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BTK and PI3K inhibition produced responses but unexpected PK data in relapsed/refractory PCNSL.
Treatment with the BTK inhibitor ibrutinib (Imbruvica) in concurrent or sequential combination with the PI3K inhibitor copanlisib (Aliqopa) generated responses in patients with primary central nervous system lymphoma (PCNSL), according to data from a first-in-human phase 1b study (NCT03581942) presented at the 2025 Society of Neuro-Oncology (SNO) Annual Meeting.1
However, the study was terminated early following the 2023 voluntary removal of copanlisib from the United States market.2 The agent was previously indicated for the treatment of patients with relapsed follicular lymphoma who have previously received at least 2 prior systemic treatments. Despite the trial’s termination, lead study author Lauren Schaff, MD, argued that the results of the phase 1b study highlighted the potential for combination BTK and PI3K inhibition in the PCNSL population.1
Results presented at SNO showed that patients who received both ibrutinib and copanlisib (n = 18)—either as sequential dosing (n = 4) or concurrent administration (n = 14)—achieved an overall response rate (ORR) of 56%. More specifically, patients who received the drug combination on concurrently achieved an ORR of 57%, whereas patients who were sequentially dosed achieved an ORR of 50%.
Pharmacokinetics (PK) for ibrutinib and copanlisib were also monitored throughout the study. Findings indicated that patients treated sequentially had higher levels of ibrutinib plasma concentration vs those who were concurrently dosed. In patients treated concurrently, copanlisib concentrations in the cerebral spinal fluid (CSF) and plasma exceeded the known half-maximal inhibitory concentration for the agent; however, concentrations for ibrutinib were below expected, prompting researchers to implement sequential dosing for patients.
“The real take-home point of this [study] is the importance of PK monitoring for first-in-human studies. There is no expected drug:drug interaction between these two compounds, [with] nothing expected by us and nothing expected by pharmaceutical companies. [The drug:drug interactions in this study] were quite surprising. PI3K inhibitors in combination with BTK inhibitors remains a compelling strategy but requires novel PI3K inhibitors and close monitoring,” said Schaff, who is a neurologist, neuro-oncologist, and associate director of the Neuro-Oncology Fellowship Program at Memorial Sloan Kettering Cancer Center.
BTK inhibitor monotherapy has demonstrated the ability to drive high rates of radiographic response in patients with PCNSL, Schaff explained; however, this strategy has been associated with short progression-free survival (PFS). She also explained that, along with activation of B-cell receptor signaling pathway mediated by BTK, PCSNL appears to rely on activation of PI3K. Hence, combining BTK inhibitors with PI3K inhibitors might serve as a more well-rounded treatment suited for patients with PCNSL.
The dose-escalation phase 1b trial was the first to evaluate the combination of ibrutinib and copanlisib. Investigators enrolled patients who were at least 18 years of age with histologically documented PCNSL who had an ECOG performance status of 2 or less, a life expectancy of 3 months or longer, adequate bone marrow and organ function, and recovery to grade 1 toxicity from prior therapy.3 At least 1 prior CNS-directed therapy was required for patients with relapsed/refractory disease.
If patients had active concurrent malignancies that required active therapy, were newly diagnosed patients with PCNSL who qualified for standard methotrexate-based chemotherapy, or had clinically significant cardiovascular disease, they were not included in the trial.
The concurrent arm featured a 3+3 design with 2 dose levels. At dose level 1, patients received 560 mg of ibrutinib daily plus 60 mg of copanlisib intravenously on days 1, 8 and 15 of each 28-day cycle.1 The second dose level evaluated ibrutinib at 840 mg per day plus the same copanlisib dosing and schedule. Patients who received sequential dosing of the drug combination also received 840 mg of ibrutinib daily in cycle 1, then 60 mg of copanlisib on days 1, 8 and 15 of cycles 2 and 3, and this sequence was reported every 3 cycles.
ORR and determining the maximum tolerated dose of the combination served as the trial’s primary end points. Secondary end points included safety/tolerability, PFS, duration of response (DOR), overall survival (OS), and PK data.
Patients from the trial had a median age of 63 years (range, 40-80), a median ECOG performance status of 1, and a median number of prior regimens of 2 (range, 1-10). Moreover, 61% of patients were treatment refractory, and 33% had received prior ibrutinib.
Additional data showed that the median PFS was 2.93 months for patients who received ibrutinib and copanlisib concurrently and 3.65 months for patients who received sequential dosing (P = .8048). Data for other secondary end points like OS and DOR were not reported.
In terms of safety and tolerability, 1 patient experienced grade 5 PCP pneumonia, which led to the implementation of PCP prophylaxis. Eight non–dose limiting toxicity grade 4 adverse effects (AEs) were reported, including increased alanine aminotransferase levels (11%), increased absolute lymphocyte count (11%), increase aspartate aminotransferase levels (6%), decreased absolute neutrophil count (6%), decreased white blood cell count (6%), and rash (6%).
Hyperglycemia, decreased absolute neutrophil count, rash, and nausea were amongst some of the most common AEs reported in the study. One patient experienced grade 2 aspergillosis.
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