On-Target Pharmacodynamic Activity of the PI3K Inhibitor Copanlisib in Paired Biopsies from Patients with Malignant Lymphoma and Advanced Solid Tumors

Abstract

The PI3K inhibitor copanlisib has efficacy and manageable safety in patients with indolent lymphoma and solid tumors. Pharmacodynamic effects relative to copanlisib dose and plasma exposure were evaluated. Patients with lymphoma or solid tumors received copanlisib 0.4 or 0.8 mg/kg on days 1, 8, and 15 of a 28-day cycle. Primary variables were maximum changes in phosphorylated AKT (pAKT) levels in platelet-rich plasma (PRP) and plasma glucose. Other evaluations included PI3K signaling markers and Tlymphocytes in paired tumor biopsies, the relationship between estimated plasma exposure and pharmacodynamic markers, response, and safety. Sixty-three patients received copanlisib. PRP pAKT levels showed sustained reductions from baseline following copanlisib [median inhibition: 0.4 mg/kg, 73.8% (range À94.9 to 144.0); 0.8 mg/kg, 79.6% (range À96.0 to 408.0)]. Tumor pAKT was reduced versus baseline with copanlisib 0.8 mg/kg in paired biopsy samples (P < 0.05). Dose-related transient plasma glucose elevations were observed. Estimated copanlisib plasma exposure significantly correlated with changes in plasma pAKT and glucose metabolism markers. There were two complete responses and six partial responses; seven of eight responders received copanlisib 0.8 mg/kg. Adverse events (all grade) included hyperglycemia (52.4%), fatigue (46.0%), and hypertension (41.3%). Copanlisib demonstrated dosedependent pharmacodynamic evidence of target engagement and PI3K pathway modulation/inhibition in tumor and immune cells. Results support the use of copanlisib 0.8 mg/kg (or flat-dose equivalent of 60 mg) in solid tumors and lymphoma, and provide a biomarker hypothesis for studies of copanlisib combined with immune checkpoint inhibitors (NCT03711058).

Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer

“…The lack of objective responses observed here, despite enrichment for tumor types with RAS-MAPK or PI3K signaling pathway mutations in the expansion cohort, may be partially explained by the MTD of the combination being lower than that of the individual compounds as monotherapy [ 7 , 11 ]. This is consistent with a recent pharmacodynamic study showing that copanlisib 0.4 mg/kg as monotherapy was less active than 0.8 mg/kg [ 33 ]. Further, median duration of treatment was short due to toxicities, likely resulting in insufficient exposure.…”

“…Rash TEAEs were generally mild (grade 1 or 2); although infrequent, rash was among the most common grade 3 TEAEs leading to discontinuation. Hyperglycemia (all-grade, 40.6%) is an on-target effect of PI3K inhibitors and was treatment-related and reversible, similar to copanlisib monotherapy reports [ 8 , 21 , 23 ]. The incidence of hypertension (all-grade, 39.1%) was also consistent with reports of copanlisib monotherapy [ 7 , 8 , 21 ].…”

Single-agent activity of phosphatidylinositol 3-kinase inhibition with copanlisib in patients with molecularly defined relapsed or refractory diffuse large B-cell lymphoma

“…Overall, copanlisib demonstrated a safety profile that was recognizable and manageable. TEAEs most commonly reported were hypertension, diarrhea, and hyperglycemia, consistent with toxicities observed with copanlisib in previous trials [19,20,30]. Hyperglycemia events were generally grade <4.…”

“…However, the majority of hypertension events observed in patients treated with copanlisib were transient, which may be related to acute vasoconstriction resulting from the intravenous infusion of copanlisib [32]. Overall, hyperglycemia and hypertension were transient and considered manageable, with almost all patients reporting values approaching baseline prior to subsequent infusions, consistent with previous pharmacodynamic studies [30].…”

Long‐term safety and efficacy of the PI3K inhibitor copanlisib in patients with relapsed or refractory indolent lymphoma: 2‐year follow‐up of the CHRONOS‐1 study

“…The incidence and severity of hyperglycemia with copanlisib were similar to those reported with the orally administered α‐selective PI3K inhibitor alpelisib . Although hyperglycemia with the latter agent is presumably more prolonged due to daily administration, hyperglycemia observed with copanlisib administered intravenously once weekly is transient and returns to baseline within 24 hours . Interestingly, the incidences of hyperglycemia and hypertension appeared to decrease in later use compared with the earlier time points.…”