Can nivolumab alone cure patients with relapse or refractory Hodgkin lymphoma? A 5‐year analysis of the French early access program (EPA) (2022)

Checkpoint blockade with anti-programmed-death 1 (PD-1) monotherapy has shown great efficacy in patients with relapsed/refractory Hodgkin lymphoma (R/R HL).1-4 Patients who are unable to achieve a complete response (CR) usually experience limited progression-free survival (PFS) in the absence of consolidation with allogenic haematopoietic stem cell transplantation (alloHSCT).4, 5 Despite its curative potential, alloHSCT cannot be performed in all patients due to its particular toxicity profile after anti-PD-1 therapy.6, 7 On the other hand, patients achieving a CR may experience durable remission without further therapy.4, 5, 8 These prolonged responses may persist even after anti-PD-1 discontinuation.9 It has been suggested that younger patients with an early and deep response have a higher probability of being relapse-free 1 year after anti-PD-1 discontinuation.10 However, in these studies, the median follow-up remained limited (median 1.5–2.8 years) and data are lacking to assess whether some of these patients may be cured with anti-PD-1 therapy alone. Here, we report the 5-year analysis of the Autorisation Temporaire d’Utilisation-nivolumab (ATU-nivo) study, a retrospective, nationwide study of patients aged ≥18 years with R/R HL who were treated with nivolumab in the French early access program (EAP). The study included patients with HL relapsing or refractory after three lines of chemotherapy (including brentuximab-vedotin) and autoHSCT, or four lines of chemotherapy if the patient was not eligible for HSCT. All patients who had received at least one dose of nivolumab as part of the French EAP were eligible for the study. Nivolumab was administered at 3 mg/kg every 2 weeks until progression, death of any cause, unacceptable toxicity, consent withdrawal, or treating physician’s decision. Treatment efficacy was assessed using 18F-fluorodeoxyglucose-positron emission tomography/computed tomography. Patients were allowed to undergo subsequent alloHSCT according to primary physician’s decision. The protocol was approved by the Comité Consultatif sur le Traitement de l'Information en matière de Recherche dans le domaine de la Santé (CCTIRS; approval no. 16.861). The 3-year analysis of the cohort has been previously published.4 We included 76 patients in the efficacy analysis. After a median follow-up of 5.7 years, the estimated 5-year PFS and overall survival (OS) were 27% and 53% respectively. In all, 30 (39.5%) patients had a CR as best response, of whom 11 received a consolidation therapy: nine with an alloHSCT, one with an auto-HSCT, and one with chemotherapy. As previously reported,10 patients in CR had a significantly better outcome than non-CR patients (Figure S1). To assess whether some patients might be cured with nivolumab alone as systemic treatment, we analysed the 19 patients who achieved a CR and did not receive a consolidation (concomitant radiotherapy was performed in five patients). Their characteristics are summarised in Table 1. These patients were young (median [range] age 39.4 [19–77] years) and heavily pre-treated with a median number of six prior systemic lines of treatment, including brentuximab-vedotin (100%), autoHSCT (57.9%) and alloHSCT (36.8%). They received a median of 20 cycles of nivolumab. The median (range) time to CR was 2.1 (1–5) months. All patients had discontinued nivolumab therapy at the time of analysis, mostly because of prolonged remission (52.6%) or adverse events (21%; two acute graft-versus-host disease, one laryngeal oppression and one cerebellar syndrome). Three (15.8%) patients discontinued because of disease recurrence and two (11.1%) because of non-haematological malignancies. After a median follow-up of 5.6 years (4.0 years from nivolumab discontinuation), nine of 19 (47.4%) patients remained alive and disease free. The median PFS was 41.9 months and the median OS was not reached (Figure 1). The 5-year estimated PFS was 42.3%. Nine patients have relapsed, of whom six received a salvage therapy: three received a second course of anti-PD-1, three received radiotherapy and/or chemotherapy. Half of the patients achieved a CR upon salvage therapy. Most relapses occurred within the first 2 years of treatment (seven patients). Two patients had late relapses, at 40 and 60 months after nivolumab initiation respectively. In total, two patients died: one due to metastatic colorectal cancer (6 months after nivolumab initiation) and one from coronavirus disease 2019 (COVID-19.) There was no late adverse events reported. In the entire cohort (n = 76), the estimated 5-year PFS was 27% after a median follow-up of 5.7 years, which is to the best of our knowledge, the longest follow-up ever reported in this setting. All patients who remain in remission had either achieved a CR or had been consolidated with an alloHSCT after a partial response. Although most relapses seem to occur during the first 3 years, some patients may experience late relapses, sometimes beyond 5 years, and no clear plateau can yet be seen (Figure S1). Among CR patients who have not been consolidated (n = 19), the estimated 5-years PFS was 42.3%. Although late relapses (>3 years) may occur (two patients), some patients experienced a very long remission (>5 years) with anti-PD-1 alone (six patients in our cohort), suggesting that a subset of patients may be cured. In conclusion, our study confirms that, with a long follow-up, nivolumab is an effective strategy in this very heavily pre-treated population. Furthermore, a subset of patients (10%–15%) may be cured with anti-PD-1 therapy alone. Guillaume Manson and Roch Houot performed the research, analysed the data and wrote the manuscript. All remaining authors reviewed and approved the final manuscript. Guillaume Manson and Pauline Brice have received consulting fees and/or honoraria from Bristol-Myers Squibb. Emmanuelle Nicolas-Virelizier received consulting fees from Sanofi. Aspasia Stamatoullas has received consulting fees from Takeda and Celgene. Roch Houot received honoraria from Bristol-Myers Squibb, MSD, Gilead, Kite, Roche, Novartis, Janssen, and Celgene. The remaining authors declare no competing financial interests. Figure S1.PFS (A and C) and OS (B and D) of the entire cohort (A and B) and according to best response upon nivolumab monotherapy (C and D). CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; PFS, progression-free survival; OS, overall survival. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.