Nivolumab in Combination with Dose Adjusted (DA) R-EPOCH for First-Line Treatment of Large B-Cell Lymphoma: Results from a Phase II Trial

Background:

Improving outcomes with frontline treatment remains a priority for large B-cell lymphoma (LBCL). Dose adjusted (DA) R-EPOCH is commonly used as frontline therapy in specific sub-groups including double hit lymphoma (DHL) and primary mediastinal B-cell lymphoma (PMBCL). PD-1 inhibitors have modest single agent activity in relapsed LBCL, though their use frontline may better harness immune response and improve immunogenicity of chemo-immunotherapy. We report the primary analysis of a phase 2 study of nivolumab (Nivo) in combination with DA R-EPOCH in LBCL (NCT03749018).

Methods:

Eligible patients were age ≥ 18 years, untreated or had one cycle of standard therapy, with an eligible LBCL subtype including DHL, PMBCL, LBCL with increased MYC and BCL2 expression (DEL), or LBCL with Ki67 index ≥ 80%. Treatment included Nivo 3 mg/kg IV day 1 followed by DA R-EPOCH dosed as previously described (Wilson et al, JCO 2008) for 6 cycles followed by 6 cycles of Nivo 480 mg IV consolidation dosed day 1 of 28-day cycles in responding patients. Responses were assessed by PET per Lugano criteria after cycle 4 and 6 of induction and at end of consolidation. Plasma was collected at baseline, after cycles 2 and 6, and serially during consolidation for purposes of circulating tumor (ct) DNA analysis. ctDNA was quantified and tracked using the ClonoSeq assay by Adaptive Biotechnologies. The primary endpoint was 2-year progression free survival (PFS), measured from treatment start to progression or death and estimated through the Kaplan-Meier method. Target accrual was 30 patients with primary analysis to be performed after 13 progression events were observed, however due to a lower than anticipated number of progression events, the study was amended to analyze the primary endpoint over 2 years after the final patient enrolled. Data were downloaded for analysis July 16, 2024.

Results:

From May 17, 2019, to June 15, 2022, a total of 30 patients were enrolled. 21 were male, median age was 58 (20-76), median diagnosis to treatment interval 17 days (7-41), 22 patients (73%) were stage 3/4, IPI risk score was 0-1 in 8 (27%), 2 in 6 (7%), 3 in 8 (10%), and 4-5 in 8 (27%). LBCL subtypes included DHL 13, PMBCL 9, DEL 4, and LBCL with Ki67 > 80% in 4.

In total 21 patients completed treatment; treatment discontinuation occurred due to adverse events (AEs) in 4 patients (during induction in 2 and during maintenance in 2), progressive disease (PD) in 3 patients, and for other reasons in 2 patients. There were no deaths on treatment. The highest dose level (DL) achieved was DL 1 in 4 patients (13%), DL 2 in 8 patients (27%), DL 3 in 11 patients (37%), DL 4 in 6 patients (20%), and DL 5 in 1 patient (3%).

Of 30 patients, 29 were evaluable for response, with 1 patient not evaluable due to treatment discontinuation due to AEs. The best response was complete response (CR) in 24 patients (80%), partial response (PR) in 2 patients (7%), and PD in 3 patients (10%). After a median follow-up of 36 months, the median PFS was not reached with a 2-year PFS of 83% (95% CI 65-93%). Among patients with DHL the 2-year PFS was 77%, and among patients with PMBCL the 2-year PFS was 100%. ctDNA analysis is underway and results will be presented at the meeting.

The most common treatment associated AEs of any grade included neuropathy in 19 patients (63%), mucositis in 18 patients (60%), fatigue in 16 patients (53%), nausea in 11 patients (37%), constipation in 10 patients (33%), and rash in 7 patients (23%). Grade ≥ 3 AEs included febrile neutropenia in 7 patients (23%), mucositis in 4 patients (13%), lung infection in 4 patients (13%), infection, other in 2 patients (7%), diarrhea (attributed to Nivo) in 1 patient (3%), and glucose intolerance (new immune mediated DM with ketoacidosis) in 1 patient (3%). Other immune-related AEs (irAEs) included Grade 2 colitis in 1 patient and hyperthyroidism in 2 patients.

Conclusions: The combination of Nivo + DA R-EPOCH demonstrated a high rate of durable PFS as frontline treatment for specific subgroups of patients with LBCL, including high risk populations. Promising results were observed in patients with PMBCL and DHL, supporting further study. While irAEs were observed consistent with the known Nivo safety profile, Nivo + DA R-EPOCH was feasible at standard dosing.