Abstract
Introduction Chemoimmunotherapy with R-CHOP is an established standard of care for diffuse large B-cell lymphoma (DLBCL) but is not curative in all patients (pts). Approximately 20% of DLBCL have aberrations involving the PD-L1/PD-L2 locus. This justifies the investigation of PD-1 checkpoint inhibitors in pts with DLBCL. This Phase 1b study was conducted to determine the maximum tolerated dose (MTD) for nivolumab in combination with R-CHOP in pts with DLBCL and to evaluate the preliminary efficacy of the regimen. Methods Patients with newly diagnosed de novo DLBCL or transformed low-grade lymphoma (tLL) were enrolled from 2019-2022. Treatment comprised a lead-in phase (LIP) with nivolumab 240 mg x 1 followed 2 weeks later by combination nivolumab-R-CHOP given every 3 weeks for 6 cycles. For combination therapy, nivolumab was administered on Day 1 followed by R-CHOP on Days 1-5 (Days 2-6 for Cycle 1). To establish MTD with Phase 1, nivolumab dosing followed a modified 3+3 dose escalation, starting with 1 mg/kg (dose level 1), escalating to 240 mg (dose level 2). MTD was administered for the Phase Ib portion of the study. Primary endpoints were determination of MTD and rate of complete metabolic response (CMR) by PET/CT using Lugano 2014 as best response by completion of 6 cycles of combination therapy (EOT). Correlations of immune subsets with durability of response and toxicity were exploratory. Results Thirty-three patients were enrolled, of which 25 and 22 pts were evaluable for toxicity and efficacy, respectively. The majority were men (n=21, 64%), White (n=26, 79%) with ECOG performance status of 0-1 (n=30, 91%). Twenty-seven (82%) had advanced stage and/or intermediate/high risk IPI score and 20 (65%) had germinal center subtype. Fifteen (45%) and 16 (48.5%) had tLL (2 with prior therapy for LL prior to transformation) and MYC aberrancy (13 with gains; 2 with single-hit and 1 with double-hit rearrangements), respectively. A dose of 240 mg of nivolumab was established as MTD. Twenty of 22 (91%) achieved CMR and 2 partial metabolic response (PMR) by EOT with overall response in 100%. One pt died from COVID-19 after 4 cycles but was in CMR on interim imaging. With median follow-up of 12 months (mo), 4 pts had progression. Both pts with PMR by EOT have not relapsed. Estimated 18-mo OS & PFS were 95.4% & 71.6%, respectively. Correlation of PFS with PD-L1 expression is underway. Most common therapy-related adverse events (TRAEs) attributed to nivolumab-R-CHOP were fatigue in 22 (88%), HTN in 21 (84%), lymphopenia in 21 (84%), and neutropenia in 18 (72%). High-grade (grade 3/4) neutropenia occurred in 15 (60%) with growth factor use per discretion of treating physician. Fifteen (60%) pts had infections, 47% high-grade. Immunotoxicities (IT) were the most common TRAEs attributed to nivolumab in 18 pts (72%), including thyroiditis (n=5, 20%), dermatitis (n=4, 16%), hepatitis (n=3, 12%), and infusion reactions (n=3, 12%). Most common high-grade IT: 1 case each of colitis, hepatitis, myocarditis (discontinued nivolumab), and dermatitis (discontinued nivolumab). For biologic correlates (Figures 1 & 2): non-progressors (NP) were enriched for T regulatory cell (e.g., IFN-γ producing CD4+Foxp3+ phenotype) fragility while progressors (PD) were enriched for exhausted T cell immunophenotype (CD4+PD-1+CD39+) prior to both LIP and initiation of combination therapy (C1D1). Furthermore, exhausted-like T cell levels were significantly reduced at C1D1 in comparison to LIP in NP but not PD. Toxicities correlated to less exhausted-like effector T cell phenotype, decreased CD4+ naïve and central memory T cells, and increased circulating B cells and myeloid-derived suppressor cells. Conclusions This study demonstrates promising efficacy of frontline combination nivolumab-R-CHOP for high-risk DLBCL including pts with intermediate/high risk IPI, tLL, and MYC aberrancy. While limited by small sample size, this regimen resulted in response, PFS, and OS rates above historical rates reported in high-risk pts and provides basis for further evaluation of nivolumab-based therapies in such pts. We found correlations between progression, toxicity and specific immune subset populations. Attention to these biologic correlates as predictors of durable response and toxicity may allow for better patient selection to optimize benefits of therapeutic effect and risks of increased toxicity with nivolumab-based therapies in DLBCL.
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