CHRONOS-1: Copanlisib Shows Promise for Patients With Relapsed/Refractory Indolent B-Cell NHL

Patients with relapsed/refractory indolent B-cell lymphomas often have limited options beyond standard therapies once their disease progresses. Copanlisib, an intravenously administered pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor, was studied in this patient population in the pivotal, phase II CHRONOS-1 trial presented at the 2017 AACR Annual Meeting. Copanlisib demonstrated a durable tumor response and manageable safety profile, according to Martin H. Dreyling, PhD, MD, of Klinikum der Universität München-Grosshadern in Munich, Germany, and co-authors.

The trial enrolled 141 patients with indolent B-cell non-Hodgkin lymphomas, including follicular lymphoma (FL; n=104), marginal zone lymphoma (MZL; n=23), small lymphocytic leukemia (n=8), and lymphoplasmacytoid/Waldenström macroglobulinemia (n=6). All patients had relapsed or were refractory to ≥2 prior lines of treatment and were previously treated with rituximab and an alkylating agent.

Copanlisib 60 mg was intermittently administered on days 1, 8, and 15 of a 28-day cycle. At primary analysis, the median duration of treatment was 22 weeks (range = 1-105 weeks) and 46 patients remained on treatment.

The most common any-grade treatment-related adverse events (AEs) were transient hyperglycemia (49%) and hypertension (29%). Other AEs included neutropenia (25%), diarrhea (18%), lung infection (14%), pneumonitis (7%), and colitis (0.7%). Two non-fatal opportunistic infections were reported. Six deaths occurred; three of which were deemed related to copanlisib and were attributed to lung infection, respiratory failure, and a thromboembolic event.

The objective tumor response rate (ORR; primary endpoint) was 59.2 percent, including a complete response (CR) rate of 12 percent and a partial response (PR) rate of 47.2 percent. Another 29.6 percent of patients achieved stable disease, and two percent experienced disease progression.

Dr. Dreyling and researchers noted that response rates varied slightly depending on the type of lymphoma. For example, in patients with FL, the ORR was 58.7 percent (14.4% CR and 44.2% PR); in patients with MZL, the ORR was 69.6 percent (8.7% CR and 60.9% PR).

The estimated duration of response in the overall patient population was 687 days (range = 0-687 days) but nearly half that in the FL subgroup (370 days; range = 0-687 days). Overall median progression-free survival was 340 days (range = 0-736 days); the median overall survival was not reached.

“Copanlisib demonstrated significant efficacy, and the safety profile was manageable and distinct, compared with that of oral PI3K inhibitors, possibly due to the intermittent schedule and intravenous route of administration,” Dr. Dreyling said. However, the study did not have a comparator arm, so the results will need to be assessed against other approved kinase inhibitors for this patient population, including idelalisib. Ongoing phase III studies are investigating copanlisib in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, hydroxydaunomycin, vincristine, prednisolone) chemotherapy.

Dreyling M, Santoro A, Leppä S, et al. Copanlisib in patients with relapsed or refractory indolent B-cell lymphoma: primary results of the pivotal Chronos-1 study. CT149. Presented at the 2017 AACR Annual Meeting, April 4, 2017; Washington, DC.