Superior recurrence-free survival benefit was observed with nivolumab vs ipilimumab—and was consistent across disease stage, programmed cell death ligand 1 (PD-L1) expression levels, and BRAF mutation 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 by Weber et al at the European Society for Medical Oncology (ESMO) Congress 2019 (Abstract 1310O).

Jeffrey S. Weber, MD, PhD

Presenting author Jeffrey S. Weber, MD, PhD, of the Perlmutter Cancer Centre, NYU Langone Medical Center, shared updated results with 36 months of follow-up from the trial. Previously reported findings in the Journal of Clinical Oncology showed that the efficacy benefit demonstrated with nivolumab compared with ipilimumab was sustained at 24 months.

Methods

CheckMate 238 enrolled patients aged 15 years old or older with completely resected stage IIIB/C or IV melanoma. The patients were randomly assigned 1:1 to receive nivolumab 3 mg/kg every 2 weeks (n = 453) or ipilimumab 10 mg/kg every 4 weeks for 4 doses and every 12 weeks thereafter (n = 453) 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 in patients with stage III disease as well as potential biomarkers of efficacy.

3-Year Follow-up Results

At a median follow-up of 36 months, patients receiving nivolumab had superior RFS compared with patients receiving ipilimumab (hazard ratio [HR] = 0.68; 95% confidence interval [CI] = 0.56–0.82, P < .0001).

In the respective treatment arms, 3-year RFS rates were 58% vs 45%; with nivolumab vs ipilimumab, 188 vs 239 events occurred in the 453 patients in each treatment arm, respectively.

Distant metastasis–free survival was improved with nivolumab vs ipilimumab (HR = 0.78; 95% CI = 0.62–0.99).

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 favored nivolumab vs 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 was improved with nivolumab vs ipilimumab in patients with a BRAF mutation (HR = 0.79; 95% CI = 0.59–1.06) and wild-type BRAF (HR = 0.60; 95% CI = 0.45–0.80).

An evaluation of distant metastasis–free survival revealed similar results favoring nivolumab for the same disease characteristics: stage IIIB (HR = 0.78) and stage IIIC (HR = 0.81). Distant metastasis–free survival 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 treatment resulted in improved distant metastasis–free survival vs ipilimumab in patients with a BRAF mutation (HR = 0.84; 95% CI = 0.58–1.20) and wild-type BRAF (HR = 0.75; 95% CI = 0.53–1.07).

The investigators evaluated the association of RFS with a tumor interferon-gamma gene expression signature, tumor mutational burden, tumor CD8-positive T-cell infiltration, and myeloid-derived suppressor cell levels. Individually, high tumor mutational burden, high interferon-gamma gene expression signature levels, high CD8+ T-cell infiltration levels, and low myeloid-derived suppressor cell 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 tumor mutational burden and interferon-gamma gene expression signature levels correlated with improved RFS with both nivolumab and ipilimumab. Correlations were also observed between the combination of tumor mutational burden and myeloid-derived suppressor cell levels or myeloid-derived suppressor cell 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.

Disclosure: CheckMate 238 was funded by Bristol-Myers Squibb. For full disclosures of the study authors, visit esmo.org.