Copanlisib Lymphoma Data Updated as FDA Considers Approval

Copanlisib showed an objective response rate of 59.2% without inducing major colitis events or elevation of hepatic transaminases in patients with relapsed or refractory indolent B-cell lymphoma.

Martin Dreyling, MD, PhD

Copanlisib showed an objective response rate (ORR) of 59.2% (95% CI, 50.6%-67.3%) without inducing major colitis events or elevation of hepatic transaminases in patients with relapsed or refractory indolent B-cell lymphoma, according to findings from the pivotal CHRONOS-1 study presented at the 2017 International Conference on Malignant Lymphoma (ICML) biennial meeting in Lugano, Switzerland.

A cohort of 142 patients with diverse B-cell lymphoma demonstrated the clinical activity of copanlisib, which targets PI3K alpha and delta. The ORR comprised 17 patients (12%) with complete response (CR) and 67 patients (47.2%) showing partial response (PR). Stable disease (SD) was attained by 42 patients (29.6%), and just 3 patients (2.1%) experienced progressive disease (PD). The disease control rate (ORR plus SD) was 85.9% (95% CI, 79.1%-91.2%).

The median duration of response (DoR) was 22.6 months with copanlisib (range, 0-22.6 months; 95% CI, 7.4-22.6). The median progression-free survival (PFS) was 11.2 months (95% CI, 8.1-24.2) and median overall survival (OS) was not yet reached.

“The favorable risk—benefit profile supports the use of copanlisib in relapsed or refractory indolent lymphoma,” commented lead investigator Martin Dreyling, MD, PhD, of the Medizinische Klinik und Poliklinik III, Klinikum der Universität München-Grosshadern, in Munich, Germany.

In May 2017, the FDA granted a priority review designation to copanlisib as a treatment for patients with relapsed/refractory follicular lymphoma who have received at 2 least prior therapies. This priority review designation was based on findings from the phase II CHRONOS-1 trial. The FDA is scheduled to decide on the application before the end of the year.

The CHRONOS trial enrolled 212 patients with indolent B-cell lymphoma who had failed at least 2 prior lines of therapy. Of the enrolled patients, 70 had screening failure and 142 patients were treated with intravenous copanlisib at 60 mg intermittently administered on days 1, 8, and 15 of a 28-day cycle. The primary efficacy endpoint was ORR by central review and secondary endpoints included PFS, DoR, OS, safety, and quality of life.

The treatment group was 50% male with a median age of 63 years (range, 25-82) and the median number of prior treatments was 3 (range, 2-9). Most patients (80.3%) had advanced stage III or IV disease at study entry. The subtypes of lymphoma included follicular lymphoma grades 1 to 3a (n = 104), marginal zone lymphoma (MZL; n = 23), small lymphocytic lymphoma (SLL; n = 8), and lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia (LPL/WM; n = 6).

The ORR was 58.7% for those with follicular lymphoma, which included a 14.4% CR rate. The ORR was 69.6% for those with MZL, 75.0% in the SLL group, and 16.7% for those with LPL/WM. Overall, 91% of patients had some level of tumor shrinkage. DoR was 12.2 months in refractory patients (range, 0-22.6 months; 95% CI, 7.4-22.6) and 12.2 months in patients with follicular lymphoma (range, 0-22.6 months; 95% CI, 6.9-22.6).

Tumor tissue obtained from patients was used for mRNA extraction and gene expression profiling, which revealed that PI3K and B cell receptor (BCR) pathway gene expression was associated with the copanlisib response (P = .0009 for PI3K and P = .035 for BCR). “The response rates with copanlisib associated to expression of PI3K / BCR signaling genes,” Dreyling noted. This is under further exploration, specifically the role of PI3KCA mutation/amplifications.

The median duration of treatment with copanlisib was 22 weeks (range, 1-105 weeks) at the time of analysis, with 46 patients remaining on treatment. Copanlisib was discontinued by 96 patients (67.7%) in the study, which was due to an adverse event (AE; 24.6%), progressive disease (radiologic or clinical; 25.3%), patient withdrawal (11.3%), physician decision (3.5%), and other reasons (3.5%)

The most common treatment-related all grade AEs were hyperglycemia in 45.5% and hypertension in 28.9% of patients. Grades 3/4 AEs included hyperglycemia (33.1%/7.0%), hypertension (22.5%/0%), decreased neutrophil count (6.3%/12.7%), lung infection (9.2%/1.4%), and decreased platelet count (3.5%/0.7%).

Treatment-related AEs of special interest included non-infectious pneumonitis and colitis; 2 patients had grade 3 pneumonitis and 1 patient had grade 4 colitis. Three deaths were attributed to copanlisib that included lung infection, respiratory failure, and a thromboembolic event each occurring in 1 patient.

“It is important to note the low rates of severe diarrhea, pneumonitis, and colitis with copanlisib, which may be due in part to the drug design and partly due to the intermittent dosing schedule and IV administration,” said Dreyling. He explained that the oral PI3K inhibitor idelalisib, which is FDA-approved as third-line treatment in follicular lymphoma, has a black box warning for fatal or severe diarrhea or colitis, hepatotoxicity, pneumonitis, and intestinal perforation. “Recently a high incidence of these idelalisib-associated adverse events has led to early termination of a number of clinical trials,” he added.

The phase III CHRONOS-3 trial is exploring copanlisib in combination with rituximab (Rituxan) for patients with B-cell non-Hodgkin lymphoma. The study plans to enroll 567 patients randomized to rituximab plus placebo or copanlisib. The primary endpoint of the study is PFS (NCT02367040). Other studies are also currently enrolling participants, Dreyling pointed out. “Phase III studies of copanlisib in combination with rituximab and R-CHOP or rituximab plus bendamustine are underway,” he added.

Dreyling M, Santoro A, Mollica L, et al. Copanlisib in patients with relapsed or refractory indolent B-cell lymphoma (CHRONOS-1). Presented at: 14th International Conference on Malignant Lymphoma; June 14-17, 2017; Lugano, Switzerland. Abstract 108. doi:10.1002/hon.2437_107.

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