Sintilimab for R/R classical HL patients: Results from the ORIENT-1 phase II trial

On 15 January 2019, the results of the multicenter, phase II trial ORIENT-1 were published in The Lancet Haematology by Yuankai Shi, from the Beijing Key Laboratory of the Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, CN, and colleagues.

The aim of this multicenter, open-label, single-arm, phase II trial was to investigate the activity and safety of sintilimab in refracted or refractory (R/R) classical Hodgkin lymphoma (cHL) Chinese patients. Sintilimab is a fully humanised, monoclonal antibody that targets the programmed cell death protein 1 (PD-1) receptor and blocks any receptor-ligand interaction. The primary endpoint of this study was objective response rate, as assessed by an independent radiological review committee (IRRC). Secondary endpoints, included investigator-assessed objective response rates, safety, duration of response (DoR), and progression-free survival (PFS) among others.

Study design

• N = 96 R/R (after ≥ 2 lines) patients with histopathologically-confirmed cHL from 18 hospitals in China, were aged ≥ 18, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0−2, at least one measurable lesion (> 15 mm long axis or > 10 mm short axis), and uptake on ¹⁸F-fluorodeoxyglucose PET-CT
• Dosing:
  • 200 mg of intravenous sintilimab over a period of 30−60 min, once every three weeks for a maximum of 24 months or until disease progression, death, withdrawal or unacceptable toxicity
  • Dose modifications were not allowed, only dose interruptions in the case of treatment-related adverse events (> 6 weeks interruption = discontinuation)
• Data cut-off: 16 April 2018
  • By that date, 10 patients had discontinued treatment and 86 remained on treatment
• Median follow-up (range): 10.5 (9.2−1) months
• Median number of treatment cycles (range): 12 (10−13) cycles
• Median duration of sintilimab exposure (range): 8.4 (7.6−4) months
• Key baseline characteristics:
  • Median age (range): 33 (28−43)
  • Sex: 56% males
  • Confirmed cHL by central pathology review: 96% (n = 92)
  • Median number of previous lines (range): 3 (2−5)
  • Patients previously received at least 2 prior chemotherapy lines: 94% (n = 90)
  • Patients received prior autologous stem cell transplant: 19% (n = 18)
  • Patients received prior radiotherapy: 54% (n = 52)

Key findings

• Full analysis set (n = 92):
  • Objective response by IRRC was achieved by 80.4% of patients (n = 74)
  • Complete remission by IRRC was observed in 34% of patients (n = 31)
    • Complete metabolic PET-CT remission: 18% of patients (n = 17)
    • Complete remission on CT: 27% of patients (n = 25/92)
  • Disease control (IRRC) was observed in 97.8% (n = 90)
  • Disease control by investigator-assessment was observed in 100% (n = 92)
• Total enrolled population (n = 96):
  • Objective response by IRRC: 79.2% (95% CI, 69.7−86.8; n = 76)
  • Objective response by investigator-assessment: 79.3% (95% CI, 69.6−87; n = 73)
• Consistency between IRRC and investigator-assessment: 66% for the best overall response
• Among responders (n = 74; IRRC assessment):
  • Median time to IRRC-assessed response: 42 days (95% CI, 42−43)
  • Responses achieved by first scan at week six: 77% (n = 57).
  • Response achieved by 24 weeks: 97% (n = 72)
  • One patient (1%) achieved partial remission at week 36 and one patients (1%) achieved partial remission at week 48
  • Median duration of response: not reached (95% CI, not reached)
  • No disease progression: 84% of patients (n = 62/74)
• Six-month PFS (range): 77.6% (66.6−85.4)
• Median PFS: not reached (95% CI, 8.3−not reached)
• Disease progression occurred in 25% of patients by cut-off date (n = 23/92)
• No deaths occurred by the cut-off date
• Subgroup analyses showed similar objective response rates and disease control if stratifying by number of previous chemotherapy lines, history of radiotherapy, history of ASCT, baseline B symptoms, refractoriness to first-line chemotherapy etc.

Safety

• All patients experienced at least one treatment-emergent adverse event (TEAE)
• Most TEAEs were Grade 1−2
• Grade 3−4 AEs occurred in 25% of patients (n = 24/96)
• No Grade 5 AEs occurred
• Serious AEs of any cause were reported in 15% of patients (n = 14/96); with the most common being:
  • Pneumonitis: 3% (n = 3)
  • Lung infections: 3% (n = 3)
  • Upper respiratory tract infection: 2% (n = 2)
• Drug-related serious AEs were reported in 11% of patients (n = 11/96); with the most common being:
  • Pneumonitis: 3% (n = 3)
  • Lung infections: 3% (n = 3)
  • Infusion reaction: 2% (n = 2)
  • Upper respiratory tract infection: 1% (n = 1)
  • Abnormal liver function: 1% (n = 1)
• Permanent treatment discontinuation due to TEAE occurred in 3% of patients (n = 3)

Conclusions

• Sintilimab showed favourable efficacy in R/R cHL patients
• Sintilimab administration was generally well-tolerated with only three patients permanently discontinuing treatment
• Most AEs were manageable and mild and no deaths occurred
• A limitation of this study is the fact that in China the main therapeutic options for R/R cHL are chemotherapy regimens. This differs from Europe and USA (pembrolizumab and nivolumab options) and thus limits the adaptation of these study results to other continents