Long-term safety and efficacy of the PI3K inhibitor copanlisib in patients with relapsed or refractory indolent lymphoma: 2-year follow-up of the CHRONOS-1 study.

Martin Dreyling,Marina Kosinova,Liana Rodrigues,Judit Demeter,Ashok Miriyala,Georg Lenz,Franck Morschhauser,Pier Luigi Zinzani,Florian Hiemeyer,Barrett H Childs,Won Seog Kim,Sirpa Leppä,Don A Stevens,Maria Dimou,Arnon Nagler,Luigina Mollica,Krimo Bouabdallah,Armando Santoro,George Follows,Javier Muñoz ,Muhıt Özcan ,David R Trevarthen ,J Garcia‐Vargas

doi:10.1002/ajh.25711

Abstract

Safety profiles of oral PI3K inhibitors have resulted in US FDA black box warnings regarding fatal/serious toxicities. The approved intravenous PI3K inhibitor copanlisib has low incidence of severe toxicities and no black box warnings, but chronic treatment effects were unknown. We provide an update on safety and efficacy of copanlisib with a minimum 2-year follow-up of the CHRONOS-1 study. A total of 142 patients with histologically confirmed indolent B-cell lymphoma who had relapsed after or were refractory to ≥2 prior treatments received intravenous copanlisib 60 mg on days 1, 8, and 15 (28-day cycle). The primary efficacy endpoint was objective response rate (ORR) after ≥4 cycles (independent assessment). The predominant histology was follicular lymphoma (n = 104). The ORR was 60.6% (seven additional complete responses since primary analysis). Secondary endpoints of median duration of response, progression-free survival, and overall survival were 14.1 months (median follow-up, 16.1 months), 12.5 months (median follow-up, 14.0 months), and 42.6 months (median follow-up, 31.5 months), respectively. Median safety follow-up was 6.7 months; 26% of patients received treatment for >1 year. Common treatment-emergent adverse events (TEAEs) (all grade/grade 3/grade 4) were transient hyperglycemia (50.0%/33.1%/7.0%), diarrhea (35.2%/8.5%/0%), transient hypertension (29.6%/23.9%/0%), and neutropenia (28.9%/9.2%/14.8%). Serious AEs were largely unchanged, with no new cases of pneumonitis (4.2%), diarrhea (2.8%), or grade 5 events. Note, TEAEs showed no evidence for increased incidence or worsening following longer exposure in patients treated >1 year. Long-term follow-up of patients with relapsed/refractory indolent B-cell lymphoma treated with intravenous copanlisib demonstrated durable, enhanced responses without evidence of worsening TEAEs, as reported for orally administered PI3K inhibitors.

Highlights

Indolent B-cell lymphomas are often incurable due to frequent relapse following an initial response to first-line therapy and eventual development of refractory disease, representing a significant challenge for treatment and a high unmet need.[1]
To gain a better understanding of the safety and efficacy associated with long-term use of an intravenous phosphatidylinositol 3-kinase (PI3K) inhibitor, including patients treated for 1 year or more, we report here the safety and efficacy from a 2-year follow-up of patients treated with copanlisib in the CHRONOS-1 study
Because of reports of delayed or late-onset adverse events (AEs) associated with continuously dosed oral PI3K inhibitors, in addition to the overall incidence of AEs as commonly reported (Table 2), we further evaluated the incidence and severity of AEs over the course of treatment

Summary

| INTRODUCTION

Indolent B-cell lymphomas are often incurable due to frequent relapse following an initial response to first-line therapy and eventual development of refractory disease, representing a significant challenge for treatment and a high unmet need.[1]. Several orally administered agents targeting the PI3K pathway have demonstrated adverse events (AEs), such as autoimmune dysfunction and opportunistic infections,[8] with reports of more severe late-onset toxicities such as diarrhea and ulcerative colitis.[9,10] Such PI3K-associated toxicities have caused the US Food and Drug Administration (FDA) to include warning statements as part of the prescribing information for orally administered PI3K inhibitors.[11,12] there is an unmet need for long-term treatment options that are both safe and effective in this patient population with advanced and difficult-to-treat lymphoma. To gain a better understanding of the safety and efficacy associated with long-term use of an intravenous PI3K inhibitor, including patients treated for 1 year or more, we report here the safety and efficacy from a 2-year follow-up of patients treated with copanlisib in the CHRONOS-1 study

| METHODS

| RESULTS

Findings

| DISCUSSION