Copanlisib (Aliqopa)

Number: 0923

Policy

Aetna considers copanlisib (Aliqopa) medically necessary as second-line or subsequent therapy for refractory or progressive follicular lymphoma that is refractory to at least 2 prior therapies.

Aetna considers copanlisib experimental and investigational for all other indications.

See also CPB 0314 - Rituximab (Rituxan).

 

Background

Follicular lymphoma (FL) is an indolent (slow-growing) form of non-Hodgkin lymphoma (NHL), a type of B-cell lymphoma. FL accounts for approximately 35% of NHLs in the United States. Despite FL’s usual slow-growing nature, most cases are not curable, and some can grow quickly and behave like or transform into a more aggressive form of lymphoma (i.e. diffuse large B-cell lymphoma (DLBCL)). The median age at diagnosis for people with FL is 65, and is known to be rare in children and adolescents. This type of lymphoma usually occurs in many lymph node sites throughout the body, and can involve organs and bone marrow.  Features that usually require treatment include progressively enlarging lymph nodes, fever, weight loss, night sweats, and/or low blood counts.  The two best measures of outcome are the Follicular Lymphoma International Prognostic Index and tumor grade. For patients with advanced forms of FL (i.e. stages III and IV disease), the average survival is approximately 19 years. Rituximab is a medication used to treat FL, and is frequently combined with chemotherapy treatments; however many patients will relapse with treatment (ACS, 2017; Freedman and Aster, 2017).

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. In a clinical study, copanlisib has been shown to induce tumor cell death by apoptosis and inhibition of proliferation of primary malignant B cell lines. Copanlisib inhibits several key cell-signaling pathways, including B-cell receptor (BCR) signaling, CXCR12 mediated chemotaxis of malignant B cells, and NFκB signaling in lymphoma cell lines (FDA, 2017).
 
On September 14, 2017, the U.S. Food and Drug Administration (FDA) granted accelerated approval for the kinase inhibitor injectable drug, 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.

The accelerated approval of Aliqopa was based on the efficacy outcomes in the CHRONOS-1 (NCT 01660451) phase 2, single-arm, open-label, multicenter clinical trial which included 104 subjects (median age 62; range 25 to 81) with follicular B-cell non-Hodgkin lymphoma who had relapsed disease following at least two prior treatments. Patients must have received rituximab and an alkylating agent. 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. Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. It is not known if Aliqopa is safe and effective in pediatric patients (FDA, 2017).

The National Comprehensive Cancer Network Drugs and Biologics Compendium (NCCN, 2017) recommends copanlisib for follicular lymphoma (grade 1 -2) as second-line or subsequent therapy for refractory or progressive disease that is refractory to at least 2 prior therapies.

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.

Appendix

Copanlisib (Aliqopa) is available for injection as a 60 mg (or 0.8 mg/kg) lyophilized solid in single-dose vial for reconstitution and dilution for intravenous infusion only.

Recommended dosing per FDA-approved labeling is as follows:

• 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).
• To continue treatment until disease progression or unacceptable toxicity.
• Manage toxicities with dose reduction, treatment delay, or discontinuation of Aliqopa. Recommendation of minimum 7 days between any two consecutive infusions (see Table 1).

Table 1: Toxicity Management and Dosing Adjustment Recommendations

Toxicity	Adverse Reaction Grade	Recommended Management
Infection	Grade 3 or higher	Withhold Aliqopa until resolution.
	Suspected pneumocystis jiroveci pneumonia (PJP) infection of any grade.	Withhold Aliqopa. If confirmed, treat infection until resolution, then resume Aliqopa at previous dose with concomitant PJP prophylaxis.
Hyperglycemia	Pre-dose fasting blood glucose 160 mg/dL or more or random/non-fasting blood glucose of 200 mg/dL or more.	Withhold Aliqopa until fasting glucose is 160 mg/dL or less, or random/non-fasting blood glucose of 200 mg/dL or less.
	Pre-dose or post-dose blood glucose  500 mg/dL or more.	On first occurrence, withhold Aliqopa until fasting blood glucose is 160 mg/dL or less, or a random/non-fasting blood glucose of 200 mg/dL or less. Then reduce Aliqopa from 60 mg to 45 mg and maintain. On subsequent occurrences, withhold Aliqopa until fasting blood glucose is 160 mg/dL or less, or a random/non-fasting blood glucose of 200 mg/dL or less. Then reduce Aliqopa from 45 mg to 30 mg and maintain. If persistent at 30 mg, discontinue  Aliqopa.
Hypertension	Pre-dose blood pressure (BP) 150/90 or greater.	Withhold Aliqopa until BP is less than 150/90 based on two consecutive BP measurements at least 15 minutes apart.
	Post-dose BP 150/90 or greater (non-life-threatening).	If anti-hypertensive treatment is not required, continue Aliqopa at previous dose. If anti-hypertensive treatment is required, consider reduction of Aliqopa from 60 mg to 45 mg or from 45 mg to 30 mg. Discontinue Aliqopa if BP remains uncontrolled (BP greater than 150/90) despite anti-hypertensive treatment.
	Post-dose elevated BP with life-threatening consequences.	Discontinue Aliqopa.
Non-infectious pneumonitis (NIP)	Grade 2	Withhold Aliqopa and treat NIP. If NIP recovers to Grade 0 or 1, resume Aliqopa at 45 mg. If Grade 2 NIP recurs, discontinue Aliqopa.
	Grade 3 or higher	Discontinue Aliqopa.
Neutropenia	Absolute neutrophil count (ANC) 0.5 to 1.0 x 103 cells/mm3	Maintain Aliqopa dose. Monitor ANC at least weekly.
	ANC less than 0.5 x 103 cells/mm3	Withhold Aliqopa. Monitor ANC at least weekly until ANC 0.5 x 103 cells/mm3 or greater, then resume Aliqopa at previous dose. If ANC 0.5 x 103 cells/mm3 or less recurs, then reduce Aliqopa to 45 mg.
Severe cutaneous  reactions	Grade 3	Withhold Aliqopa until toxicity is resolved and reduce Aliqopa from 60 mg to 45 mg or from 45 mg to 30 mg.
	Life-threatening	Discontinue Aliqopa.
Thrombocytopenia	Less than 25 x 109/L	Withhold Aliqopa; resume when platelet levels return to 75.0 x 109/L or greater. If recovery occurs within 21 days, reduce Aliqopa from 60 mg to 45 mg or from 45 mg to 30 mg. If recovery does not occur within 21 days, discontinue Aliqopa.
Other severe and non-lifethreatening  toxicities	Grade 3	Withhold Aliqopa until toxicity is resolved and reduce Aliqopa from 60 mg to 45 mg or from 45 mg to 30 mg.

Table adapted from the FDA Prescribing Information (FDA, 2017).

Adverse grade reaction based on the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03 (FDA, 2017).

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
96413 - 96417	Chemotherapy administration
HCPCS codes covered if selection criteria are met:
C9030	Injection, copanlisib, 1 mg
ICD-10 codes covered if selection criteria is met :
C82.00 - C82.99	Follicular lymphoma

The above policy is based on the following references: