Exploratory biomarker analysis from a phase III study of the PI3K inhibitor, copanlisib, in combination with rituximab in patients with indolent non-Hodgkin lymphoma, a retrospective study.

Purpose: There has been increased difficulty in developing safe and effective treatment using PI3K inhibitors in heme malignancies, despite the role of PI3K/AKT being well defined in this population. This study was an attempt to conduct exploratory biomarker analysis retrospectively from the phase III CHRONOS-3 trial with the aim to identify a sub-set of patients that could benefit from treatment.

Patients and methods: Patients with CD20-positive indolent B-cell lymphoma were randomized 2:1 to receive intravenous copanlisib plus rituximab (C + R) or placebo plus rituximab (P + R). Biomarker analyses were performed to examine potential associations between treatment outcome and phosphatase and tensin homolog (PTEN) protein expression, EZH2 and BCL2 mutation status via next-generation sequencing, and plasma cytokine levels.

Results: PTEN presence was associated with significant improvements in progression-free survival (PFS) for C + R over P + R in patients with iNHL (P = 0.001) and FL (P = 0.012). Both the mutant and wild-type EZH2 FL patients had equal PFS benefits when treated with copanlisib. A significant improvement in PFS was observed for patients with mutant versus wild-type BCL2 FL in the C + R arm (P = 0.002). Overall survival (OS) was significantly improved for patients with iNHL and low or undetectable versus high baseline IL-2 levels in the C + R arm (P < 0.0001, unadjusted).

Conclusions: PTEN presence, BCL2 mutations, and low or undetectable baseline IL-2 levels were associated with improved patient survival following treatment with C + R, supporting a potential role for these biomarkers in guiding treatment selection for patients with indolent non-Hodgkin lymphoma.