Lauren Shaff, MD, is a neuro-oncologist and associate director of the Neuro-Oncology Fellowship Program at Memorial Sloan Kettering Cancer Center.

Dr Schaff on a Phase 1 Study of Copanlisib Plus Ibrutinib in Relapsed/Refractory PCNSL

"[When] we analyzed pharmacokinetics…we realized that…there was an apparent drug-drug interaction driving down the concentrations of ibrutinib. For that reason, we actually redesigned the study to [feature] sequential rather than concurrent dosing of copanlisib and ibrutinib.”

Lauren Shaff, MD, a neuro-oncologist and associate director of the Neuro-Oncology Fellowship Program at Memorial Sloan Kettering Cancer Center, shared findings from a phase 1 trial evaluating the pan PI3K inhibitor copanlisib (Aliqopa) in combination with the BTK inhibitor ibrutinib (Imbruvica) in relapsed or refractory primary CNS lymphoma, and what they indicate about the viability of combining BTK and PI3K inhibitors for this disease. 

Findings presented at the 2025 Society for Neuro-Oncology Annual Meeting demostrated that the combination was considered fairly well tolerated, Shaff reported. The most common adverse effect (AE) was hyperglycemia, typically categorized as grade 1 or grade 2. However, one grade 5 AE of PCP pneumonia occurred, prompting an amendment to the protocol to require PCP prophylaxis. No subsequent patients developed PCP pneumonia after this prophylaxis was introduced.

A critical issue arose during pharmacokinetic analysis of the serum and cerebral spinal fluid (CSF). Although copanlisib concentrations were on par with expectations, ibrutinib concentrations were found to be substantially lower than anticipated based on prior single-agent studies, and ibrutinib was nearly undetected in the CSF, Schaff noted. Schaff and her fellow investigators accordingly realized that an apparent drug-drug interaction was the culprit for the reduced concentration of ibrutinib. Consequently, the study was redesigned from concurrent dosing to sequential dosing: patients received one cycle of daily ibrutinib, followed by 2 cycles of weekly copanlisib, with the regimen repeating every 3 cycles, she explained

The trial ultimately enrolled 18 patients, 14 of whom received concurrent treatment and 4 who were administered sequential treatment, Shaff detailed. The overall radiographic response rate was 56%, and the sequentially dosed group achieved a 50% response rate, she stated. Radiographic response appeared to correlate positively with drug concentration. However, the study was terminated early due to 

 from the United States market by the drug’s developer, halting further development, Schaff noted.

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 TEAEs, including decreased neutrophil count (14.3%) and decreased platelet count (28.6%). Crucially, no patients discontinued treatment due to TEAEs, and all patients completed the DLT evaluation.

Accordingly, the recommended combinatory dose (RCD) was established as 40 mg of vorasidenib administered daily, combined with a standard dose of temozolomide, de la Fuente shared. This dose combination is currently being evaluated in the phase 2 portion of the study. Researchers expressed excitement over the safety profile, as this is the first time this specific combination has been studied in 

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Lauren Shaff, MD, contextualizes results from a phase 1 study evaluating copanlisib plus ibrutinib in relapsed/refractory primary and secondary CNS lymphoma.




Lauren Shaff, MD

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Dr Schaff on a Phase 1 Study of Copanlisib Plus Ibrutinib in Relapsed/Refractory PCNSL