Nivolumab for Relapsed/Refractory Classic Hodgkin Lymphoma After Failure of Autologous Hematopoietic Cell Transplantation: Extended Follow-Up of the Multicohort Single-Arm Phase II CheckMate 205 Trial

Abstract

Purpose Genetic alterations causing overexpression of programmed death-1 ligands are near universal in classic Hodgkin lymphoma (cHL). Nivolumab, a programmed death-1 checkpoint inhibitor, demonstrated efficacy in relapsed/refractory cHL after autologous hematopoietic cell transplantation (auto-HCT) in initial analyses of one of three cohorts from the CheckMate 205 study of nivolumab for cHL. Here, we assess safety and efficacy after extended follow-up of all three cohorts. Methods This multicenter, single-arm, phase II study enrolled patients with relapsed/refractory cHL after auto-HCT treatment failure into cohorts by treatment history: brentuximab vedotin (BV)-naïve (cohort A), BV received after auto-HCT (cohort B), and BV received before and/or after auto-HCT (cohort C). All patients received nivolumab 3 mg/kg every 2 weeks until disease progression/unacceptable toxicity. The primary end point was objective response rate per independent radiology review committee. Results Overall, 243 patients were treated; 63 in cohort A, 80 in cohort B, and 100 in cohort C. After a median follow-up of 18 months, 40% continued to receive treatment. The objective response rate was 69% (95% CI, 63% to 75%) overall and 65% to 73% in each cohort. Overall, the median duration of response was 16.6 months (95% CI, 13.2 to 20.3 months), and median progression-free survival was 14.7 months (95% CI, 11.3 to 18.5 months). Of 70 patients treated past conventional disease progression, 61% of those evaluable had stable or further reduced target tumor burdens. The most common grade 3 to 4 drug-related adverse events were lipase increases (5%), neutropenia (3%), and ALT increases (3%). Twenty-nine deaths occurred; none were considered treatment related. Conclusion With extended follow-up, responses to nivolumab were frequent and durable. Nivolumab seems to be associated with a favorable safety profile and long-term benefits across a broad spectrum of patients with relapsed/refractory cHL.

Trial registration: ClinicalTrials.gov NCT02181738.

Fig 1.

CONSORT diagram. (*) Includes seven patients who discontinued nivolumab because of persistent complete remission for 1 year. AE, adverse event.

Fig 2.

Best change in (A) target lesions, (B) duration of response (DOR), (C) progression-free survival (PFS), and (D) overall survival (OS), according to best overall response. (*) Indicates responders; open square indicates change truncated to 100%. (B, C, and D) Values are median (95% CI) unless stated otherwise. Shading around lines represents 95% CIs. Auto-HCT, autologous hematopoietic cell transplantation; BV, brentuximab vedotin; CR, complete remission; NA, not available; NE, not estimable; PD, progressive disease; PR, partial remission; SD, stable disease.

Fig 3.

Outcomes in patients treated beyond progression. (A) Investigator-assessed best change in target lesion tumor burden and (B, C, and D) investigator-assessed change in target lesion burden over time for patients treated beyond progression according to best overall response to nivolumab before initial progression. (A) Patients with missing postfirst progression tumor data are not included. Horizontal reference line indicates the 50% reduction consistent with a response per revised International Working Group 2007 criteria. (B, C, and D) All patients with a last available nivolumab dose date after initial investigator-assessed progression per International Working Group 2007 criteria were included, except one patient treated beyond progression who did not have an evaluable best overall response. Per protocol, patients who did not have a tumor assessment after the first dose of treatment beyond progression were censored.

Fig 4.

Cumulative incidence of (A) transplant-related mortality (TRM) and disease progression, (B) acute graft-versus-host disease (aGVHD) and chronic graft-versus-host disease (cGVHD), and (C) overall survival (OS) and progression-free survival (PFS) after allogeneic hematopoietic cell transplantation (allo-HCT). Cumulative incidence (95% CI) at 100 days and 6 months for TRM, disease progression, and GVHD, and median (95% CI) PFS and OS are shown. Death was considered a competing risk to GVHD, and post-transplant disease progression was considered a competing event to TRM. G, grade; NA, not available; NE, not estimable.

Fig A1.

Response characteristics among all responders. CR, complete remission; PR, partial remission.

Fig A2.

Duration of response in cohorts A, B, and C. All values are median (95% CI).

Fig A3.

Progression-free survival (PFS) in cohorts A, B, and C. All values are median (95% CI).

Fig A4.

Overall survival (OS) from date of initial disease progression in patients treated beyond initial progression (TBP) and not TBP. All values are median (95% CI). NA, not available; NE, not estimable.

Fig A5.

Estimated nivolumab concentration at the time of allogeneic hematopoietic cell transplantation (μg/mL) and occurrence of (A) transplant-related mortality or (B) grade 3 to 4 acute graft-versus-host disease (GVHD). Box plots represent 25th and 75th percentiles; lines within the box plots represent median values and circles represent individual patients.