Superior recurrence-free survival benefit was observed with nivolumab over the active comparator ipilimumab that was consistent across disease stage, PD-L1 expression levels, and BRAF status in patients with resected stage III/IV melanoma and a high risk of recurrence, according to long-term findings from the phase III CheckMate 238 study reported at the ESMO Congress 2019 in Barcelona, Spain.
Jeffrey S. Weber of the Perlmutter Cancer Centre, NYU Langone Medical Centre in New York, USA presented updated results with 36 months of follow-up from the CheckMate 238 trial. Previously reported findings showed that the efficacy benefit demonstrated with nivolumab compared with ipilimumab was sustained at 24 months.
CheckMate 238 enrolled patients aged 15 years or more with completely resected stage IIIB/C or IV melanoma. The patients were randomly assigned 1:1 to receive nivolumab at 3 mg/kg every 2 weeks (453 patients) or ipilimumab at 10 mg/kg every 4 weeks for 4 doses and every 12 weeks thereafter (453 patients) for 1 year or less or until disease recurrence or unacceptable toxicity occurred.
The primary endpoint was recurrence-free survival (RFS), and exploratory endpoints included distant metastasis-free survival (DMFS) in patients with stage III disease, as well as potential biomarkers of efficacy.
Recurrence-free survival benefit was greater with nivolumab
At a median follow-up of 36 months, patients receiving nivolumab had superior RFS compared with patients on ipilimumab (hazard ratio [HR] 0.68; 95% confidence interval [CI], 0.56–0.82; p < 0.0001).
In the respective treatment arms, 3-year RFS rates were 58% versus 45%; with nivolumab versus ipilimumab 188 versus 239 events occurred in the 453 patients in each treatment arm.
DMFS was improved with nivolumab compared with ipilimumab, HR 0.78 (95% CI, 0.62–0.99).
Superior recurrence-free survival was consistent across subgroups according to stage, PD-L1 expression, and BRAF status
Prespecified subgroup analyses were performed that provided results that were consistent with the findings in the overall population at 36 months, and with the analysis done at 24 months.
HRs favoured nivolumab compared with ipilimumab across disease stages: stage IIIB HR 0.70, stage IIIC HR 0.68, and stage IV HR 0.71.
RFS was improved with nivolumab compared with ipilimumab in patients with PD-L1 expression ≥5% (HR 0.57; 95% CI, 0.39–0.83) and in patients with PD-L1 expression <5% (HR 0.73; 95% CI, 0.58–0.92). RFS favoured nivolumab in comparison with ipilimumab in patients with mutated BRAF (HR 0.79; 95% CI 0.59–1.06) and BRAF wild-type (HR 0.60; 95% CI, 0.45–0.80).
An evaluation of DMFS revealed similar results favouring nivolumab for the same disease characteristics: stage IIIB HR 0.78 and stage IIIC HR 0.81. DMFS was improved with nivolumab compared with ipilimumab in patients with PD-L1 expression ≥5% (HR 0.66; 95% CI, 0.41–1.06) and in patients with PD-L1 expression <5% (HR 0.83; 95% CI, 0.63–1.10). Nivolumab improved DMFS over ipilimumab in patients with mutated BRAF (HR 0.84; 95% CI, 0.58–1.20) and BRAF wild-type (HR 0.75; 95% CI, 0.53–1.07).
Exploratory biomarkers correlated with RFS with both nivolumab and ipilimumab
The investigators evaluated the association of RFS with a tumour interferon-gamma gene expression signature, tumour mutational burden (TMB), tumour CD8+ T-cell infiltration, and myeloid-derived suppressor cell (MDSC) levels. Individually, high TMB, high interferon-gamma gene expression signature levels, high CD8+ T-cell infiltration levels, and low MDSC levels correlated with improved RFS with both nivolumab and ipilimumab based on 36-month data.
Analysis of biomarker combinations (also based on 36-month data) suggested that high TMB and interferon-gamma gene expression signature levels correlate with improved RFS with both nivolumab and ipilimumab. Correlations were also observed between the combination of TMB and MDSC levels or MDSC and interferon-gamma gene expression signature levels and RFS.
The investigators concluded that nivolumab continued to demonstrate superior efficacy over ipilimumab with 36 months of follow-up in patients with stage III/IV melanoma at high risk of recurrence. This superior efficacy was observed across subgroups based on disease stage, PD-L1 expression, and BRAF status.
This trial was sponsored by Bristol-Myers Squibb.
1310O – Weber JS, Del Vecchio M, Mandala M, et al. Adjuvant nivolumab (NIVO) versus ipilimumab (IPI) in resected stage III/IV melanoma: 3-year efficacy and biomarker results from the phase 3 CheckMate 238 trial.