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

Anas Younes, Armando Santoro, Margaret Shipp, Pier Luigi Zinzani, John M. Timmerman, Stephen Maxted Ansell, Philippe Armand, Michelle Fanale, Voravit Ratanatharathorn, John Kuruvilla, Jonathon B. Cohen, Graham Collins, Kerry J. Savage, Marek Trneny, Kazunobu Kato, Benedetto Farsaci, Susan M. Parker, Scott Rodig, Margaretha G M Roemer, Azra H. Ligon & 1 others Andreas Engert

Research output: Contribution to journalArticle

346 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1283-1294
Number of pages12
JournalThe Lancet Oncology
Volume17
Issue number9
DOIs
StatePublished - Sep 1 2016

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Stem Cell Transplantation
Hodgkin Disease
Safety
Advisory Committees
cAC10-vcMMAE
nivolumab
Immune Evasion
Blocking Antibodies
North America
Exanthema
Neutropenia
Drug-Related Side Effects and Adverse Reactions
Lipase
Fatigue
Fever
Therapeutics

ASJC Scopus subject areas

  • Oncology

Cite this

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. / Younes, Anas; Santoro, Armando; Shipp, Margaret; Zinzani, Pier Luigi; Timmerman, John M.; Ansell, Stephen Maxted; Armand, Philippe; Fanale, Michelle; Ratanatharathorn, Voravit; Kuruvilla, John; Cohen, Jonathon B.; Collins, Graham; Savage, Kerry J.; Trneny, Marek; Kato, Kazunobu; Farsaci, Benedetto; Parker, Susan M.; Rodig, Scott; Roemer, Margaretha G M; Ligon, Azra H.; Engert, Andreas.

In: The Lancet Oncology, Vol. 17, No. 9, 01.09.2016, p. 1283-1294.

Research output: Contribution to journalArticle

Younes, A, Santoro, A, Shipp, M, Zinzani, PL, Timmerman, JM, Ansell, SM, Armand, P, Fanale, M, Ratanatharathorn, V, Kuruvilla, J, Cohen, JB, Collins, G, Savage, KJ, Trneny, M, Kato, K, Farsaci, B, Parker, SM, Rodig, S, Roemer, MGM, Ligon, AH & Engert, A 2016, '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', The Lancet Oncology, vol. 17, no. 9, pp. 1283-1294. https://doi.org/10.1016/S1470-2045(16)30167-X
Younes, Anas ; Santoro, Armando ; Shipp, Margaret ; Zinzani, Pier Luigi ; Timmerman, John M. ; Ansell, Stephen Maxted ; Armand, Philippe ; Fanale, Michelle ; Ratanatharathorn, Voravit ; Kuruvilla, John ; Cohen, Jonathon B. ; Collins, Graham ; Savage, Kerry J. ; Trneny, Marek ; Kato, Kazunobu ; Farsaci, Benedetto ; Parker, Susan M. ; Rodig, Scott ; Roemer, Margaretha G M ; Ligon, Azra H. ; Engert, Andreas. / 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. In: The Lancet Oncology. 2016 ; Vol. 17, No. 9. pp. 1283-1294.
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T1 - Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin

T2 - a multicentre, multicohort, single-arm phase 2 trial

AU - Younes, Anas

AU - Santoro, Armando

AU - Shipp, Margaret

AU - Zinzani, Pier Luigi

AU - Timmerman, John M.

AU - Ansell, Stephen Maxted

AU - Armand, Philippe

AU - Fanale, Michelle

AU - Ratanatharathorn, Voravit

AU - Kuruvilla, John

AU - Cohen, Jonathon B.

AU - Collins, Graham

AU - Savage, Kerry J.

AU - Trneny, Marek

AU - Kato, Kazunobu

AU - Farsaci, Benedetto

AU - Parker, Susan M.

AU - Rodig, Scott

AU - Roemer, Margaretha G M

AU - Ligon, Azra H.

AU - Engert, Andreas

PY - 2016/9/1

Y1 - 2016/9/1

N2 - 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.

AB - 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.

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