Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: Long-term efficacy and quality of life analyses

The Keynote-54 trial studied pembrolizumab vs. placebo in patients who had had their high-risk stage III melanomas surgically removed. At five years of follow-up, recurrence-free survival, distant metastasis-free survival, and the time from randomisation until a second disease recurrence, progression of the first recurrence, or death, were all significantly improved in the patients who had received pembrolizumab. In addition, there were no clinically relevant differences in long-term quality of life between pembrolizumab and placebo.

The randomised phase III double-blind EORTC 1325/Keynote-054 trial evaluated pembrolizumab vs. placebo in patients with resected high-risk stage III melanoma. At a median follow-up of 3.5-year, pembrolizumab improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) as compared to placebo. By reducing the risk of metastasis after complete resection in high-risk stage III melanoma, pembrolizumab may also reduce exposure to new treatments, deterioration of physical functioning and global quality of life (QoL). Yet, pembrolizumab may cause long-term toxicities, negatively affecting QoL. Therefore, it is also important to investigate the treatment effect of pembrolizumab on long-term Global health status/QoL and physical functioning in the EORTC 1325-MG/Keynote-054 double-blinded trial. At ESMO 2022, 5-year results in terms of both efficacy and QoL were reported.

Study design

Between August 2015 and November 2016, 1,019 patients with resected high-risk stage III melanoma were randomised to pembrolizumab 200 mg or placebo every 3 weeks for a total of one year (18 doses). The EORTC QLQ-C30 questionnaire was administered at baseline, every 12 weeks during the first 2 years and then every 6 months until 4 years from randomisation. Long-term QoL was defined as the average QoL between 2 and 4 years from randomisation. The co-primary endpoints of the trial were RFS in the intention-to-treat (ITT) overall population and in patients with PDL1-positive tumours. DMFS was a secondary endpoint and progression/recurrence-free survival 2 (PFS2, time from randomisation until the second disease recurrence, a progression of the first recurrence, or death) an exploratory endpoint. With regard to the QoL assessments, the primary endpoints were the change from baseline to long-term global QoL and physical functioning scales. A difference >5 points between the treatment arms was deemed as clinically relevant.

Results

In this randomised, double-blind phase III trial, pembrolizumab, at a median follow-up of 4.9 years, was still associated with longer RFS than placebo (5-year rate of RFS 55% vs. 38%; HR[95%CI]: 0.61[0.51-0.72]), a longer DMFS (5-year rate of DMFS, 61% vs. 44% HR[95%CI]: 0.62[0.52-0.75]) and a longer PFS2 (5-year rate of PFS2, 68% vs. 56%, HR[95%CI]: 0.65[0.53-0.80]). With regard to the QoL assessments, the compliance was 93% at baseline and approximately 70% thereafter. The mean change from baseline to long-term global QoL was -0.56 in the pembrolizumab arm and 1.63 in the placebo arm, resulting in a treatment difference of -2.19 (95%CI: -4.65, 0.27), p= 0.08. The mean change from baseline to long-term physical functioning was -0.46 in the pembrolizumab group and 0.10 in the placebo group; the treatment difference was -0.56 (95%CI: -2.31, 1.19), p= 0.53. Furthermore, the differences regarding role, emotional, cognitive, and social functioning, as well as fatigue were neither statistically significant nor clinically relevant. Immune-related adverse events were not associated with clinically relevant changes in the investigated scales. In contrast, distant metastasis was associated with a clinically relevant deterioration in long-term global QoL, role and social functioning, and fatigue.

Conclusion

In this randomised, double-blind phase III trial, pembrolizumab, at a median follow-up of 4.9 years, was still associated with longer RFS, DMFS and PFS2 than placebo. Furthermore, there were no clinically relevant differences regarding long-term global QoL and physical functioning between the treatment arms. The occurrence of a distant metastasis was associated with a deterioration of the HRQoL. In the pembrolizumab arm, there was no evidence of impact of immune-related adverse events on the long-term HRQoL.

References

Eggermont A, et al. Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: 5-year results of the EORTC 1325-MG/Keynote-054 double-blinded phase III trial. Presented at ESMO 2022; Abstract P804.
Eggermont A, et al. Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: long-term quality of life analysis results of the EORTC 1325-MG/Keynote-054 double-blinded phase 3 trial. Presented at ESMO 2022; Abstract LBA44.