INTEGRATED SAFETY DATA WITH COPANLISIB MONOTHERAPY FROM PHASE I AND II TRIALS IN PATIENTS WITH RELAPSED INDOLENT NON‐HODGKIN'S LYMPHOMA

Abstract

Introduction: Phosphatidylinositol 3-kinase (PI3K) is a therapeutic target for patients (pts) with indolent non-Hodgkin's lymphoma (iNHL). Copanlisib is a pan-Class I PI3K inhibitor with predominant activity against PI3K-α and PI3K-δ isoforms. In contrast to oral PI3K inhibitors that are dosed continuously, intermittent IV administration of copanlisib has demonstrated a different safety profile. We report results here from a pooled safety analysis. Methods: Safety data from 4 studies (NCT00962611, NCT01660451 parts A and B, and NCT02155582) including iNHL pts were pooled for analysis. All pts had received IV copanlisib on days 1, 8, and 15 of a 28-day cycle at either 0.8 mg/kg or an equivalent fixed dose of 60 mg. Treatment emergent adverse events (TEAE) were reported using MedDRA terms and worst NCI CTCAE grading. Results: A total of 168 pts with iNHL were available for safety analysis, including follicular (75%) and marginal zone lymphoma (15%) pts. Median prior lines of therapy was 3 (range 1-10); including rituximab (n = 168) and alkylating agents (n = 167). The mean duration of treatment was 30.2 weeks (±30.4) and mean number of cycles 7.5 (±7.6). The most commonTEAEs (occurring in ≥20% of the pts) were transient hyperglycemia (51%), diarrhea (36%), transient hypertension (35%), fatigue (29%), nausea (26%), neutropenia (25%), and pyrexia (24%). The most common grade 3 TEAEs (≥5%) were hyperglycemia (32%), hypertension (27%), neutropenia (8%), and pneumonia (8%); hyperglycemia and hypertension were transient and largely asymptomatic. Grade 4 TEAEs (≥5%) were neutropenia (12%) and hyperglycemia (6%). SeriousTEAEs (≥2%) were pneumonia (10%), pyrexia, hyperglycemia and pneumonitis (5% each), neutropenia, diarrhea and lung infection (2% each). There were six grade 5 TEAEs, with 3 reported as drug-related: lung infection, respiratory failure, and embolism. Infections (≥5%) included upper respiratory (14%), pneumonia (11%), bronchitis (9%), urinary (7%), oral herpes (6%), and rhinitis (5.4%). Opportunistic fungal infections occurred in 3 pts; two Pneumocystis jiroveci pneumonia and one bronchopulmonary aspergillosis. GI toxicity included grade 3 diarrhea (5%) and one case of colitis (grade 4) was reported. Suspected non-infectious pneumonitis was reported in 9% (3% grade 3 and no grade 4/5). Treatment discontinuations due to TEAEs (24%) included pneumonitis (2%), neutropenia, thrombocytopenia, fatigue, pneumonia, platelet count decreased, and hyperglycemia (1.8% each). Conclusions: Integrated safety analysis demonstrates that copanlisib had a tolerable and manageable safety profile with a low rate of severe gastrointestinal toxicities, hepatotoxicities, pneumonitis, and opportunistic infections. The most common grade 3 AEs were transient hyperglycemia and transient hypertension, both of which were predictable and manageable and did not lead to significant discontinuation.