Ipilimumab addition to nivolumab showed no significant clinical benefit in resected advanced stage melanoma

  1. There was no significant difference in recurrence-free survival observed between all randomly assigned patients and the PD-L1 < 1% subgroup.
  2. The Incidence of adverse events of grades 3 or 4 was higher in the combination group. An increase in lipase levels, an increase in ALT levels, and fatigue were the most common grades 3 or higher in the combination arm.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Nivolumab and ipilimumab (both immune checkpoint inhibitors) each previously showed clinical benefit in patients with resected stage 3 or 4 melanoma. This randomized, double-blind clinical trial explored the efficacy and safety of adjuvant nivolumab and ipilimumab compared to adjuvant nivolumab alone. Patients were then stratified by tumour stage and tumour PD-L1 expression levels, whereby the PD-L1 < 1% subgroup was of specific interest. Minimum follow-up was 23.7 months. No significant difference in recurrence-free survival (RFS) was observed between all randomly assigned patients and the PD-L1 < 1% subgroup. Median RFS was not observed for all randomly assigned patients, but 24-month RFS rates in these patients were similar in both arms. Health-related quality of life was similar in both arms, with no clinically significant changes from baseline. Occurrence of treatment-related adverse events (TRAEs) of grades 3 or 4 were higher in the combination group. An increase in lipase levels, an increase in ALT levels, and fatigue were the most common TRAEs of grades 3 or 4 in the combination arm, whereas for the nivolumab arm it was an increase in lipase levels, a rash, and diarrhea. A cautionary note in this study includes its lower dosing compared to other combination trials of nivolumab and ipilimumab as other trials with higher doses have suggested survival benefit. Overall, ipilimumab addition to nivolumab combination treatment for resected advanced stage melanoma patients remains a controversial topic, it is unclear whether single agent vs. dual blockade is the ideal adjuvant treatment and possibly related to drug exposure differences.

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Relevant Reading: Role of immune checkpoint inhibitors in the revolutionization of advanced melanoma care

In-Depth [randomized control trial]: This international phase III trial randomly assigned 1833 patients with resected stage IIIB-D or stage IV melanoma to receive either nivolumab or nivolumab plus ipilimumab; 916 were in the nivolumab arm and 917 in the combination arm. Patients were later stratified by tumour stage and tumour PD-L1 expression levels, whereby the PD-L1 < 1% subgroup was of specific interest. In all randomly assigned patients, 24-month RFS rates were 64.6% in the combination arm and 63.2% in the nivolumab arm (hazard ratio [HR], 0.92; 97.295% confidence interval [CI], 0.77 to 1.09; P=0.269). For the PD-L1 < 1% subgroup, 24-month RFS rates were 53.6% and 52.4%, respectively (HR, 0.91; 95% CI, 0.73 to 1.14; P=0.417). TRAEs of grades 3 or 4 occurred in 32.6% and 12.8% of patients in the combination arm and nivolumab arm, respectively. In the combination group, an increase in lipase levels (5.2%), an increase in ALT levels (3.3%), and fatigue (2.4%) were the most common TRAEs of grades 3 or 4, but for the nivolumab arm it was an increase in lipase levels (1.9%), a rash (0.7%), and diarrhea (0.5%. Overall, addition of ipilimumab to nivolumab did not improve RFS further studies are needed to ascertain whether drug levels are key factors in survival differences compared to other trials.

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