CheckMate 205: Nivolumab monotherapy followed by AVD combination for naïve, aggressive cHL

Nivolumab, a programmed death protein 1 (PD-1) antibody, is under accelerated approval by the US Food and Drug administration (FDA)¹ for patients with relapsed and refractory (R/R) classical Hodgkin lymphoma (cHL), who have relapsed or progressed after autologous stem cell transplant (ASCT). For newly-diagnosed cHL, multiagent chemotherapy is the current standard of care.^2,3 This has proved a good treatment strategy for early-stage, naive cHL but remains suboptimal for advanced-stage patients.²

The CheckMate 205 (NCT02181738)  phase II trial⁴ demonstrated that nivolumab monotherapy has an acceptable safety profile and leads to good and durable responses in patients with R/R cHL. In an extended cohort (Cohort D) of the CheckMate 205 study, single-agent nivolumab followed by a period of nivolumab in combination with doxorubicin, vinblastine, and dacarbazine (N-AVD), was evaluated for safety and efficacy in advanced-stage previously-untreated cHL. These results were published in the Journal of Clinical Oncology³ by Radhakrishnan Ramchandren from the University of Tennessee, Knoxville, TN, USA, and colleagues on 21 May 2019.

The primary endpoints of this analysis were safety and tolerability, measured as an increase in Grade 3–5 treatment-emergent adverse events (TEAEs) between first dose and one month after last dose. Secondary endpoints, included overall response rate (ORR) and complete response (CR) rate, as assessed by an independent radiology review committee (IRC).

Study design & baseline characteristics

• Cohort D, CheckMate 205: N = 51 patients with untreated, advanced-stage cHL (Ann Arbor III–IV; or bulky Stage IIB), aged ≥18 years, with Eastern Cooperative Oncology Group (ECOG) performance status 0–1, and hemoglobulin-adjusted carbon monoxide lung diffusion capacity >60%
• Patients were treated with nivolumab monotherapy and then with N-AVD combination therapy, as follows:
  • Nivolumab monotherapy phase: 4 doses of intravenous (IV) nivolumab (240mg over 30 minutes), once every 2 weeks
  • N-AVD combination phase: 12 doses of IV N-AVD, once every 2 weeks (six cycles):
    • Nivolumab: 240mg
    • Doxorubicin: 25mg/m²
    • Vinblastine: 6mg/m²
    • Dacarbazine: 375mg/m²
  • After the N-AVD combination phase, patients entered follow-up assessments at 39, 65, and 104 weeks after last N-AVD dose
• Response assessment was performed by fludeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT) or magnetic resonance imaging (MRI) at:
  • Baseline
  • End of monotherapy phase
  • After 2 combination therapy cycles (N-AVD)
  • End of treatment (EOT; 9 ±2 weeks from last dose)
    

Table 1. Key baseline characteristics

Baseline characteristic

Patients (N = 51)

Median age (range)

37 (18–87) years

Ann Arbor stage:

II

III

IV

 

20% (n= 10)

24% (n= 12)

57% (n= 29)

International Prognostic Index (IPI) score:

0–1

2–3

≥4

Unreported

 

24% (n= 12)

41% (n= 21)

25% (n= 13)

10% (n= 5)

Bulky disease

31% (n= 16)

Extranodal disease

49% (n= 25)

Key findings

Safety

• Number of patients with TEAEs of any grade: 96% (n= 49)
• Observed hematological toxicities of any grade:
  • Neutropenia: 55% (n= 28)
  • White blood count reduction: 14% (n= 7)
  • Febrile neutropenia: 10% (n= 5)
  • Anemia: 10% (n= 5)
  • Alanine aminotransferase (ALT) increase: 8% (n= 4)
  • Amylase increase: 6% (n= 3)
• Number of patients with Grade 3–4 TEAEs: 59% (n= 30)
• Most common Grade 3–4 hematological toxicities:
  • Neutropenia: 49% (n= 25)
  • White blood count reduction: 2% (n= 1)
  • Febrile neutropenia: 10% (n= 5)
  • Anemia: 4% (n= 2)
  • ALT increase: 4% (n= 2)
• Patients with infusion-related reactions (all Grade 1–2):
  • During monotherapy: 29% (n= 15)
  • During N-AVD combination therapy: 6% (n= 3)
• One Grade 5 TEAE was reported (combination cycle 5) leading from acute respiratory infection, febrile neutropenia, congestive heart failure, and acute respiratory failure

Efficacy

Table 2. Efficacy data per IRC at different study stages

 

At end of nivolumab  monotherapy

After two N-AVD combination cycles

At end of N-AVD combination treatment (EOT)

ORR (95% CI)
(N = 51)

69% (54–81)

90% (79–97)

84% (71–93)

CR rate (95% CI)
(N = 51)

18% (8–31)

51% (37–65)

67% (52–79)

Tumor lesion burden reduction >50%
(n/total evaluable patients)

71% (35/49)

98% (45/46)

100% (46/46)

Progressive disease (PD)

-

-

6%

• At EOT, five patients (10%) were not evaluable for response due to:
  • Consent withdrawal (n= 1)
  • Lost to follow-up (n= 1)
  • Death (n= 1)
  • Monotherapy continuation at EOT (n= 1)
  • Lack of EOT assessment (n= 1)
• ORR at EOT without the non-evaluable patients above (IRC; n= 46) was 93% and CR rate was 74%
• With a minimum follow-up of 9.4 months:
  • Nine-month progression-free survival (PFS): 92% (95% CI, 80–97)
  • Median PFS: not reached
  • Nine-month overall survival (OS): 98% (95% CI, 86–100)

Conclusions

Nivolumab monotherapy, followed by a period of nivolumab in combination with AVD chemotherapy, showed a manageable safety profile and led to very good responses in previously-untreated, advanced-stage patients with cHL.