Investigators Collaborate to Create Strategies for Unique AE Management With Copanlisib in Follicular Lymphoma

Bruce D. Cheson, MD

Bruce D. Cheson, MD

New guidance has been developed for the management of adverse events (AEs) observed with the use of copanlisib (Aliqopa) in patients with follicular lymphoma (FL) who are on third-line or later therapy. A panel composed of experts in lymphoma, diabetes, and hypertension convened to create supportive strategies for physicians who see treatment-emergent (TE) AEs such as hyperglycemia, hypertension, noninfectious pneumonitis, infections, diarrhea and colitis, and hepatobiliary toxicities with copanlisib treatment in this patient population.¹

“Given copanlisib’s atypical AEs and the need to properly manage for safe drug administration, it is essential to educate physicians, nurses, and patients to ensure appropriate patient selection for treatment and adherence to the recommendations provided in this article,” the investigators, led by Bruce D. Cheson, MD, of the Lombardi Comprehensive Cancer Center, Washington, DC, commented.

Several unique AEs have been observed from the intravenous (IV) administration of the phosphoinositol 3-kinase (PI3K) inhibitor copanlisib, however these effects are considered transient and reversible by clinicians and the agent’s overall safety profile is manageable compared to others in its class.

Idelalisib (Zydelig), another PI3K inhibitor that targets the δ isoform, was the first in its class to receive FDA approval in the third-line treatment of FL. But enthusiasm about the agent was quickly dulled due to its toxicity profile and the drug subsequently gained a black box warning for AEs such as hepatotoxicity and intestinal perforations.²Similarly, duvelisib (Copiktra), the oral dual inhibitor of PI3K-δ and PI3K-γ that is approved for FL in the third line, has a black box warning on its label for AEs such as fatal infections and pneumonitis.³

Unlike the former, copanlisib has few late-onset toxicities and has a more favorable safety profile in regard to colitis, pneumonitis, hepatotoxicity, and infectious episodes, possibly due to its intermittent and parenteral dosing schedule. However, “copanlisib is associated with several troublesome and potentially serious adverse conditions, some of which are unique to this agent,” the study authors wrote.

In a phase II trial published by Dreyling et al, there was an objective response rate of 43.7% with a median progression-free survival of 294 days in a cohort of patients with either FL or peripheral T-cell lymphoma who were treated with copanlisib in the third line or later. Out of all of the patients (n = 84) on the trial, which included those with indolent and aggressive lymphomas, the most common all-grade TEAEs observed were hyperglycemia (59.5%), hypertension (54.8%), fatigue (48.8%), diarrhea (40.5%), and decreased neutrophil count (34.5%). Grade 3/4 TEAEs were seen at frequencies of 25%, 40.5%, 11.9%, 4.8%, and 29.8%, respectively.⁴

In the pivotal phase II CHRONOS-1 trial, copanlisib for the third line or later treatment of patients with indolent lymphoma experienced dose interruptions at a rate of 74% and dose reductions to 45 mg and 30 mg occurred in 26% and 7%, respectively. Of the dose interruptions and delays, 91% occurred due to AEs; however, 55% of dose interruptions lasted <1 week and permanent discontinuation was limited to 16% of patients whose AEs were considered drug-related.⁵

Patients treated with copanlisib are more likely to experience AEs of hyperglycemia and hypertension, among others, and these primarily occur during IV administration, are generally manageable, and resolve shortly thereafter.

Hyperglycemia

Hyperglycemia is relatively specific to copanlisib because of its inhibitory effect on the PI3K-a isoform, which is responsible for the insulin-mediated production of phosphatidylinositol-3,4,5-triphosphate in metabolic tissue. The acute inhibition of PI3K-a blocks skeletal muscle glucose uptake and increases hepatic glucose production which can lead to a transient hyperglycemic state.

Overall, several studies on the effect of copanlisib in patients both with and without diabetes have shown that hyperglycemia resulting from treatment is manageable. The FDA-approved label for copanlisib includes the recommendation to withhold the drug in patients with a pre-infusion fasting glucose level of &ge;160 mg/dL or a random glucose of &ge;200 mg/dL until levels are below these thresholds. For patients who experience a post-dose blood glucose level of &ge;500 mg/dL, copanlisib should be withheld until fasting or random glucose levels are &le;160 mg/dL or &le;200 mg/dL, respectively. No dose reduction is warranted as these effects are transient. Dose interruption should occur when the effects become too difficult to manage.

According to the expert panel on the study by Cheson et al, nondiabetics do not require postinfusion monitoring and the use of insulin is discouraged for glycemic control due to the risk of developing subsequent hypoglycemia.

In diabetics and prediabetics, glycated hemoglobin screening should occur prior to the start of therapy to identify those at risk of developing symptoms, and those patients should consider consulting with an endocrinologist. Prophylactic management of hyperglycemia may be considered with the use of sodium-glucose cotransporter-2 inhibitors or other oral hypoglycemic agents that do not cause hypoglycemia. These patients should only receive copanlisib following adequate glucose control and should be monitored closely for several hours following infusion. Patients who eat within 8 hours of their last infusion should eat a low carbohydrate diet, the panelists suggest.

Hypertension

Hypertension that is associated with copanlisib therapy usually occurs after cycle 1, day 1, peaking at 2 hours following infusion and starting to decrease 2 hours post-infusion; and these increases usually resolve within 24 hours. Investigators on the CHRONOS-1 study were advised that antihypertensive drugs may be used in the managements of this common AE, if necessary.

Cheson et al recommend treating pre-existing hypertension prior to the initiation of copanlisib therapy, with the goal of achieving an optimal blood pressure <140/90 mm Hg. Patients with a pre-dose blood pressure of &ge;150/90 mm Hg should hold treatment until 2 readings of <150/90 mm Hg are obtained and measured &ge;15 minutes apart.

Several factors play a role in deciding if patients should receive antihypertensive drugs from copanlisib-induced hypertension, such as baseline blood pressure and preexisting cardiovascular disease, but short-acting antihypertensives are preferred given the anticipated duration of the event. Dose reductions or discontinuations may be necessary in patients who continue to experience uncontrolled blood pressure of &ge;150/90 mm Hg despite efforts at control.

Noninfectious Pneumonitis and Other Infections

Only about 5% of patients taking copanlisib will experience noninfectious pneumonitis with symptoms such as cough, dyspnea, hypoxia, or interstitial infiltrates on radiologic exam. The investigators on the study suggest that patients with grade 2 pneumonitis should have copanlisib withheld until the condition resolves to grade 0 or 1 and patients should then be re-challenged with a lower dose of the drug.

In CHRONOS-1, none of the patients who had received prior lung involved-field radiation (n = 10) developed pneumonitis, but 5 patients experienced other pulmonary-related events, includingPneumocystis jiroveciipneumonia. Cheson et al said that treating physicians should consider prophylaxis for patients who are considered at high risk.

All patients taking copanlisib should be monitored closely for symptoms of infections and grade &ge;3 events should signal discontinuation of the agent.

Diarrhea and Colitis

Unlike idelalisib, which is marred by serious complication from colitis, occurring on average 8 months into therapy, patients treated with copanlisib see lower incidences of this event, most likely due to its intermittent and parenteral dose schedule. On the CHRONOS-1 trial, there was a single case of infection-related colitis in a patient with a history of diverticulitis. This patient had their therapy interrupted and a dose reduction in association with antibiotic therapy and went on to receive 5 cycles of copanlisib with no recurrence of their colitis.

The study investigators recommend instructing the patient to monitor the frequency and consistency of their stool on a daily basis. If diarrhea does develop, patients should be instructed to stay adequately hydrated and adhere to a strict diet that avoids caffeine, spicy foods, alcohol, and dairy. Grade &ge;3 diarrhea should result in dose interruption and reduction. If symptoms persist, copanlisib should be discontinued and additional work-up should be done to determine other etiologies.

Hepatobiliary Toxicity and Other Laboratory Abnormalities

Few hepatic TEAEs were reported in CHRONOS-1, which could possibly be due to the trials&rsquo; hepatic function eligibility criteria, with 1 case each of cholangitis, cholecystitis, and acute pancreatitis reported. There is no mandate for frequent liver enzyme monitoring with copanlisib, but routine monitoring of liver function tests is recommended on the agent&rsquo;s label.

Hematologic laboratory abnormalities in the trial included decreased hemoglobin (78%) and decreased platelets (65%); these AEs occurred at grade &ge;3 in 4% and 8%, respectively. Patients&rsquo; complete blood count should be monitored &ge;1 time per week while receiving copanlisib.

Overall, the study authors concluded that the safety of copanlisib was comparable with that of idelalisib except with a lower risk of colitis, pneumonitis, and hepatotoxicity—AEs that have led to the black box warning on the label of idelalisib.²

References:

1. Cheson BD, O&rsquo;Brien S, Ewer MS, et al. Optimal management of adverse events from copanlisib in the treatment of patients with non-Hodgkin lymphomas.Clin Lymphoma Myeloma Leuk. 2019;19(3):135-14 doi: 10.1016/j.clml.2018.11.021.
2. Zydelig [package insert]. Foster City, CA: Gilead Sciences, Inc; 2014.
3. Copiktra [package insert]. Needham, MA: Verastem, Inc; 2018.
4. Dreyling M, Morschhauser F, Bouabdallah K, et al. Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma.Ann Oncol. 2017;28(9):2169-2178. doi: 10.1093/annonc/mdx289.
5. Dreyling M, Santoro A, Mollica L, et al. Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma.J Clin Oncol. 2017;35(35): 3893-390 doi: 10.1200.JCO.2017.75.4648.