Outcomes for Patients with Pre-Existing Diabetes or Hypertension Treated with Copanlisib from the CHRONOS-1 Study in Patients with Relapsed or Refractory Indolent B-Cell Lymphoma
Authors: Zinzani Pier Luigi , Santoro Armando , Mollica Luigina , Leppä Sirpa , Follows George A , Lenz Georg , Kim Won Seog , Nagler Arnon , Panayiotidis Panayiotis , Demeter Judit , Morschhauser Franck , Rodrigues Liana , Reeves John , Hiemeyer Florian , Miriyala Ashok , Garcia-Vargas Jose , Childs Barrett H. , Dreyling Martin H. 
Published: October 2019

Abstract
Introduction: We previously reported that treatment of patients with relapsed or refractory indolent B-cell lymphoma with the pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor copanlisib resulted in durable responses with a manageable safety profile (Dreyling et al., J Clin Oncol 35:3898-3905, 2017). Copanlisib is administered intravenously on an intermittent schedule and two of the most commonly reported adverse events are infusion-related transient elevations in blood glucose and blood pressure. Patients with a medical history of diabetes mellitus or hypertension were allowed to enroll in the CHRONOS-1 study if these conditions were well controlled. We report here on the outcomes for these subsets of patients.
Methods: Patients with histologically confirmed indolent B-cell non-Hodgkin lymphoma and relapsed after, or refractory to, ≥2 prior lines of treatment were eligible. Previous treatment had to include rituximab and an alkylating agent or regimen. Copanlisib (60 mg) was administered I.V. on days 1, 8 and 15 of a 28-day cycle. Treatment continued until progression or unacceptable toxicity. The primary efficacy endpoint was objective response rate (ORR) per independent radiologic review (Cheson et al., JCO 20:579, 2007). Secondary efficacy endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Adverse events (AEs) were reported using MedDRA (version 19.1). The cut-off for this analysis was February 2018.
Results: A total of 142 patients were treated, with follicular lymphoma (FL) being the principal histology (n=104). The median age was 63 years (range 25-82). Median number of prior lines of treatment was 3 (range 2-9), with 61% being refractory to the last regimen. Twenty patients with diabetes were enrolled; 17 patients with a history of diabetes mellitus, 1 with history of impaired glucose tolerance, and 2 diagnosed at screening. Forty one patients with a medical history of hypertension were enrolled; baseline median systolic blood pressure was 126 mmHg in hypertensive subgroup vs 118 mmHg in non-hypertensives.
At the time of analysis, the median duration of treatment was 5.0 months in the diabetic pts, 6.0 months in non-diabetics, 6.0 months in hypertensive pts, and 5.9 months in non-hypertensives. The ORR was >60% in all subsets with the exception of the diabetic subset, where the ORR was 40% (Table). The median DOR was also the shortest for the diabetic subset (7.1 mo); 3 patients were in response for more than 2 yrs. The mDOR for non-diabetics was 14.9 mo. Interestingly, the hypertensive patient subset had the highest rate of CR (26.8%). Of the 41 pts in this subset, 31 were FL patients, and among these patients 10 (32.3%) had a CR. Likewise, the mDOR for the hypertensive subset was 22.6 mo; the non-hypertensive subset had a mDOR of 10.9 mo. Median PFS for the four subsets were: 7.2 mo for diabetics, 13.8 mo for non-diabetics, 19.0 mo for hypertensives, and 11.3 mo for non-hypertensives. Median OS had not yet been reached in the non-diabetic and non-hypertensive subsets.
Regarding AEs of interest possibly impacted by pre-existing conditions, all-grade (G) treatment-emergent hyperglycemia was reported in 85% and 44.3% of diabetic and non-diabetic groups, respectively. G4 hyperglycemia was reported in 7/20 (35%) of diabetic patients but in in only 3 (2.5% of non-diabetics). Two diabetic patients and one non-diabetic patient discontinued treatment due to hyperglycemia. Mean ± SD hemoglobin A1c values increased 0.64±0.9% from baseline to last value on treatment in diabetics and 0.50±0.8% in non-diabetics. All-grade hypertension was reported for 43.9% of hypertensive patients and was principally G3 (39.0%). In non-hypertensives the all-grade and G3 values were 23.8% and 17.8%, respectively. There were no G4 events. One patient discontinued due to hypertension (G2). There were two G3 cardiac-related events (atrial fibrillation and left ventricular dysfunction) and one G4 event (arrhythmia) in the hypertensive group.
Conclusions: These results support use of copanlisib in indolent lymphoma patients with well-controlled diabetes or hypertension. In particular, the transient hyperglycemia in diabetic patients did not exacerbate metabolic status as reflected in HbA1c values. Thus, patients with these pre-existing conditions should not be precluded treatment a priori.

Disclosures
Zinzani: Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leppä:Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Bayer: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy. Follows:Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Lenz:Celgene Corp.: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria; Novartis: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding. Demeter:Novartis: Consultancy; BMS: Consultancy; Aramis Pharma: Consultancy; Pfizer: Consultancy; Roche: Consultancy; Angelini: Consultancy; Amgen: Consultancy. Morschhauser:Janssen: Other: Scientific Lectures; Roche: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rodrigues:Bayer: Employment. Reeves:Joule INC: Employment; Bayer: Consultancy. Hiemeyer:Bayer: Employment. Miriyala:Bayer: Employment. Garcia-Vargas:Bayer: Employment. Childs:Bayer: Employment. Dreyling:Sandoz: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.