Abstract CT149: Copanlisib in patients with relapsed or refractory indolent B-cell lymphoma: Primary results of the pivotal Chronos-1 study
Authors: Dreyling Martin , Santoro Armando , Mollica Luigina , Leppä Sirpa , Follows George A. , Lenz Georg , Kim Won Seog , Nagler Arnon , Panayiotidis Panayiotis , Demeter Judit , Özcan Muhit , Kosinova Marina , Bouabdallah Krimo , Morschhauser Franck , Stevens Don A. , Trevarthen David , Giurescu Marius , Kupit Lisa , Yin Shuxin , Hiemeyer Florian , Garcia-Vargas Jose , Childs Barrett H. , Zinzani Pier Luigi 
Published: July 2017

Abstract
Introduction: There are limited treatment options for patients with indolent B-cell lymphoma who have relapsed or are refractory to standard therapies. Copanlisib is an intravenously administered pan-Class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant activity against PI3K-α and PI3K-δ isoforms. We report here the primary results from a pivotal phase II study (NCT01660451, part B).
Methods: Patients with indolent B-cell non-Hodgkin lymphoma (4 subtypes: follicular [FL], marginal zone [MZL], small lymphocytic [SLL] and lymphoplasmacytoid/Waldenström macroglobulinemia [LPL-WM]) and relapsed after, or refractory to, ≥2 prior lines of treatment were eligible. Previous treatment had to include rituximab and an alkylating agent. Copanlisib (60 mg, I.V.) was intermittently administered on days 1, 8 and 15 of a 28-day cycle. The primary efficacy endpoint was objective tumor response rate (ORR) as assessed per independent radiologic review (Cheson et al., JCO 20:579, 2007).
Results: The full analysis set comprised 142 patients, of which 141 patients had indolent lymphoma (FL/MZL/SLL/LPL-WM: 104/23/8/6). At the time of primary analysis, median duration of treatment was 22 weeks (range 1-105); 46 patients remained on treatment. The most common treatment-related AEs (all grade/grade 3+) were transient hyperglycemia (49%/40%) and hypertension (29%/23%). Other AEs of interest included neutropenia (25%/19%), diarrhea (18%/4%), lung infection (14%/11%), pneumonitis (7%/1.4%), and colitis (0.7%/0.7%). No colonic perforations occurred. There were two non-fatal opportunistic infections. Laboratory toxicities of interest were principally grade-1, including alanine aminotransferase (23% all-grade/19% grade-1) and aspartate aminotransferase (28%/25%). There were 6 deaths, 3 of which were attributed to copanlisib: lung infection, respiratory failure, and a thromboembolic event. The ORR was 59.2%, including 12.0% complete response (CR) and 47.2% partial response (PR), with stable disease in 29.6% of patients and progressive disease in 2.1% of patients. In the FL subset, the ORR was 58.7%, including 14.4% CR and 44.2% PR. In the MZL subset, the ORR was 69.6%, including 8.7% CR and 60.9% PR. The estimated Kaplan-Meier (KM) median duration of response in the full analysis set was 687 days (range 0-687) and 370 days (range 0-687) in the FL subset. The KM-estimate of median PFS was 340 days (range 0-736). Median overall survival had not yet been reached.
Conclusions: Treatment of patients with relapsed or refractory indolent B-cell lymphoma with copanlisib resulted in durable tumor responses. Administration of copanlisib had a manageable safety profile, with low rates of severe hepatic enzymopathy, diarrhea or inflammatory events, as well as low rates of opportunistic infections, fatal infections or other fatal serious adverse events.
Citation Format: Martin Dreyling, Armando Santoro, Luigina Mollica, Sirpa Leppä, George A. Follows, Georg Lenz, Won Seog Kim, Arnon Nagler, Panayiotis Panayiotidis, Judit Demeter, Muhit Özcan, Marina Kosinova, Krimo Bouabdallah, Franck Morschhauser, Don A. Stevens, David Trevarthen, Marius Giurescu, Lisa Kupit, Shuxin Yin, Florian Hiemeyer, Jose Garcia-Vargas, Barrett H. Childs, Pier Luigi Zinzani. Copanlisib in patients with relapsed or refractory indolent B-cell lymphoma: Primary results of the pivotal Chronos-1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT149. doi:10.1158/1538-7445.AM2017-CT149