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

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%] / 5.9% [0.8%] / 10.7% [1.8%]), pyrexia (19.2% [2.7%] / 16.1% [0.8%] / 10.7% [0%]), and neutropenia (19.5% [16.2%] / 13.6% [8.5%] / 21.4% [16.1%]). A similar trend was observed in pts treated for >1 year (Table), though these pts had a broad range of exposures, with 22 pts treated for ≥2 years. Incidences of g≥3 diarrhea in pts treated for >1 year remained stable and were comparable with prolonged exposure (≤180 d 8.9%; 181-360 d 7.1%; ≥361 d 12.5%). Pneumonitis was infrequent overall (all grade / g≥3: 5.2% / 2.7%) and in pts treated for >1 year (10.7% / 3.6%). Copanlisib-related TEAEs of all grades / g3 / g4 were reported for 88.7% / 54.1% / 18.4% of pts; most events were reported early (≤180 d) with generally no increase in incidence or severity observed in pts treated for >1 year. Serious AEs (SAEs) occurred in 57.1% of pts, most commonly (≥2%; all grade / g≥3) pneumonia (6.0% / 5.5%), general physical health deterioration (5.2% / 4.9%), pyrexia (4.1% / 1.4%), hyperglycemia (4.1% / 4.1%), pneumonitis (4.1% / 2.7%), lung infection (3.0% / 2.2%), and febrile neutropenia (2.2% / 2.2%). All-grade / g3 / g4 copanlisib-related SAEs were reported for 30.2% / 18.7% / 5.8% of pts. As with TEAEs, SAEs mostly occurred early with no general increase in incidence or severity with treatment >1 year. Thirty-nine pts died either during copanlisib treatment or within 35 d post discontinuation of treatment (10.7%), most commonly due to PD (4.7%). No g4 late-onset colitis, hepatotoxicity, or other intestinal toxicity occurred after 6 months of treatment. Conclusions: These data provide evidence for the manageable safety profile of long-term copanlisib treatment, with no late-onset toxicities or worsening of severity of TEAEs, and few severe gastrointestinal TEAEs. Transient, manageable hyperglycemia and hypertension were among the most common TEAEs; no new unexpected safety issues were identified. These results support the known safety profile and approved indication of copanlisib. Disclosures Zinzani: IMMUNE DESIGN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANOFI: Consultancy; CELGENE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PORTOLA: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ROCHE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KYOWA KIRIN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSAPHARMA: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; VERASTEM: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELLTRION: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GILEAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; JANSSEN-CILAG: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANDOZ: Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Santoro:Gilead: Consultancy, Speakers Bureau; Servier: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Takeda: Speakers Bureau; Abb-Vie: Speakers Bureau; Sandoz: Speakers Bureau; Arqule: Consultancy, Speakers Bureau; Lilly: Speakers Bureau; MSD: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Eisai: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; BMS: Consultancy; Roche: Speakers Bureau. Leppä:Roche: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Follows:AZ: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Lenz:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Agios: Research Funding; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Kim:Celltrion: Research Funding; Mundipharma: Research Funding; J&J: Research Funding; Roche: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; Donga: Research Funding. Panayiotidis:Bayer: Other: Support of clinical trial. Demeter:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol- Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Angelini: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Morschhauser:F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; BMS: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Munoz:Fosunkite: Speakers Bureau; AstraZeneca: Speakers Bureau; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Kite Pharma: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Portola: Research Funding; Incyte: Research Funding. Miriyala:Bayer HealthCare Pharmaceuticals, Inc.: Employment. Benson:Bayer HealthCare Pharmaceuticals, Inc.: Employment. Garcia-Vargas:Bayer Healthcare Pharmaceuticals, Inc.: Employment. Childs:Bayer Healthcare Pharmaceuticals, Inc.: Employment. Dreyling:Novartis: Other: Scien

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