Effect of Nivolumab on Patient-Reported Outcomes in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma after Autologous Transplantation: Results from the Multicohort Phase 2 Checkmate 205 Study

Introduction:Nivolumab, an immune checkpoint inhibitor targeting the programmed death-1 (PD-1) receptor, is approved for treatment of pts with classical Hodgkin lymphoma (cHL) that has relapsed after autologous hematopoietic cell transplantation (auto-HCT) and brentuximab vedotin (BV) or ≥3 lines of therapy (LoTs) including auto-HCT. In CheckMate 205 (NCT02181738), a phase 2, multicohort, single-arm study of nivolumab monotherapy in pts with relapsed/refractory (R/R) cHL after failure of auto-HCT, frequent and durable responses with acceptable safety were observed in BV-naïve pts (Cohort A), pts treated with BV after auto-HCT (Cohort B), and pts who had received BV before and/or after auto-HCT (Cohort C) (Fanale M et al. ICML 2017). In addition to clinical safety and efficacy, it is important to consider pt-reported outcomes (PROs), particularly in the R/R setting where treatment options are limited and pts may have multiple prior LoTs. Here, we assess if the improvement in PROs observed in Cohort B (Younes A et al. Lancet Oncol 2016) can be extended to the broader spectrum of pts with cHL progressing after auto-HCT, in a pooled Cohort A+B+C analysis of CheckMate 205.

Methods: General and cancer-specific PROs were assessed every 4 cycles (every 8 wk) using the 3-level EuroQoL 5 Dimensions Questionnaire (EQ-5D-3L) and the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (EORTC QLQ-C30), respectively. All treated pts with baseline (BL) and ≥1 post-BL PRO assessment in Cohorts A, B, and C were included in this analysis. Least squares (LS) means were used to describe score changes from BL over time. EORTC QLQ-C30 scores range from 0 to 100 (for functioning/global health status [GHS], higher scores indicate better function/GHS; for symptom scales, higher scores indicate greater symptom burden). Subscale-specific thresholds for clinically meaningful change were prespecified (Cocks K et al. Eur J Cancer 2012); clinically meaningful improvements (CMIs) were reported if also statistically significant. EQ-5D visual analog scale (VAS) scores range from 0 to 100 and EQ-5D utility index scores range from −0.6 to 1.0 (higher scores indicate better health); a 7- and 0.08-point change represents a minimally important difference in VAS and utility index, respectively (Pickard A et al. Health Qual Life Outcomes 2007).

Results:The analysis population included 219 pts (of 243 treated); 58 (26%) in Cohort A, 72 (33%) in Cohort B, and 89 (41%) in Cohort C. At Wk 93, 35/48 (73%) pts with an on-treatment study visit completed both questionnaires. At BL, pts had a median (range) age of 34 (18-72) y, 41% were female, 57% had BL ECOG performance status 0, and 58% had International Staging System stage IV disease. CMIs from BL in EORTC QLQ-C30 symptom scores of fatigue, pain, dyspnea, insomnia, appetite loss, and financial difficulties; functional domains of physical/role/emotional/social functioning; and GHS were reported as early as Wk 9 (7/15 EORTC QLQ-C30 subscales). Median (95% CI) time from randomization to first improvement was 26 (17-49) wk for EORTC QLQ-C30 GHS and 17 (16-24) wk for EQ-5D VAS. EORTC QLQ-C30 symptom scores of fatigue, pain, dyspnea, insomnia, appetite loss, and financial difficulties showed CMIs at ≥5 timepoints, and physical/role/emotional/social functioning at ≥3 timepoints; GHS at all timepoints. Clinically meaningful and statistically significant deterioration was observed only in the EORTC QLQ-C30 cognitive functioning score, and only at Wk 17 (without a clinically meaningful change at other timepoints). EQ-5D VAS showed a CMI at Wk 17-33, Wk 57, and Wk 93, and EQ-5D utility index showed a CMI at Wk 45 and Wk 81. At Wk 93, CMIs of 9.2 (standard error: 2.7) and 10.0 (4.6) were reported for EORTC QLQ-C30 GHS and EQ-5D VAS, respectively; EQ-5D utility index increased by 0.05 (0.02). Pts with an objective response to nivolumab had LS mean improvements > overall LS mean improvement from BL in EORTC QLQ-C30 GHS, all symptom scales except financial difficulties, EQ-5D VAS, and utility index at ≥1 timepoint.

Conclusions: In addition to a high rate of durable responses across all 3 cohorts of pts with R/R cHL that had relapsed after auto-HCT in CheckMate 205, nivolumab treatment resulted in an early and sustained trend (Wk 9-93) towards improvement in general and cancer-specific PROs.

Funding: Bristol-Myers Squibb (BMS). Medical writing: A Gill, Caudex, funded by BMS