Dose Optimization of Check-Point Inhibitors: A Comparison of Standard Dose and Low Dose Nivolumab in Relapsed/Refractory Hodgkin Lymphoma
Authors: Trivedi Chirag , Kumar Sujith , Selvarajan Sushil , Lionel Sharon Anbumalar , Devasia Anup J , N. Fouzia , Kulkarni Uday , Abraham Aby , Srivastava Alok , George Biju , Mathews Vikram , Korula Anu 
Published: December 2024

Context: Immune check-point inhibitors are highly effective in the treatment of Hodgkin lymphoma (HL) following relapse after stem cell transplant (SCT), in disease refractory to Brentuximab and in upfront therapy of advanced stage disease. At the approved dose of nivolumab, the cost of therapy makes it beyond the reach of the vast majority of patients in lower- and middle-income countries. The lack of a dose-response relationship in Phase I trials suggest that lower doses are equally effective, allowing for effective therapy at lower doses, with significant cost benefits. The use of nivolumab at lower than approved doses is gaining traction, especially in places where medical costs are borne as out-of-pocket expense. There is however a paucity of data comparing different dosing regimens using PD-1 inhibitors.

Objective: The objective of this analysis is to compare treatment outcomes in relapsed/refractory HL with nivolumab at standard dose (3mg/kg) versus low dose (flat dose of 40mg).

Methodology: A single-center retrospective analysis of patients with primary progressive/relapsed refractory HL who failed at least 1 salvage regimen and were treated with nivolumab from 2015-2023. From 2015-2019, nivolumab was given at a dose of 3mg/kg rounded to nearest vial size (standard dose (SD)) every 2 weeks. From 2020-2023, nivolumab was given at a flat dose of 40mg every 2 weeks (low dose (LD)). Nivolumab was used as either monotherapy or in combination with lenalidomide (10mg 21/28).

Treatment response was assessed with F-18 FDG-PET-CT after 4 doses of nivolumab, using the Deauville score (DS) and LYRIC criteria (where applicable). Complete response (CR) was defined as a DS of 1-3, partial response (PR) as a DS of 4 and stable disease (SD)/progressive disease (PD) as a DS of 5a and 5b respectively.

Baseline characteristics and treatment outcomes were compared using the Mann-Whitney test, t test, and Fisher's exact tests, as applicable. Progression-free survival (PFS) was calculated using Kaplan-Meier survival curves and the log-rank test. A two-sided p value of &lt;0.05 was considered significant for all tests.

Results: A total of 45 patients with HL were treated with nivolumab, of whom 25 patients (16 relapse, 9 primary progressive) received SD nivolumab at 3mg/kg, and 20 patients (6 relapse, 14 primary progressive) received LD nivolumab at a flat dose of 40mg. The median age was 27 years (range 16-67) in the SD group and 28 years (range 18-64) in the LD group (p=0.776). The mean patient weight was similar in both groups - SD group 61.8kg (S.D 14.8); LD group 62kg (S.D 11.2) (p=0.960). The mean dose delivered was 2.9mg/kg (SD 0.31) in the SD group versus 0.6mg/kg (SD 0.10) in the LD group (p&lt;0.001). Lenalidomide was used in combination with nivolumab in 84% versus 50% of patients in the SD and LD groups (p=0.02). Baseline characteristics and treatment outcomes are shown in Table 1.

Treatment response after 4 doses of nivolumab were similar in the SD versus LD group: CR (48% vs 50%), PR (12% vs 10%), SD (20% vs 20%), PD (20% vs 20%) (p=0.997). ORR (CR+PR) was 60% in both groups (15/25 in SD and 12/20 in LD), and all patients with CR/PR were considered eligible for SCT. Treatment responses (ORR) were similar with (58.1%) and without (64.3%) the use of lenalidomide (p=0.753). Immune-related adverse effects were similar in the SD and LD groups (12% vs 10%; p=0.790).

The 2-year PFS in all patients treated with nivolumab at SD and LD was 47% and 49.5% respectively (p=0.788). 22 out of 45 patients underwent SCT (11 from each group), and in transplanted patients the 2-year PFS was 77.5% versus 81.5% in the SD and LD groups respectively (p=0.975) with median follow-up 28 and 23 months respectively. Reasons for not undergoing SCT were disease progression (n=18), financial constraints (n=4) and advanced age (n=1).

Discussion: Relapsed/primary progressive HL responds well to a short course of nivolumab, permitting consolidation with stem cell transplant. In this comparative analysis there was no benefit of standard dose nivolumab over a flat dose of 40mg (0.6mg/kg), with equivalent response rates and progression-free survival in both groups. There are limitations in the data due to the retrospective nature of the study, and prospective clinical trials comparing SD and LD nivolumab are warranted to confirm these findings for cost-effective therapy.

Disclosure: This abstract discusses the use of nivolumab at doses not approved by the regulatory authority