Copanlisib was granted a priority review designation by the Food and Drug Administratioin (FDA) for the treatment of patients with relapsed/refractory follicular lymphoma who had at least two therapies beforehand, according to Bayer, the manufacturer of the drug.
The new drug application (NDA) for copanlisib is based primarily on findings from the phase 2 CHRONOS-1 trial, which included patients with multiple types of lymphoma. In the study, 59 percent 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 one year.
Under the priority review program, the FDA will decide on the NDA for copanlisib within six months, compared with the standard 10-month review.
“With this milestone, we are 1 step closer to making copanlisib available in the United States to the community of doctors and patients facing a very difficult-to-treat disease,” Carsten Brunn, Ph.D., head of Bayer Pharmaceuticals, Americas Region, said in a statement. “We look forward to continuing to work with the FDA throughout the review process.”
Copanlisib is an intravenous pan-class I PI3K inhibitor that has predominant activity against the PI3K-alpha and delta isoforms. 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.
Lymphoma subtypes included in the CHRONOS-1 study were follicular lymphoma (grades 1-3a), marginal zone lymphoma, small lymphocytic lymphoma, and lymphoplasmacytic lymphoma (LHL)/Waldenstrom macroglobulinemia (WM). Eligible patients had relapsed or refractory disease and failure of at least two prior lines of therapy.
Patients received copanlisib at 60 mg on days one, eight 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 three prior regimens. All of the patients had prior exposure to Rituxan (rituximab) and one or more alkylating agents, and 60.6 percent had disease that was refractory to the last regimen received.
Across the lymphoma subgroups, 80.3 percent of the patients had advanced disease (stage 3 or 4) at enrollment. Follicular lymphoma was the dominant lymphoma subtype, accounting for 73.2 percent 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 percent of planned copanlisib doses.
All but a few patients had some degree of target lesion shrinkage in response to treatment with copanlisib. Patients with all lymphoma subtypes had lesion shrinkage.
The 59.2 percent overall response rate included complete responses in 12.0 percent of patients and partial responses in 47.2 percent of patients. An additional 29.6 percent of patients had stable disease, resulting in a disease control rate of 85.9 percent. Objective response rates were 59 percent or higher across all lymphoma subtypes except LHL/WM, wherein one of six patients with the subtype achieved an objective response with copanlisib.
The study population had a median PFS of 11.2 months. In the follicular lymphoma subgroup, the median PFS was also 11.2 months.
The most common adverse events (all grades) were hyperglycemia (48.6 percent), hypertension (28.9 percent) and decreased neutrophil count (24.6 percent). Grade 3 hyperglycemia occurred in 33.1 percent of patients and grade 4 in 7.0 percent. Grade 3 hypertension occurred in 22.5 percent. Grade 3 decreased neutrophil count occurred in 6.3 percent and grade 4 in 12.7 percent of the patients. The most common laboratory abnormalities were elevated liver enzymes, which was grade 1/2 in all but a few cases.