactions I should be aware of?
More than 90 percent of copanlisib is metabolized by CYP3A. A dose reduction to 45 mg is recommended when co-administered with strong CYP3A inhibitors due to increased drug exposure and risk for toxicity. Likewise, use should be avoided with concurrent strong CYP3A inducers.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
Excretion is primarily in the biliary tract, 64 percent, with 22 percent renal elimination. No dose adjustment is required for renal or mild hepatic dysfunction. Copanlisib has not been studied in moderate to severe hepatic dysfunction, severe renal dysfunction, or end-stage renal disease with or without dialysis.
Practical tips
Copanlisib should only be used in patients with diabetes mellitus with adequate blood glucose control. Blood glucose peaked between 5 and 8 hours post-infusion and, despite the majority resolving quickly, 18 percent of patients experienced elevated blood glucose 1 day post-infusion.
Patients with hypertension should achieve adequate blood pressure control prior to each dose of copanlisib and be monitored pre- and post-infusion. Consider holding, reducing, or discontinuing copanlisib based on severity and persistence of hypertension.
What should my patients know about copanlisib?
Patients should avoid use of St. John's Wort and grapefruit juice while receiving copanlisib therapy. Patients should contact their health care provider if they experience any of the following: allergic reaction (itching, shortness of breath, flushing); infection (fever, chills, sore throat, cough); high blood sugar (confusion, increased thirst/hunger/urination); high blood pressure (headache, dizziness, change in eyesight); or bleeding (blood in stool/urine, coughing up blood, coffee ground emesis).
What else should I know about copanlisib?
Pneumocystis jiroveci pneumonia (PJP) was noted in 0.6 percent of patients. Given the incidence of decreased ALC, consideration for PJP prophylaxis in populations at risk prior to copanlisib initiation is warranted. Treatment with copanlisib should be held if PJP is suspected.
What useful links are available regarding copanlisib?
* https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209936s000lbl.pdf
* https://www.hcp.aliqopa-us.com
Any ongoing clinical trials related to copanlisib?
Clinical trials are ongoing in numerous subtypes of lymphoma, HER2-positive/negative breast cancer, head and neck cancer, and cholangiocarcinoma. Copanlisib in combination with other chemotherapy agents is also being studied. More information is available at https://clinicaltrials.gov.
KENDALL C. SHULTES, PHARMD, is Assistant Professor of Pharmacy, Belmont University College of Pharmacy, Department of Pharmacy Practice, and Clinical Pharmacy Specialist, Vanderbilt University Cool Springs Oncology Clinic, Nashville, Tenn. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; and Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor. SARA K. BUTLER, PHARMD, BCPS, BCOP, is Clinical Oncology Pharmacy Supervisor, Barnes-Jewish Hospital, St. Louis, Mo., and serves as a Pharmacy Forum column co-editor. JANELLE E. MANN, PHARMD, BCOP, is an Investigational Drug Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as Pharmacy Forum column co-editor.