Aliqopa (Copanlisib), an Intravenous PI3K Inhibitor, Approved for Patients with Relapsed Follicular Lymphoma

March 2018, Vol 11, Ninth Annual Payers' Guide - Select Drug Profiles, Payers' Guide

Follicular lymphoma is the second most common subtype of non-Hodgkin lymphoma (NHL). Approximately 20% of all NHL cases are follicular lymphoma.1 This condition is characterized by a translocation between chromosomes 14 and 18, which causes the overexpression of BCL-2 and enhances resistance to treatment. Follicular lymphoma is typically an indolent disease, but in a small percentage of patients, the disease transforms into an aggressive lymphoma.1

Patients with early-stage disease are often asymptomatic. Patients with stage II follicular lymphoma whose disease is in the lymph nodes and those with stage III or IV disease receive treatment based on their age, performance status, symptoms, and other features. Chemoimmunotherapy regimens that include rituximab (Rituxan) are considered standard initial treatment for follicular lymphoma.1,2

Despite high response rates associated with chemoimmunotherapy in follicular lymphoma, the disease relapses in approximately 20% of patients within 2 years of initial treatment.3 Retrospective data analysis shows that the 5-year overall survival rate in patients with relapsed disease is only 50% compared with 90% in patients whose disease does not progress early.4

Recently, a few new nonchemotherapy treatments were approved by the US Food and Drug Administration (FDA) for follicular lymphoma. In 2014, the FDA approved idelalisib (Zydelig), an oral phosphatidylinositol 3-kinase (PI3K)-δ inhibitor, for the treatment of patients with relapsed follicular lymphoma after ≥2 previous therapies.5,6 In February 2016, the FDA approved obinutuzumab (Gazyva) injection, a humanized anti-CD20 monoclonal antibody, for use in combination with bendamustine, for patients with follicular lymphoma whose disease relapsed after or was refractory to a rituximab-based regimen.7 Obinutuzumab was later approved as first-line treatment with chemotherapy for certain patients with follicular lymphoma.8

Aliqopa Approved for Relapsed Follicular Lymphoma

On September 14, 2017, the FDA accelerated the approval of copanlisib (Aliqopa; Bayer HealthCare) for the treatment of adults with relapsed follicular lymphoma who received ≥2 previous systemic therapies.9,10 It is the first intravenous (IV) PI3K inhibitor approved in the United States.

“For patients with relapsed follicular lymphoma, the cancer often comes back even after multiple treatments. Options are limited for these patients and today’s approval provides an additional choice for treatment, filling an unmet need for them,” said Richard Pazdur, MD, Director, FDA’s Oncology Center of Excellence.9

Mechanism of Action

Copanlisib is predominantly active against PI3K-α and PI3K-δ isoforms that are expressed in malignant B-cells. Copanlisib has been shown to induce tumor-cell death by apoptosis and through inhibition of proliferation of primary malignant B-cells.10 This agent also blocks cell-signaling pathways, including B-cell receptor signaling, CXCR12-mediated chemotaxis of malignant B-cells, and NFκB signaling in lymphoma cell lines.10

Dosing and Administration

The recommended dose of copanlisib is 60 mg administered as a 1-hour IV infusion on days 1, 8, and 15 of a 28-day treatment cycle that comprises 3 weeks on and 1 week off treatment. Treatment with copanlisib should continue until disease progression or until unacceptable toxicity.10

CHRONOS-1: Pivotal Clinical Trial

The efficacy of copanlisib was evaluated in the CHRONOS-1 clinical trial, a single-arm, phase 2 study involving 142 patients, of whom 104 had follicular lymphoma. All patients had received ≥2 previous regimens that included rituximab and an alkylating agent.10,11 Previous treatment with PI3K inhibitors was not allowed.12

Overall, 130 patients received fixed-dose 60 mg and 12 patients received 0.8 mg/kg equivalent. Patients received treatment with copanlisib until disease progression or until unacceptable toxicity.10,11

The primary efficacy outcome measure was overall response rate according to the International Working Group response criteria for malignant lymphoma and was assessed by an independent review committee.10,11

The 104 patients with follicular lymphoma were aged between 25 and 81 years (median age, 62 years).10 Their median number of previous therapies was 3 (range, 2-8).10,11 The majority (62%) of patients had disease that was refractory to previous treatment.10,11

Overall, 58.7% of patients responded to treatment, including 14.4% complete responses and 44.2% partial responses. The median duration of response was 12.2 months (Table).10,11


Adverse Reactions

The safety and tolerability data reflect exposure to copanlisib in 168 patients with follicular lymphoma and other hematologic malignancies; the median duration of exposure to copanlisib was approximately 5 months.10

Copanlisib was discontinued in 16% of patients because of adverse reactions, most often because of pneumonitis (2%) and hyperglycemia (2%).10 Dose reductions were required in 21% of patients, most often because of hyperglycemia (7%), neutropenia (5%), and hypertension (5%).10

All-grade adverse events and other hematologic malignancies (incidence ≥25%) with copanlisib were hyperglycemia (54%), leukopenia (36%), decreased gen­eral energy and strength (36%), diarrhea (36%), hypertension (35%), neutropenia (32%), and nausea (26%).10

Serious adverse reactions were pneumonia (8%), pneumonitis (5%), and hyperglycemia (5%).10

Copanlisib has no contraindications.10

Drug Interactions

Copanlisib should not be used with strong cytochrome (CY) P3A inducers. The dose of copanlisib should be reduced to 45 mg when administered concomitantly with strong CYP3A inhibitors.10

Use in Specific Populations

Women and men of reproductive potential should use effective contraception during copanlisib treatment and for at least 1 month after the last dose.10

Nursing women should not breastfeed during treatment with copanlisib and for at least 1 month after the last dose.10

Patients with diabetes mellitus should receive copanlisib only if glucose levels are adequately controlled. Glucose control should be optimized before each infusion of copanlisib.10

No dose adjustment is necessary in patients aged ≥65 years. No clinically relevant differences in the efficacy of copanlisib were observed between older and younger patients.10

Warnings and Precautions

Severe, including fatal, infections have been reported in patients who received copanlisib, including pneumonia and Pneumocystis jiroveci pneumonia. P jiroveci pneumonia prophylaxis should be considered for patients at risk. Copanlisib should be withheld if serious infection is confirmed.10

Copanlisib can lead to infusion-related hyperglycemia. Blood glucose levels typically peaked 5 to 8 hours postinfusion and subsequently declined to baseline levels.10

Infusion-related hypertension can occur with copanlisib therapy. Blood pressure control should be achieved before each infusion of copanlisib, and should be monitored before and after infusion.10

Noninfectious pneumonitis has been reported in patients who received copanlisib. Patients with cough, dyspnea, hypoxia, or interstitial infiltrates on radiologic examination should be tested. Withholding copanlisib and administering systemic corticosteroids are recommended if pneumonitis is diagnosed.10

Because of the risk for neutropenia, blood counts should be assessed at least weekly during copanlisib treatment.10

Severe cutaneous reactions, including dermatitis exfoliative, exfoliative rash, pruritus, and maculopapular rash, can occur with copanlisib therapy.10


Copanlisib, an IV therapy that inhibits PI3K, has demonstrated safety and efficacy in patients with relapsed follicular lymphoma who received ≥2 previous systemic therapies in the single-arm, phase 2, CHRONOS-1 clinical trial. Copanlisib is the first IV PI3K inhibitor approved in the United States for this condition. Additional studies of copanlisib are underway in patients with relapsed or refractory indolent NHL and in patients with diffuse large B-cell lymphoma.

1. Leukemia & Lymphoma Society. Treatment for indolent NHL subtypes.­nhl-subtypes. Accessed November 6, 2017.
2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): B-Cell Lymphomas. Version 7.2017. Accessed November 12, 2017.
3. Barrientos JC. Idelalisib for the treatment of indolent non-Hodgkin lymphoma: a review of its clinical potential. Onco Targets Ther. 2016;9:2945-2953.
4. Casulo C, Byrtek M, Dawson KL, et al. Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the National LymphoCare Study. J Clin Oncol. 2015;33:2516-2522. Erratum in: J Clin Oncol. 2016;34:1430.
5. National Cancer Institute. FDA approval for idelalisib. July 29, 2014. Accessed November 6, 2017.
6. Zydelig (idelalisib) tablets [prescribing information]. Foster City, CA: Gilead Sciences; November 2017.
7. US Food and Drug Administration. Obinutuzumab. February 26, 2016. Accessed January 16, 2018.
8. US Food and Drug Administration. FDA approves obinutuzumab for previously untreated follicular lymphoma. November 16, 2017. Accessed January 16, 2018.
9. US Food and Drug Administration. FDA approves new treatment for adults with relapsed follicular lymphoma. September 14, 2017. Accessed December 14, 2017.
10. Aliqopa (copanlisib) for injection [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals; September 2017.
11. Dreyling M, Santoro A, Mollica L, et al. Copanlisib in patients with relapsed or refractory indolent B-cell lymphoma: primary results of the pivotal Chronos-1 study. Cancer Res. 2017;77(13 suppl):Abstract CT149.
12. Open-label, uncontrolled phase II trial of intravenous PI3K inhibitor BAY80-6946 in patients with relapsed, indolent or aggressive non-Hodgkin’s lymphomas. Accessed November 12, 2017.

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