Long-term findings from the phase III, CheckMate 238 study showed that nivolumab improved 4-year recurrence-free survival (RFS) compared with ipilimumab in patients with resected stage IIIB-C or IV melanoma in the overall population and across subgroups of patients stratified by disease stage (per AJCC 7th edition) and tumour programmed death ligand 1 (PD-L1) expression levels. The findings were presented by Jeffrey Weber of the NYU Langone Perlmutter Cancer Centre in New York, NY, USA at the ESMO Virtual Congress 2020.
Dr. Weber cited previous findings from this study, which demonstrated that adjuvant nivolumab improved RFS over ipilimumab. At ESMO 2020, he presented updated 48-month RFS, distant metastases-free survival (DMFS) and primary overall survival (OS) results from a comparison of nivolumab versus ipilimumab in patients with resected stage IIIB-C/IV melanoma who participated in the phase III CheckMate 238 study.
The study enrolled patients aged ≥15 years with completely resected stage IIIB–C or IV melanoma who were stratified by stage and tumour PD-L1 status. The patients were randomised 1:1 to receive nivolumab at 3 mg/kg every 2 weeks (453 patients) or ipilimumab at 10 mg/kg every 3 weeks for 4 doses and every 12 weeks thereafter (453 patients). Treatment was administered for ≤1 year or until of disease recurrence or unacceptable toxicity.
The primary endpoint of CheckMate 238 was RFS; key secondary endpoints included OS and safety, while DMFS in stage III disease was a key exploratory endpoint.
Long-term outcomes with nivolumab were superior to ipilimumab at 48 months
With 48 months of follow-up, nivolumab continued to demonstrate superior RFS compared with ipilimumab with 4-year RFS rates of 52% vs 41% and median RFS of 52.4 months vs 24.1 months (hazard ratio [HR] 0.71; 95% confidence interval [CI] 0.60–0.86]; p = 0.0003). Nivolumab showed improved RFS compared with ipilimumab in IIIB-C, and IV disease stage subgroups (HR 0.71; 95% CI 0.58-0.88) and (HR 0.74; 95% CI 0.49–1.11), respectively.
Regarding the exploratory endpoint, nivolumab also improved DMFS over ipilimumab in patients with stage III disease with 4-year DMFS rates of 59% vs 53% (HR 0.79; 95% CI 0.63–0.99).
With 48 months of follow-up, 211 OS events were observed, which was lower than the anticipated 302 events, and, in the overall population, yielded comparable OS rates of 78% with nivolumab and 77% with ipilimumab (HR 0.87; 95.% CI 0.66–1.14, p = 0.315).
Improved RFS was observed in nivolumab-treated patients with in-transit metastases without nodal involvement with 4-year RFS rates of 49% vs 41% (HR 0.73; 95% CI 0.47–1.12) as well as patients with BRAF mutant tumours with rates of 52% vs 44% (HR 0.79; 95% CI 0.60–1.05) and BRAF wild-type tumours with rates of 50% vs 39% (HR 0.69; 95% CI 0.53–0.91).
Fewer patients on nivolumab required subsequent treatment
Subsequent systemic therapy was administered to 150 (33%) nivolumab-treated patients compared with 189 (42%) patients in the ipilimumab arm. A greater proportion of ipilimumab-treated than of nivolumab-treated patients (34% vs 23%) received subsequent systemic immunotherapy.
Of patients who had disease recurrence in the nivolumab (212 patients) and ipilimumab arm (253 patients), 69% and 70% of patients received subsequent systemic therapy, respectively, with more patients in the ipilimumab arm (57%) receiving subsequent systemic immunotherapy compared with patients in the nivolumab arm (49%).
More patients in the ipilimumab arm experienced any grade late-emergent, treatment-related adverse events (TRAEs; those voluntarily reported >100 days after the last dose). Late-emergent TRAEs were reported by 18 (4%) nivolumab-treated patients versus 25 (6%) ipilimumab-treated patients. In the respective arms, 3 (1%) patients had grades 3/4 late-emergent TRAEs versus 7 (2%) patients.
Based upon these 48-month data, which showed that nivolumab had sustained improvement of RFS and DMFS compared to ipilimumab in patients with stage IIIB–C/IV resected melanoma and high risk of recurrence, the authors concluded that nivolumab provided superior patient benefit.
With fewer OS events than anticipated, the OS rates were similar for both agents, with more patients in the ipilimumab arm receiving subsequent therapy, and more ipilimumab-treated patients receiving subsequent immunotherapy.
No new safety concerns were noted based on the low rate of voluntarily reported late-emergent TRAEs.
In addition to this presentation, the analysis will also appear in a simultaneous publication in The Lancet Oncology (Ascierto PA, et al. Lancet Oncol 2020;ePub ahead of print and covered in an editorial article).
The study was funded by Bristol Myers Squibb.
1076O – Weber J, Del Vecchio M, Mandala M, et al. Adjuvant nivolumab (NIVO) vs ipilimumab (IPI) in resected stage III/IV melanoma: 4-y recurrence-free and overall survival (OS) results from CheckMate 238. ESMO Virtual Congress 2020.