Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial

Abstract

Background: Malignant cells of classical Hodgkin's lymphoma are characterised by genetic alterations at the 9p24.1 locus, leading to overexpression of PD-1 ligands and evasion of immune surveillance. In a phase 1b study, nivolumab, a PD-1-blocking antibody, produced a high response in patients with relapsed and refractory classical Hodgkin's lymphoma, with an acceptable safety profile. We aimed to assess the clinical benefit and safety of nivolumab monotherapy in patients with classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin.

Methods: In this ongoing, single-arm phase 2 study, adult patients (aged ≥18 years) with recurrent classical Hodgkin's lymphoma who had failed to respond to autologous stem-cell transplantation and had either relapsed after or failed to respond to brentuximab vedotin, and with an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled from 34 hospitals and academic centres across Europe and North America. Patients were given nivolumab intravenously over 60 min at 3 mg/kg every 2 weeks until progression, death, unacceptable toxicity, or withdrawal from study. The primary endpoint was objective response following a prespecified minimum follow-up period of 6 months, assessed by an independent radiological review committee (IRRC). All patients who received at least one dose of nivolumab were included in the primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02181738.

Findings: Among 80 treated patients recruited between Aug 26, 2014, and Feb 20, 2015, the median number of previous therapies was four (IQR 4-7). At a median follow-up of 8·9 months (IQR 7·8-9·9), 53 (66·3%, 95% CI 54·8-76·4) of 80 patients achieved an IRRC-assessed objective response. The most common drug-related adverse events (those that occurred in ≥15% of patients) included fatigue (20 [25%] patients), infusion-related reaction (16 [20%]), and rash (13 [16%]). The most common drug-related grade 3 or 4 adverse events were neutropenia (four [5%] patients) and increased lipase concentrations (four [5%]). The most common serious adverse event (any grade) was pyrexia (three [4%] patients). Three patients died during the study; none of these deaths were judged to be treatment related.

Interpretation: Nivolumab resulted in frequent responses with an acceptable safety profile in patients with classical Hodgkin's lymphoma who progressed after autologous stem-cell transplantation and brentuximab vedotin. Therefore, nivolumab might be a new treatment option for a patient population with a high unmet need. Ongoing follow-up will help to assess the durability of response.

Funding: Bristol-Myers Squibb.

Figure 1. Efficacy outcomes per IRRC assessment

IRRC=independent radiologic review committee. Shown are the results for: Panel A – IRRC assessment of best change from baseline in target lesion for all response-evaluable patients, where crosses denote responders and the square symbol represents percentage change truncated to 100% (response evaluable was defined as patients with a best overall response of complete or partial remission, stable disease, or disease progression of target lesion[s] assessed at baseline, and at least one on-study time point with all baseline target lesion[s] assessed; negative or positive value indicates maximum tumour reduction or minimum tumour increase); Panel B – response characteristics in all responders; Panel C – duration of response; and Panel D – progression-free survival (Panel D).

Figure 2. PD-L1/PD-L2 alterations and PD-1 ligand expression in tumour biopsies from trial patients

Panel A: the proportion of evaluable cases with polysomy, copy gain, and amplification. Panel B: box plots showing the distribution of PD-L1 H-scores across cases with polysomy, copy gain, and amplification. There is an increase in median PD-L1 H-score with increasing 9p24·1 genetic alteration (p=0·034, Kruskal-Wallis test). Panel C: objective responses among patients with Reed-Sternberg cells exhibiting polysomy, copy gain, or amplification. Panel D: objective responses by PD-L1 H-score.