title: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Bristol-Myers Squibb.
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: younesa@mskcc.org.
authors.forename: Anas
authors.initials: A
authors.lastname: Younes
authors.affiliation: Humanitas Cancer Center, Humanitas University, Rozzano-Milan, Italy.
authors.forename: Armando
authors.initials: A
authors.lastname: Santoro
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Shipp
authors.affiliation: Institute of Hematology "Le A Seràgnoli", University of Bologna, Bologna, Italy.
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Zinzani
authors.affiliation: University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Timmerman
authors.affiliation: Mayo Clinic, Rochester, MN, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Ansell
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Philippe
authors.initials: P
authors.lastname: Armand
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Fanale
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA.
authors.forename: Voravit
authors.initials: V
authors.lastname: Ratanatharathorn
authors.affiliation: University of Toronto and Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Kuruvilla
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: Jonathon B
authors.initials: JB
authors.lastname: Cohen
authors.affiliation: Oxford Cancer and Haematology Centre, Churchill Hospital, Oxford, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Collins
authors.affiliation: Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Savage
authors.affiliation: Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: Marek
authors.initials: M
authors.lastname: Trneny
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Kato
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Benedetto
authors.initials: B
authors.lastname: Farsaci
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Parker
authors.affiliation: Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Rodig
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Margaretha G M
authors.initials: MG
authors.lastname: Roemer
authors.affiliation: Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Azra H
authors.initials: AH
authors.lastname: Ligon
authors.affiliation: University Hospital of Cologne, Cologne, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Engert
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000079963:Brentuximab Vedotin; D015331:Cohort Studies; D003131:Combined Modality Therapy / Q000009:adverse effects*; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006689:Hodgkin Disease / Q000188:drug therapy* / Q000473:pathology / Q000628:therapy; D006801:Humans; D018796:Immunoconjugates / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology / Q000628:therapy; D009367:Neoplasm Staging; D000077594:Nivolumab; D011379:Prognosis; D016879:Salvage Therapy; D015996:Survival Rate; D014182:Transplantation, Autologous
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D000077594:Nivolumab; D000079963:Brentuximab Vedotin