Sustained benefit of nivolumab over ipilimumab in the adjuvant treatment of resected stage III or IV melanoma with a high risk of recurrence

In the initial report of data from CheckMate 238, at a minimum follow-up of 18 months adjuvant nivolumab demonstrated a significantly longer recurrence-free survival (RFS) compared to ipilimumab in patients with resected stage III or IV melanoma. During ASCO 2018 updated results with an additional 6 months of follow-up were presented. These data demonstrate the sustained efficacy benefit of nivolumab compared to ipilimumab, regardless of disease stage, PD-L1 expression, or BRAF mutation status. The 24-month estimate for RFS was 63% in the nivolumab treated patients, which was significantly higher than the 50% seen with ipilimumab (HR [95%CI]: 0.66 [0.54-0.81]; p< 0.0001). In addition to this, nivolumab also showed a clinically and statistically significant improvement in the distant metastasis free survival (DMFS) compared to ipilimumab.

The 5-year recurrence rate for patients with high-risk stage III/IV resected melanoma is substantial, ranging from 50% to 80%. In the phase III EORTC 18071 trial, ipilimumab (10mg/kg) was previously shown to induce a significant improvement in RFS, DMFS and overall survival (OS) compared to placebo. Interestingly, in this study the RFS started to plateau after 3 years with RFS rates of 52%, 46%, 43% and 41% at 2, 3, 4 and 5 years, respectively. Building further on the success of this trial, the CheckMate 238 study evaluated whether adjuvant therapy with nivolumab would lead to even better outcomes than adjuvant ipilimumab. To this end, 906 patients with high-risk, completely resected stage IIIB/C or stage IV melanoma who received no prior systemic therapy were randomised (1:1) to either nivolumab (3mg/kg q2w), or ipilimumab (10 mg/kg IV q3w for 4 doses and then q12w from week 24) for a total duration of maximum 1 year. The primary endpoint of the trial was RFS, with OS, RFS by PD-L1 expression, safety and quality of life as secondary objectives. In addition to that, DMFS formed an exploratory endpoint of the study.

The median age of patients in the trial was 55 years, 58% was male and 81% had stage IIIB or IIIC disease. One third of patients had PD-L1 expression in at least 5% of tumour cells, 42% was found to be BRAF mutant and 91% had an LDH level at or below the upper limit of normal. The majority of patients had cutaneous melanoma (approximately 85%), with some cases of mucosal and acral melanoma. In total, 61% of patients on nivolumab and 27% of patients in the ipilimumab arm completed 1 year of treatment.

At a minimum follow-up of 24 months, the median RFS continued to be significantly longer for nivolumab compared to ipilimumab. The median RFS in the nivolumab arm was 30.8 months as compared to 24.1 months in patients treated with ipilimumab (HR [95%CI]: 0.66 [0.54-0.81]; p< 0.0001). At 24 months, 63% of patients in the nivolumab arm was recurrence free as compared to 50% of ipilimumab treated patients. This difference in the incidence of recurrence events was mainly driven by distant metastasis, which was seen in 21% of patients on nivolumab vs. 28% in the ipilimumab arm. The benefit of nivolumab over ipilimumab was consistently seen in all investigated subgroups, irrespective of age, sex, disease stage, the presence of ulceration, the extent of lymph node involvement, the PD-L1 expression level and the BRAF mutation status. Also the DMFS continued to be significantly longer for nivolumab treated patients compared to ipilimumab, with 24-month DMFS rates of 71% and 64% respectively (HR [95%CI]: 0.76 [0.59-0.98]; p= 0.0340). Subsequent therapies were received by 31.1% of patients in the nivolumab group and by 41.1% in the ipilimumab group. Interesting to see in this respect was that 8% of patients in the nivolumab arm was subsequently treated with a PD1 immune checkpoint inhibitor.

In summary, with extended follow-up, adjuvant nivolumab demonstrated a sustained efficacy benefit over ipilimumab in patients with resected stage III/IV melanoma at high risk of recurrence, regardless of disease stage, PD-L1 expression, or BRAF mutation status. These data further support the use of nivolumab in patients with resected stage III or IV melanoma.

Reference

JS. Weber, Mandalà M, Del Vecchio M, et al. Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: Updated results from a phase III trial (CheckMate 238). Presented at ASCO 2018; Abstract 9502