Abstract
Despite advances in targeted and cellular therapies, outcomes for patients with Richter's transformation (RT) and transformed non-Hodgkin lymphoma (tNHL) remain dismal. In this report of a phase I multicenter investigator-sponsored study we describe the safety and efficacy of the combination of copanlisib, a selective, small molecule inhibitor of phosphoinositide- 3-kinase, and nivolumab, an antibody against programmed cell death protein 1. Twenty-seven adult patients with relapsed and/or refractory RT or tNHL were treated with escalating doses of copanlisib IV on days 1, 8, and 15 (dose level [DL] 1 - 45 mg, DL2 - 60 mg) combined with nivolumab 240 mg IV on days 1 and 15 of a 28-day cycle. Three dose-limiting toxicities occurred in two patients treated at DL2, hence 45 mg was determined to be the maximum tolerated dose and utilized in the expansion cohort. The most common treatment-related adverse events were diarrhea and anemia. All patients went off protocol, predominantly because of progressive disease and adverse events (67% and 26% of patients, respectively). The overall response rate (ORR) was 46%. Patients with transformed follicular lymphoma had an ORR of 67% (2 complete responses), with median progression-free survival of 4.4 months (95% confidence interval: 1.4-12.2). Patients with RT had an ORR of 31% (2 complete responses) with a median progression-free survival of 2.0 months (95% confidence interval: 0.7- 4.9). Treatment resulted in downregulation of MYC and NFκB pathways in malignant B cells. Responding RT patients exhibited sustained activation of interferon-α and interferon-γ signaling pathways in CD4+ and CD8+ T cells. Overall, treatment with copanlisib and nivolumab demonstrated manageable toxicity and promising clinical efficacy in tNHL patients.