Elsevier

The Lancet Oncology

Volume 17, Issue 9, September 2016, Pages 1283-1294
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(16)30167-XGet rights and content

Summary

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.

Introduction

For patients with first relapse of classical Hodgkin's lymphoma, as defined in the 2008 WHO classification,1 the standard of care is high-dose chemotherapy followed by autologous stem-cell transplantation (ASCT).2 In this population, only 55% of patients have been shown to be free from treatment failure at 3 years.2 In patients who relapse after ASCT, prognosis is worse and only a small minority of patients can still be cured.3, 4 In the past 5 years, treatment with brentuximab vedotin after ASCT failure has resulted in a median overall survival of 22·4 months (95% CI 21·7–not estimable),5 and median progression-free survival associated with the subsequent line of treatment following brentuximab vedotin is 3·5 months.6 For patients who progress after ASCT and brentuximab vedotin, no standard treatment options exist at present. Thus, an unmet medical need for effective therapies persists in this patient population.

Classical Hodgkin's lymphoma is characterised by rare Reed–Sternberg cells,7 which have copy number alterations involving chromosome 9p24.1, resulting in overexpression of the PD-1 ligands PD-L1 and PD-L2 on the tumour cell surface.8, 9, 10, 11 JAK2 is also located on chromosome 9p24.1, and alterations in this gene increase JAK–STAT signalling, further inducing PD-L1 overexpression.9 Under normal physiological conditions, activation of the PD-1 pathway via PD-L1 and PD-L2 engagement limits T-cell-mediated immune responses.12 Therefore, increased PD-L1 and PD-L2 expression by Reed–Sternberg cells might enable these cells to evade immune surveillance, suggesting that blockade of this pathway could be an effective treatment approach for patients with classical Hodgkin's lymphoma.13

Research in context

Evidence before this study

To establish the role of brentuximab vedotin in treatment of classical Hodgkin's lymphoma, we searched PubMed on March 18, 2016, for all clinical trials with the terms “Hodgkin lymphoma” AND “brentuximab vedotin”. We did not apply any language restrictions. Among the 16 articles we identified, brentuximab vedotin generally had clinically meaningful efficacy and acceptable tolerability in Hodgkin's lymphoma after autologous stem-cell transplantation (ASCT). Brentuximab vedotin is the only approved treatment for relapsed or refractory Hodgkin's lymphoma following failure of ASCT. In one study, responses upon re-treatment with brentuximab vedotin were reported in patients who progressed after an initial response to brentuximab vedotin; however, no studies investigated new agents for patients who did not respond to brentuximab vedotin treatment.

Added value of this study

In this phase 2 study of nivolumab in a heavily pre-treated population who had not responded to ASCT and brentuximab vedotin, the proportion of patients achieving an objective response was high, and most patients had ongoing responses, including some durable responses that might extend with ongoing follow-up. Nivolumab was well tolerated and had an acceptable safety profile in this patient population. These results validate earlier findings from a phase 1b trial, and will hopefully contribute to research progress in an area with an unmet medical need.

Implications of all the available evidence

Brentuximab vedotin has improved outcomes in patients with classical Hodgkin's lymphoma and is the preferred treatment for patients who have progressed after ASCT. However, many patients eventually become refractory to brentuximab vedotin and have no good therapeutic options. Duration and depth of response are important, because patients are often young and otherwise healthy. Nivolumab provides a new treatment option for patients with classical Hodgkin's lymphoma and has the potential to produce durable responses, even in heavily pre-treated patients.

Nivolumab, a fully human immunoglobulin G4 immune checkpoint inhibitor antibody that targets PD-1, is approved by the US Food and Drug Administration for the treatment of advanced-stage melanoma,14 non-small-cell lung cancer,15 and renal cell carcinoma.16 A phase 1b study17 assessed nivolumab in 23 patients with relapsed or refractory classical Hodgkin's lymphoma, including 15 patients who had progressed after ASCT or brentuximab vedotin treatment: the safety profile was acceptable, investigator-defined objective response was reported in 20 (87%) of 23 patients, and 86% (95% CI 62–95) of patients had progression-free survival at 24 weeks. With extended follow-up (median 20 months, range 7–25), durable responses to nivolumab have been shown: seven (35%) of 20 responders maintained a response for more than 1·5 years.18 In all ten evaluable tumour samples, Reed–Sternberg cells had copy number alterations of chromosome 9p24.1 and increased PD-L1 and PD-L2 expression. Additionally, phosphorylated STAT3 was detected in Reed–Sternberg cell nuclei in all cases, suggesting active JAK–STAT signalling.17 To explore the effects of PD-1 blockade in patients who relapse after treatment with approved, standard therapies, we initiated a phase 2 study, with the aim of assessing the activity and safety of nivolumab in patients with classical Hodgkin's lymphoma after failure of ASCT and brentuximab vedotin.

Section snippets

Study design and participants

This trial was a multicentre, non-comparative, multicohort, single-arm phase 2 study. In this Article, we report results from one cohort: patients with classical Hodgkin's lymphoma after failure of both ASCT and subsequent brentuximab vedotin treatment. Other study cohorts included patients after failure of ASCT who were brentuximab vedotin naive, patients after failure of ASCT who received brentuximab vedotin at any time prior to receiving the study drug, and patients with newly diagnosed

Results

Between Aug 26, 2014, and Feb 20, 2015, 80 patients were recruited and enrolled into the trial, all of whom were given treatment and included in the analyses. The median age of the patients was 37 years (IQR 28–48), the median number of previous lines of therapy was four (4–7), although nearly half of patients had received five or more previous lines, and three-quarters had previous radiotherapy (table 1; appendix pp 5, 6). The median time between the most recent brentuximab vedotin treatment

Discussion

In this phase 2 study, nivolumab resulted in frequent responses in patients with classical Hodgkin's lymphoma after failure of ASCT and brentuximab vedotin, and most of these responses were maintained through the reported follow-up period. The safety profile was acceptable. Reduction in tumour burden in the target lesion was noted in most patients, according to both IRRC and investigator assessment. Importantly, response to nivolumab was reported in more than two-thirds of patients who did not

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