Patient Co-Morbidity Profile Should Drive PI3K Inhibitor Selection for Relapsed Follicular Lymphoma

Background: Idelalisib (Zydelig®, IDELA), an oral agent, and copanlisib (Aliqopa®, COPA), an intravenous agent, are the only B-cell receptor pathway targeting agents approved for treatment of follicular lymphoma (FL). Both agents target PI3Kδ while COPA also targets PI3Kα. These drugs received accelerated approvals, and overall response rates in their respective phase 2 trials were comparable. Safety profiles may be impacted by distinct kinase inhibitory profiles, delivery method, and dosing. Given similar response rates with these agents, the administration schedule and safety profile become important considerations. A challenge is the appropriate regimen choice to maximize anti-tumor benefit while limiting treatment-emergent adverse events (TEAEs) or exacerbation of pre-existing co-morbidities.

Objective: To compare the safety profiles of IDELA and COPA to determine which drug may be more suitable for select patient populations.

Methods: We selected key AEs for analysis based on the "Highlights of Prescribing Information" in each drug's United States package insert (USPI) to assess the incidence of TEAEs in patients receiving COPA or IDELA. Using the Safety Analysis Set for patients with iNHL treated with IDELA (N=163, median duration of treatment [mDoT] 27 weeks) and TEAEs reported for patients with FL and other hematological malignancies treated with COPA (Aliqopa® USPI [N=168, mDoT 22 weeks], Dreyling et al., J. Clin. Oncol. 2017; 35:3898 [N=142, mDoT 22 weeks], and Dreyling et al., Blood. 2017; 130:2777 [N=142, mDoT 26 weeks]), we ascertained the most common TEAEs, compared the incidence of specific TEAEs (estimate difference in proportions, Fisher's exact test), and assessed the effect of pre-existing conditions on IDELA- and COPA-mediated AEs.

Results: All grade (aGr) and grade 3/4 (Gr3/4) diarrhea and transaminitis were significantly more common in IDELA-treated patients, and aGr and Gr3/4 hyperglycemia (blood glucose >160 mg/dL and >250 mg/dL, respectively) and hypertension (systolic blood pressure [SBP] >120 mmHg; diastolic blood pressure [DBP] > 80 mmHg and SBP > 160 mmHg; DBP > 100 mmHg, respectively) were significantly more common in COPA-treated patients (Figs. 1 and 2). The incidences of aGr and Gr3/4 infection, neutropenia, and pneumonitis were similar in IDELA- and COPA-treated patients. IDELA-treated patients with pre-existing diabetes mellitus or hyperglycemia experienced more Gr3/4 hyperglycemia than IDELA-treated patients without either diagnosis (7.1% vs. 0%, p=0.0286), but at rates lower than in COPA-treated patients (10.7% vs. 53.6%, p<0.0001 for aGr and 7.1% vs. 39.3%, p=0.0005 for Gr3/4 hyperglycemia). In contrast, pre-existing hypertension had no impact on the frequency of aGr and Gr3/4 hypertension among IDELA-treated patients; IDELA-treated patients with pre-existing hypertension also experienced lower rates of aGr and Gr3/4 hypertension compared to COPA-treated patients (3.2% vs. 35.1% for aGr; 1.6% vs. 27.4% for Gr3/4; both p<0.0001). Similarly, a history of or predisposition to diarrhea did not increase the rate of diarrhea in IDELA-treated patients, but Gr3/4 diarrhea was more frequent in IDELA-treated patients with no history of diarrhea than in COPA-treated patients (13.2% vs. 4.8%, p=0.0094). Finally, pre-existing ALT/AST elevations also did not increase the risk for treatment-emergent ALT/AST elevations in IDELA-treated patients, but IDELA-treated patients without pre-existing ALT/AST elevations demonstrated higher rates of aGr and Gr3/4 ALT/AST elevation than COPA-treated patients (39% vs. 1.4% for Gr3/4 ALT; 31.7% vs. 1.4% for Gr3/4 AST; both p<0.0001).

Conclusion: Pre-existing co-morbidities and the nature of emergent therapy-associated side effects (including type, severity, and duration [transient vs. chronic]) may impact PI3K inhibitor choice for the treatment of relapsed FL. Findings in this analysis suggest that for patients with pre-existing diabetes mellitus or hypertension, IDELA may be a more appropriate option. For patients at increased risk for diarrhea-related complications, COPA may be a more appropriate option. IDELA-treated patients should be followed closely for diarrhea and should be monitored routinely for hepatotoxicity regardless of hepatic status at treatment initiation. Patients treated with either compound should be followed closely for infection, neutropenia, and pneumonitis.

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