bay-80-6946 and Hyperglycemia

Copanlisib is an intravenously administered pan-class I PI3K inhibitor that has been demonstrated to have appreciable effects in the treatment of patients with lymphoma. The purpose of this meta-analysis was to evaluate the efficacy and safety of copanlisib for treating patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL).. PubMed, Web of Science, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for relevant studies published prior to July 2022. The efficacy evaluation included complete response rate (CR), partial response rate (PR), rate of stable disease (SDR), overall response rate (ORR), disease control rate (DCR), rate of progressive disease (PDR), median progression-free survival (PFS), and median overall survival (OS). Any grade adverse events (AEs) and grade ≥3 AEs were synthesized to assess its safety.. Eight studies with a total of 652 patients with R/R B-NHL were identified. The pooled CR, PR, ORR, SDR, DCR, and PDR from all 8 articles were 13%, 40%, 57%, 19%, 86%, and 9%, respectively. The CR and ORR of combination therapy with rituximab were higher than those with copanlisib monotherapy for R/R B-NHL (34% vs. 6%, p<0.01; 89% vs. 42%, p<0.01). For patients with R/R indolent B-NHL, CR and ORR were lower with copanlisib monotherapy than with combination therapy with rituximab (7% vs. 34%, p<0.01; 58% vs. 92%, p<0.01). In R/R B-NHL patients receiving copanlisib monotherapy and combination therapy with rituximab, the risk of any grade AEs was 99% and 96%, respectively, and the risk of grade ≥3 AEs was 84% and 91%, respectively. The common any grade AEs included hyperglycemia (66.75%), hypertension (48.57%), diarrhea (35.06%), nausea (34.98%) and fatigue (30.33%). The common grade ≥3 AEs included hyperglycemia (45.14%), hypertension (35.07%), and neutropenia (14.75%). The comparison of AEs between the copanlisib monotherapy and the combination therapy with rituximab showed that hyperglycemia of any grade (p<0.0001), hypertension of any grade (p=0.0368), fatigue of any grade (p<0.0001), grade ≥3 hypertension (p<0.0001) and grade ≥3 hyperglycemia (p=0.0074) were significantly different between the two groups.. Our meta-analysis demonstrated that the efficacy of both copanlisib monotherapy and combination therapy with rituximab in patients with R/R B-NHL was satisfactory, while treatment-related AEs were tolerable. Compared with copanlisib monotherapy, combination therapy with rituximab showed superior efficacy for treating R/R B-NHL, and its safety was manageable.. https://inplasy.com/inplasy-2022-10-0008/, identifier INPLASY2022100008.

Topics: Fatigue; Humans; Hyperglycemia; Hypertension; Lymphoma, B-Cell; Neoplasm Recurrence, Local; Phosphoinositide-3 Kinase Inhibitors; Prospective Studies; Rituximab

B-cell receptor signaling is important in the pathogenesis of non-Hodgkin lymphoma. The PI3K pathway is activated by B-cell receptor signaling. Recently, several PI3K inhibitors have been in development for the treatment of indolent non-Hodgkin lymphomas. Copanlisib is a PI3Kα and PI3Kδ inhibitor that has been approved for its use as third-line therapy in the treatment of relapsed or refractory follicular lymphoma. The two other PI3k inhibitors approved by the US FDA in this setting are idelalisib and duvelisib. In this review, we compare the efficacy and adverse event profile of these different PI3K inhibitors and discuss the advantages and challenges of using copanlisib along with a guide on managing routinely encountered adverse events in the clinics.

Topics: Biomarkers; Clinical Trials as Topic; Disease Management; Disease Susceptibility; Humans; Hyperglycemia; Hypertension; Lymphoma, Non-Hodgkin; Molecular Targeted Therapy; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Prognosis; Pyrimidines; Quinazolines; Signal Transduction; Treatment Outcome

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.

Topics: Adult; Aged; Aged, 80 and over; Allografts; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Combined Modality Therapy; Diarrhea; Drug Administration Schedule; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Hyperglycemia; Hypertension; Lymphoma, B-Cell; Male; Middle Aged; Multicenter Studies as Topic; Neutropenia; Phosphoinositide-3 Kinase Inhibitors; Progression-Free Survival; Pyrimidines; Quinazolines; Salvage Therapy; Survival Analysis; Transplantation, Autologous; Treatment Outcome