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PI3K Inhibition in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

Dreyling, Martin, MD, PhD

doi: 10.1097/01.COT.0000530875.36363.e3

Non-Hodgkin lymphoma (NHL) is the tenth most common cancer worldwide, with nearly 386,000 new cases diagnosed in 2012 (Int J Cancer 2015;136(5): E359-386). NHL is divided into two prognostic groups: the indolent, or slow-growing lymphomas, and the aggressive lymphomas.

Initial treatment for indolent B-cell lymphoma—one of the most common types of NHL, accounting for about 40 percent of cases, according to the Leukemia & Lymphoma Society—usually entails rituximab immunotherapy, either alone or in combination with chemotherapy (such as the alkylating agent bendamustine) (Ann Oncol 2017;28(12):3109, NCCN Guidelines: B-Cell Lymphomas Version 1.2017).

However, a considerable number of patients relapse after, or are refractory to, current treatments. Response rates and duration of response decline with each successive line of therapy, underscoring the need for new treatments for these patients (J Clin Oncol 2017;35:3898-3905).

In September 2017, copanlisib was granted accelerated approval by the FDA for the treatment of adult patients with relapsed follicular lymphoma who have received at least two prior systemic therapies. Follicular lymphoma, a B-cell lymphoma, is the most common indolent form of lymphoma, accounting for approximately 20-30 percent of all NHLs.

Copanlisib is a novel phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant activity against the alpha and delta isoforms. The PI3K pathway is involved in cell growth, survival, and metabolism, and its dysregulation plays an important role in lymphoma. Targeted inhibition of the PI3K pathway is an established therapeutic strategy for relapsed or refractory indolent B-cell lymphoma, according to NCCN and other international guidelines (NCCN Guidelines: Non-Hodgkin's Lymphomas Version 4.2014, Ann Oncol 2017;28(12):3109, N Engl J Med 2014;370:1008-1018).

Copanlisib has demonstrated durable responses and a manageable safety profile in phase I and II studies in patients with relapsed or refractory indolent B-cell lymphoma (Ann Oncol 2016;27:1928-1940, Ann Oncol 2017;28:2169-2178). In addition, it is the only approved PI3K inhibitor to be administered intravenously on an intermittent dosing schedule, which contributes to its favorable safety profile when compared with oral, continuously dosed PI3K inhibitors (Blood 2017;130:2777, Expert Rev Anticancer Ther 2017;17:271-279, Clin Cancer Res 2015;21:1525-1529).

To further examine the mechanism of PI3K inhibitors, and as a starting point to explore the safety and efficacy of copanlisib, we conducted the CHRONOS-1 study (NCT01660451).

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Study Design & Results

CHRONOS-1 was an open-label, single-arm, phase II trial that included 142 patients with indolent B-cell lymphoma who had at least two prior lines of therapy (61% of patients [n=86] were refractory to their last treatment), including 104 (73%) patients with follicular lymphoma and 23 (16%) with marginal zone lymphoma (MZL).

The median age of patients was 63. Copanlisib 60 mg was administered to patients intravenously on an intermittent schedule on Days 1, 8, and 15 of a 28-day cycle. The primary endpoint of the trial was objective response rate; secondary endpoints included duration of response, progression-free survival, and overall survival (J Clin Oncol 2017;35:3898-3905).

The results showed copanlisib achieved an overall response rate of 59 percent (95% CI, 51, 67; P<0.001), 59 percent in patients with follicular lymphoma (95% CI, 49, 68), and 70 percent in patients with MZL, an indolent B-cell lymphoma that accounts for approximately 12 percent of all B-cell lymphomas.

The median duration of response was 22.6 months overall (range, 0 to 22.6 months; 95% CI, 7.4, 22.6), and 12.2 months (range, 0 to 22.6 months; 95% CI, 6.9, 22.6) in patients with follicular lymphoma. Copanlisib also demonstrated a complete response rate in 15 (14%) patients with follicular lymphoma and in two (9%) MZL patients.

The results of the study found that copanlisib is associated with a manageable safety profile. The most common treatment-related adverse events included transient infusion-related hyperglycemia—which occurred in 49 percent of all patients (41% grade 3 or 4)—and transient infusion-related hypertension, which occurred in 29 percent of all patients (23% grade 3). One patient (0.7%) developed colitis and two patients (1.4%) had pneumonitis (Ann Oncol 2016;27:1928-1940, Ann Oncol 2017;28:2169-2178, Clin Cancer Res 2015;21:3160-3169, J Clin Oncol 2012;30:282-290, Clin Cancer Res 2015;21:77-86), none of which were a significant cause of treatment discontinuation (J Clin Oncol 2017;35:3898-3905).

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Implications of CHRONOS-1 Data

In the CHRONOS-1 study, treatment with copanlisib resulted in significant and durable responses in patients with relapsed or refractory indolent B-cell lymphoma.

In contrast to the clinical trial results of oral PI3K-targeting agents (Expert Rev Anticancer Ther 2017;17:271-279, Clin Cancer Res 2015;21:1525-1529), we observed low rates of severe hepatic transaminitis, diarrhea, colitis, and noninfectious pneumonitis. Overall, the findings indicate a favorable efficacy and safety profile that supports intermittent IV administration with copanlisib, filling a significant need for new and effective options in this clinical setting.

At the most recent American Society of Hematology Annual Meeting, we presented an updated analysis of the CHRONOS-1 trial, which included data from 8 months after the primary analysis with 29.6 percent of patients followed for >1 year. These results confirmed that copanlisib's robust efficacy and safety benefits persist with longer follow-up.

Copanlisib achieved a 58.5 percent overall response rate and a complete response rate of 14.1 percent with a median duration of response of 12.2 months. The safety profile remained mostly unchanged. We observed low rates of severe adverse events and no late-onset toxicities, reaffirming copanlisib's safety benefits through intermittent IV dosing (Blood 2017;130:2777).

Building on the promise of the initial CHRONOS-1 trial and this updated analysis, additional studies are ongoing investigating copanlisib in earlier lines of therapy. There are two phase III randomized, double-blind, placebo-controlled trials, CHRONOS-3 (NCT02367040) and CHRONOS-4 (NCT02626455), analyzing copanlisib in combination with standard immunochemotherapy in patients with relapsed or refractory indolent B-cell lymphoma and are now enrolling patients.

We look forward to exploring the future benefit of copanlisib in other lymphoma subtypes such as mantle cell lymphoma, T-cell lymphoma, or diffuse large B-cell lymphoma.

MARTIN DREYLING, MD, PHD, is Professor of Medicine and Head of the Lymphoma Program in the Department of Medicine III, University Hospital Grosshadern, Ludwig Maximilians-University, Munich, Germany.

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