Copanlisib, a PI3K Inhibitor, Demonstrates a Favorable Long-Term Safety Profile in a Pooled Analysis of Patients with Hematologic Malignancies

• Published in: Blood 2019-11, Vol.134 (Supplement_1), p.4009-4009
• Main 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, Munoz, Javier, Miriyala, Ashok, Benson, Alice, Garcia-Vargas, Jose, Childs, Barrett H, Dreyling, Martin
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2019-131779

Introduction: Copanlisib, a pan-class I phosphatidylinositol 3-kinase inhibitor, is approved in the US for the treatment of patients (pts) with relapsed follicular lymphoma (FL) who have received ≥2 prior systemic therapies; it also has Breakthrough Therapy designation for pts with relapsed marginal zone lymphoma who have received ≥2 prior therapies. The Phase II CHRONOS-1 study in pts with indolent lymphoma treated with copanlisib (NCT01660451; Part B) demonstrated an objective response rate of 59.2% with manageable safety and low rates of severe adverse events (AEs) (Dreyling M et al. J Clin Oncol 2017). We report pooled safety data from 8 Phase I and II studies of pts with hematologic malignancies following long-term treatment with copanlisib. Methods: Pts with hematologic malignancies treated with copanlisib monotherapy in completed open-label Phase I or II studies were included. Copanlisib 60 mg (i.v.) was administered intermittently on days (d) 1, 8, and 15 of a 28-d cycle until disease progression (PD) or unacceptable toxicity. AEs were reported using MedDRA (v.21.1) and assessed by time of onset (worst grade or new AEs occurring ≤180 d, 181-360 d, or ≥361 d) and treatment duration. Results: A total of 364 pts received copanlisib (data cut-off Feb 2019). Median age was 65 years (range 22-93); the predominant histology was FL (42.0%). At data cut-off, 34 pts (9.3%) remained on treatment. Duration of treatment ranged from 0.2 to 62.1 months, with 56 pts (15.4%) treated for >1 year. All-grade treatment-emergent AEs (TEAEs) were reported in 97.8% of pts; 51.4% had TEAEs of worst grade [g] 3, and 24.7% had TEAEs of worst g4. The most common (≥20%) TEAEs (all grade / g3 / g4) were hyperglycemia (50.5% / 28.3% / 4.4%), hypertension (38.7% / 29.1% / 0%), diarrhea (37.1% / 4.9% / 0%), nausea (28.3% / 1.4% / 0%), fatigue (27.2% / 2.7% / 0%), pyrexia (23.1% / 3.0% / 0%), and neutropenia (23.1% / 9.3% / 9.6%). Hyperglycemia and hypertension were infusion related, transient, and manageable. Events generally were reported early, with higher incidence at ≤180 d (n=364) vs 181-360 d (n=118) or ≥361 d (n=56), and no increased incidence of g≥3 events with prolonged exposure, with the exception of diarrhea (all grade [g≥3]): hyperglycemia (49.2% [31.6%] / 21.2% [11.0%] / 19.6% [10.7%]), hypertension (37.4% [27.2%] / 21.2% [15.3%] / 21.4% [17.9%]), diarrhea (32.7% [3.0%] / 20.3% [4.2%] / 30.4% [12.5%]), nausea (27.5% [1.4%] / 0.8% [0%] / 3.6% [0%]), fatigue (24.2% [2.5