PI3K Inhibitor Copanlisib Active in Relapsed/Refractory Lymphoma

Martin Dreyling, MD, PhD

A majority of patients with relapsed or refractory indolent lymphoma responded to treatment with the PI3K dual-isoform inhibitor copanlisib, according to results from the phase II CHRONOS-1 trial.

Across subgroups representing multiple types of lymphoma, 59% of patients achieved objective responses to the intravenous inhibitor of PI3K-alpha and delta. Responses were durable, and the median progression-free survival (PFS) approached 1 year.

Treatment was associated with low rates of severe transaminase elevation and gastrointestinal effects, as reported at the 2017 AACR annual meeting.

“Copanlisib demonstrated significant efficacy, and the safety profile was manageable and distinct, compared with that of oral PI3K inhibitors, possibly due to the intermittent schedule and intravenous route of administration,” said Martin Dreyling, MD, PhD, head of the lymphoma program at University Hospital — Grosshadern in Munich, Germany.

“The favorable risk-benefit profile observed supports the use of copanlisib in relapsed or refractory indolent lymphoma. Current phase III studies are investigating copanlisib in combination with rituximab and with R-CHOP chemotherapy.”

Investigation of strategies targeting BCR and PI3K led to the development of the oral PI3K delta isoform-selective inhibitor idelalisib (Zydelig) for chronic lymphocytic leukemia, follicular lymphoma, and small lymphocytic lymphoma (SLL). In the United States, idelalisib prescribing information includes a black-box warning about a risk of severe or fatal diarrhea, colitis, hepatotoxicity, pneumonitis, and intestinal perforation. Additionally, reported high rates of serious adverse events led to early termination of some clinical trials involving idelalisib in combination with other therapies (Expert Rev Anticancer Ther. 2017;17:271-279).

Copanlisib is an intravenous pan-class I PI3K inhibitor that has predominant activity against the PI3K-alpha and delta isoforms. Dreyling explained that the alpha isoform is broadly expressed and involved in insulin signaling and angiogenesis, as well as resistance mechanisms to lymphoma. The delta isoform is expressed by leukocytes and is involved in B-cell signaling, development, and survival.

In phase I/II trials, copanlisib demonstrated clinical activity and a manageable safety profile in patients with various subtypes of heavily pretreated relapsed/refractory indolent lymphoma. Dreyling reported findings from a follow-up pivotal phase II trial to evaluate copanlisib in a larger population of patients with relapsed/refractory indolent lymphoma.

Lymphoma subtypes included in the study were follicular (grades 1-3a), marginal zone, SLL, and lymphoplasmacytic lymphoma (LHL)/Waldenstrom macroglobulinemia (WM). Eligible patients had relapsed or refractory disease and failure of at least 2 prior lines of therapy.

Patients received copanlisib at 60 mg on days 1, 8, and 15, repeated every 28 days until disease progression or development of unacceptable toxicity. The primary endpoint was objective response by central review after a minimum of 16 weeks of treatment. Secondary endpoints included PFS, duration of response, overall survival, safety, and quality of life.

Data analysis included 142 patients who had a median age of 63. The median time since the most recent disease progression was 8.3 months, and the study population had received a median of 3 prior regimens. All of the patients had prior exposure to rituximab and one or more alkylating agents, and 60.6% had disease that was refractory to the last regimen received.

Dreyling said 80.3% of the patients had advanced disease (stage III or IV) at enrollment. Follicular lymphoma was the dominant lymphoma subtype, accounting for 73.2% of the study population.

Patients remained on treatment for a median duration of 22 weeks, during which time they received a median of 5.5 cycles of therapy and 96% of planned copanlisib doses.

All but a few patients had some degree of target lesion shrinkage in response to treatment with copanlisib, said Dreyling. Patients with all lymphoma subtypes had lesion shrinkage.

The 59.2% overall response rate included complete responses in 12.0% of patients and partial responses in 47.2% of patients. An additional 29.6% of patients had stable disease, resulting in a disease control rate of 85.9%. Objective response rates were 59% or higher across all lymphoma subtypes except LHL/WM, wherein 1 of 6 patients with the subtype achieved an objective response with copanlisib.

The study population had a median PFS of 11.2 months (95% CI, 8.1-24.2). In the follicular lymphoma subgroup, the median PFS was also 11.2 months.

The most common adverse events (all grades) were hyperglycemia (48.6%), hypertension (28.9%), and decreased neutrophil count (24.6%). Grade 3 hyperglycemia occurred in 33.1% of patients and grade 4 in 7.0%. Grade 3 hypertension occurred in 22.5%. Grade 3 decreased neutrophil count occurred in 6.3% and grade 4 in 12.7% of the patients. The most common laboratory abnormalities were elevated liver enzymes, which was grade 1/2 in all but a few cases.

Dreyling M, Santoro A, Mollica L, et al. Copanlisib in patients with relapsed or refractory indolent B-cell lymphoma: primary results of the pivotal CHRONOS-1 study. Presented at: 2017 AACR Annual Meeting; April 1-5, 2017; San Washington, DC. Abstract CT149.

The B-cell receptor (BCR) PI3K signaling pathways have a key role in the evolution and progression of indolent lymphomas. The understanding provided a rationale for targeted inhibition of the pathways as a treatment strategy for relapsed/refractory indolent B-cell lymphomas, said Dreyling.