Safety and Efficacy Implications of Discontinuing Combination Ipilimumab and Nivolumab in Advanced Melanoma
A partir des données d'un essai de phase I incluant 94 patients atteints d'un mélanome de stade avancé, cette étude évalue l'efficacité, du point de vue de la survie globale à 3 ans, et la toxicité d'un traitement combinant nivolumab et ipilimumab
The advent of antibodies that block the immune checkpoints, cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1), have dramatically changed the therapeutic paradigm for melanoma.1-4 Ipilimumab, an anti-CTLA-4 antibody, was the first systemic therapy to improve overall survival (OS) in patients with advanced melanoma.1 Nivolumab and pembrolizumab, anti-PD-1 antibodies, were subsequently found to be superior to ipilimumab.2,3 Collectively, these checkpoint inhibitors result in durable responses and are now the mainstay of advanced melanoma management.1-4 Consistent with the immune-activating mechanism of these agents, induction of autoimmunity against multiple organ systems is common. Although these immune-related adverse events (irAEs) largely are manageable, they can be potentially life threatening.
Anti-CTLA-4 and anti-PD-1 antibodies exhibit complementary mechanisms of immune modulation, with ipilimumab plus nivolumab combination therapy showing improved response rates and progression-free survival (PFS) compared with either agent alone and improved OS compared with ipilimumab.4 However, this increased efficacy is accompanied by an increased rate of immune-related toxicities. Approximately 40% of patients treated with this doublet will cease therapy because of irAEs, and more than one half of these patients discontinue therapy during the induction phase.3,4 This high rate of treatment discontinuation in the first 3 months of therapy raises pertinent clinical questions. What are the efficacy implications for patients who discontinued therapy as a result of irAEs before completing induction? What are the clinical benefits and possible risks for ongoing maintenance, single-agent anti-PD-1 therapy in patients who discontinue combination induction therapy as a result of irAEs? Are severe irAEs that occur early and necessitate treatment cessation a useful clinical biomarker for treatment efficacy? What is the impact of immunosuppressive therapies used to treat irAEs on durability of response?
In the article that accompanies this editorial, Schadendorf et al5 report an analysis of pooled data from the CheckMate 069 and 067 studies to address important clinical questions with regard to toxicities seen with combination ipilimumab and nivolumab, their management, and the impact of treatment discontinuation during the induction phase on efficacy. In both studies, patients with advanced melanoma received ipilimumab 3 mg/kg every 3 weeks plus nivolumab 1 mg/kg every 3 weeks for four doses (induction), and then nivolumab alone at 3 mg/kg every 2 weeks (nivolumab maintenance) was given until progression or unacceptable toxicity. In the event of severe immune-related toxicity necessitating treatment cessation during the induction phase, both drugs were discontinued.
Of 407 patients who were treated with the combination, 176 (43%) discontinued because of an AE. Patients who discontinued treatment at any time because of an AE were less likely to have an elevated lactate dehydrogenase level (27% v 39%) or M1c disease (49% v 61%) compared with the patients who did not discontinue. This difference is consistent with the increased rate of immune-related toxicities seen with high-dose ipilimumab (10 mg/kg) in the adjuvant6 versus metastatic7 setting. Of note, in a pilot study that examined perioperative combination of ipilimumab and nivolumab, a much higher rate of treatment discontinuation in 15 of 18 patients was necessary to manage irAEs during induction.8 Taken together, these data support the hypothesis that combination therapy may carry more toxicity in patients with early-stage disease because of the immunosuppressive effects of a higher disease burden in the metastatic setting. If confirmed, the association with low-volume or microscopic disease and an increased risk of toxicity may have a significant impact on the use of combination ipilimumab and nivolumab in the adjuvant (ClinicalTrials.gov identifier: NCT03068455) or neoadjuvant (ClinicalTrials.gov identifier: NCT02977052) setting where an elevated risk of life-threatening toxicities would be considered less acceptable.
Journal of Clinical Oncology , éditorial en libre accès, 2016