Nivolumab plus AVD as first-line treatment for high-risk classic Hodgkin lymphoma

The standard care for patients with early-stage unfavorable classic Hodgkin lymphoma (cHL) is treatment with four cycles of chemotherapy consolidated with 30-Gy involved-site radiotherapy (IS-RT). The chemotherapy doxorubicin, bleomycin, vinblastine, and dacarbazine regimen (ABVD) has good tolerability but insufficient long-term progression-free survival (PFS), while more intensive regimens like two cycles of dose-escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone (eBEACOPP) improve 5-year PFS but are associated with adverse toxicity. Therefore, treatments with improved safety and sustained efficacy are needed.

Nivolumab, an antibody against the cell death protein 1 (PD-1), approved for relapsed cHL, has a favorable safety profile and induces high response rates. Paul J. Bröckelmann and colleagues conducted the open-label, multicenter, randomized, phase II NIVAHL study investigating nivolumab in combination with doxorubicin, vinblastine, and dacarbazine (N-AVD) followed by consolidation with 30-Gy IS-RT, as first-line treatment for early-stage unfavorable cHL. The study compared the efficacy of both concomitant and sequential N-AVD dosing to establish the optimal sequence. The results of the study were published in JAMA Oncology.¹

Study design

The study recruited patients aged 18–60 years with newly diagnosed, stage I-II cHL, with ≥ 1 of the following risk factors: large mediastinal mass, extranodal disease, elevated erythrocyte sedimentation rate, or three or more involved nodal areas. Patients with stage IIB who had large mediastinal mass and/or extranodal disease were excluded from the study.

Patients were stratified according to age (< 45 years vs ≥ 45 years) and gender and were randomized 1:1 to the parallel groups

• Concomitant N-AVD (standard dose of AVD and nivolumab at 240 mg) therapy on Day 1 and 15 of each 28-day cycle for four cycles
• Sequential therapy of four nivolumab infusions in 14-day intervals followed by two 28-day cycles of N-AVD and two 28-day cycles of AVD

After systemic treatment, both groups received consolidating 30-Gy IS-RT. Mandatory dexamethasone-based prophylaxis was administered from December 2017 onwards.

Positron emission tomography (PET)- and computed tomography (CT)-based response assessments were conducted after the four doses of nivolumab and after the end of systemic treatment. An additional CT-based restaging was performed 4–6 weeks after completion of IS-RT. In PET-positive patients, subsequent restaging was carried out 3 months after the end of IS-RT.

The primary endpoint was complete remission (CR) rate at the end of the study. Secondary points included treatment-related morbidity, PFS, overall survival (OS), early response to systemic therapy, and Grade 3–4 treatment-related adverse events.

Results

• In total, 110 patients were enrolled between April 2017 and October 2018, out of which 109 patients had pathology review confirmed cHL diagnosis
• Baseline patient characteristics are displayed in Table 1

Table 1. Selected baseline patient and disease characteristics

Efficacy

• Both N-AVD therapy schedules (concomitant and sequential) induced high objective response rates (ORR, Table 2)
  • The responses in the sequential group deepened over time
• Potential risk factors associated with failure to achieve CR after study treatment were:
  • baseline vitamin D deficiency
  • combination of high white blood cell count and low relative eosinophil count
• After a median follow-up of 14 months (range, 6-27) in the concomitant group and 13 months (range, 8-28) in the sequential treatment group, the 12-month PFS was 100% and 98%, respectively, while all patients in both treatment groups achieved a 100% 12-month OS

Table 2. Responses during and after N-AVD therapy

Safety

• Overall, 80% of patients in the concomitant treatment group and 91% of patients in the sequential treatment group received the planned eight infusions of nivolumab, 91% and 89% of patients respectively received four full cycles of N-AVD, while IS-RT was administered to 93% and 89% of patients, respectively
  • Four patients in each treatment group had severe protocol deviations, due to AEs (n = 5), patient refusal (n = 2) or incorrect risk group allocation (n = 1)
  • Four patients discontinued treatment due to AEs
• The incidence of any grade treatment-related AE was 98% in both treatment groups (Table 3)
  • The most common hematological AEs included leukopenia, anemia, and infection
  • Grade ≥ 3 events of any kind were experienced by 76% and 80% of patients in the concomitant and sequential groups, respectively

Table 3. Morbidity and selected AEs reported in patients on N-AVD therapy

Conclusion

The study is the first to evaluate N-AVD as a first-line treatment for patients with high-risk cHL. The results demonstrate high efficacy and manageable toxicity profiles with either concomitant or sequenced N-AVD regimen. Response rates and early PFS were higher than previously reported in the relapse setting, suggesting that the regimen could be used in early clinical settings. Interestingly, even four doses of nivolumab monotherapy resulted in a high interim CR rate. However, a longer follow-up is required to evaluate the durability of responses and potential late-emerging treatment-related AEs. 

According to the authors, this treatment could potentially offer a particular benefit to older patients with comorbidities. Something that further studies should explore.