Safety, Efficacy and T-Cell Predictive Biomarkers in a Phase I Trial of Copanlisib+Nivolumab in Patients with Richter's Transformation (RT) or Transformed Non-Hodgkin Lymphoma (tNHL)

Background. Despite advances in targeted and cellular therapy, outcomes among patients (pts) with RT and tNHL remain dismal. Copanlisib (COPA) is a selective, small molecule, PI3Kinhibitor which preferentially targets the p110αδ isoforms . COPA has shown clinical efficacy in NHL and is an approved therapy for follicular lymphoma (FL). Nivolumab (NIVO) is a PD-1 antagonist which has demonstrated activity in NHL. Furthermore, combined targeting of PI3K and PD-1 has demonstrated synergy in pre-clinical lymphoma models. Here we report results of a phase 1 study of COPA in combination with NIVO in pts with R/R RT or tNHL (NCT03884998) and correlate response to treatment and T cell functionality in RT.

Methods. This ongoing multicenter, open-label, phase I, investigator-sponsored study is enrolling pts with RT or tNHL, age ≥18 years, whose disease has relapsed or was refractory to ≥1 prior line of therapy. The phase I portion of the study follows a standard 3+3 design, followed by a dose expansion of 16 evaluable pts, with two planned dose levels of COPA administered IV (dose level [DL]1 - 45 mg on days 1, 8 and 15 and DL2 - 60 mg on days 1, 8 and 15 of a 28-day cycle). NIVO 240 mg is given IV on days 1 and 15. Pts receive up to 24 cycles of therapy. Dose limiting toxicities (DLT) were defined as grade ≥4 hematologic lasting > 7 days or grade ≥3 non-hematologic toxicities. The primary study objective is to evaluate the maximum tolerated dose (MTD) of the combination; secondary objectives are preliminary efficacy by Lugano criteria. Exploratory objectives include T-cell functionality assessed by flow cytometry analysis of cell subsets as well as scRNA-Seq performed on biospecimens banked from pts pre-treatment, after cycles 1 and 5, and at the end of treatment.

Results. The study enrolled 25 pts to date, 11 in dose finding (8 at DL1 and 3 at DL2) and 14 in dose expansion cohorts. Fourteen pts had RT and 11 had tNHL (10 tFL and 1 transformed lymphoplasmacytic lymphoma). Median (med) age was 65 years (32-77), 88% (22/25) had ECOG performance status 0-1. Pts had received a med of 4 prior lines of therapy (range, 1-10); 8 pts (2 RT, 6 tNHL) had CAR T cells. During dose finding, 8 pts were treated at DL1 (45 mg COPA), of which 2 pts did not complete the DLT period due to rapidly progressive disease and were replaced. No DLTs were observed in 6 evaluable pts at DL1. At DL2 (60 mg COPA), three DLTs (neutropenia, thrombocytopenia) occurred in 2 pts determining the MTD of COPA to be 45 mg. After a median follow-up of 14 months (range 1.8-20.6), the most common treatment-related adverse events (AEs, any grade) were diarrhea and anemia (Table 1). Twenty-three pts went off protocol after a med of 3 cycles (range 1-20); 2 remain on treatment. Sixteen pts discontinued therapy due to progressive disease and 6 due to AEs. Among the 23 efficacy-evaluable pts who completed at least one cycle of therapy, 10 pts achieved a response (ORR 43%). Pts with tFL had an ORR of 60% (2 CR and 4 PR) with median progression free survival (mPFS) 4.8 months (95%CI: 0.4-16.8) and median duration of response (mDOR) 10.2 months (95%CI: 2.0-13.6) (Figure 1). Pts with RT had an ORR of 33% (2 CR and 2 PR) with mPFS 2.0 months (95%CI: 0.7-4.9) and mDOR not reached (95%CI: 3.0-NA).

Analysis of paired samples from pts using flow cytometry and scRNA-Seq demonstrated an increase in circulating CD8+ T cell population and a decrease in exhaustion markers (PD1, CTLA-4) after exposure to COPA/NIVO. Analysis of 2 responding RT pts by scRNA-Seq demonstrated downregulation of MYC in tumor cells and upregulation of IFN response in T cells. This pattern was not observed 3 RT non-responders (NRs). By contrast, CD8+ effector T-cells from NRs exhibited downmodulation of the IFN response after cycle 1 of treatment and concurrent activation of p53-regulated genes and apoptotic genes. Tregs sourced from RT responders showed enhanced expression of apoptosis pathways after treatment, while these pathways were downregulated in NR Tregs.

Discussion. We identified COPA 45 mg IV on days 1, 8 and 15 as the MTD/RP2D in combination with NIVO in pts with R/R RT and tFL. This combination was generally well-tolerated and had activity, particularly in pts with with tFL. We observed key differences in gene expression patterns in T cell subsets between the responders and NRs. Downregulation of MYC in the tumor, activation of the apoptotic program in Tregs and enhanced CD8 T-cell IFN response were associated with treatment response in RT. Accrual is ongoing.