A long-term follow-up analysis of a large phase 3 randomized clinical trial has found that adjuvant pembrolizumab provides sustained benefits for patients with resected high-risk stage III melanoma compared to placebo. The study, published in the European Journal of Cancer in September 2024, reports 7-year outcomes from the EORTC 1325/KEYNOTE-054 trial.
This double-blind, placebo-controlled trial was conducted at 123 sites across 23 countries. It was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. The study aimed to evaluate the long-term efficacy of 12 months of adjuvant pembrolizumab versus placebo in patients who had undergone complete resection of high-risk stage III melanoma.
A total of 1019 patients were randomized 1:1 to receive either pembrolizumab 200 mg or placebo intravenously every 3 weeks for up to 18 doses (approximately 1 year). Eligible patients were 18 years or older with histologically confirmed cutaneous melanoma and metastasis to regional lymph nodes. They must have undergone complete regional lymphadenectomy within 13 weeks prior to starting treatment. Patients had either stage IIIA melanoma with at least one micrometastasis >1 mm in diameter, or stage IIIB/IIIC disease without in-transit metastases, according to AJCC 7th edition staging.
Key exclusion criteria included autoimmune disease, uncontrolled infections, use of systemic corticosteroids, and prior systemic therapy for melanoma. Patients were stratified by disease stage and geographic region. The co-primary endpoints were recurrence-free survival (RFS) in the overall population and in the subgroup of patients with PD-L1 positive tumors.
At a median follow-up of 6.9 years, the study found that pembrolizumab significantly improved RFS compared to placebo (hazard ratio 0.63, 95% CI 0.53-0.74). The 7-year RFS rate was 50% in the pembrolizumab group versus 36% in the placebo group. This benefit was consistent across subgroups, including disease stage, PD-L1 status, and BRAF mutation status.
Distant metastasis-free survival (DMFS) was also significantly prolonged with pembrolizumab (HR 0.64, 95% CI 0.54-0.76). The 7-year DMFS rate was 54% with pembrolizumab versus 42% with placebo. An exploratory endpoint, progression/recurrence-free survival 2 (PRFS2), showed improvement as well (HR 0.69, 95% CI 0.57-0.84). The 7-year PRFS2 rate was 61% for pembrolizumab versus 53% for placebo.
Importantly, the benefits of pembrolizumab were observed across all analyzed subgroups. This included patients with PD-L1 positive and negative tumors, those with BRAF V600 mutations and wild-type BRAF, and across stage IIIA, IIIB, and IIIC disease. The hazard ratios for RFS were 0.76, 0.57, and 0.64 for stage IIIA, IIIB, and IIIC, respectively.
In patients with BRAF V600 E/K mutant melanoma, the 7-year RFS rate was 50% with pembrolizumab versus 33% with placebo (HR 0.59, 99% CI 0.43-0.83). This benefit appears similar to that observed in the COMBI-AD trial of adjuvant dabrafenib plus trametinib in BRAF-mutant melanoma.
The study had some limitations to consider. The overall survival data are not yet mature, with analysis planned after 380 deaths or 10 years from randomization of the last patient. Additionally, there were differences in post-recurrence treatments between the arms that may have impacted some of the secondary endpoints. Among patients with a recurrence, anti-PD-1/PD-L1 therapy was used more frequently in the placebo arm (65% vs 28%), while BRAF/MEK inhibitors were used more often in the pembrolizumab arm (19% vs 10%).
The authors concluded that this 7-year analysis demonstrates a sustained, long-term benefit of adjuvant pembrolizumab in high-risk stage III melanoma. The improvements in RFS, DMFS, and PRFS2 were maintained with extended follow-up. The consistency of benefit across subgroups suggests broad applicability of this treatment approach.
These results have important clinical implications for the management of resected stage III melanoma. They provide further support for the use of adjuvant anti-PD-1 therapy in this patient population. The durable nature of the benefit, even years after completing the 1-year course of treatment, is particularly encouraging.
However, the landscape of melanoma management continues to evolve rapidly. Recent studies have shown promising results with neoadjuvant immunotherapy approaches. The SWOG1801 trial found improved event-free survival with 3 doses of pembrolizumab given before surgery followed by adjuvant therapy, compared to adjuvant therapy alone. Even more striking results were seen in the NADINA trial, where 2 cycles of ipilimumab plus nivolumab given preoperatively led to a major improvement in event-free survival compared to adjuvant nivolumab.
These neoadjuvant/perioperative approaches may become the new standard of care for macroscopic stage III melanoma. However, the EORTC 1325/KEYNOTE-054 data remain highly relevant for patients who have already undergone upfront surgery, as well as those with microscopic stage III disease detected by sentinel lymph node biopsy.
The study also provides valuable long-term data on the efficacy of pembrolizumab in BRAF-mutant melanoma. While targeted therapy with BRAF/MEK inhibitors is an option for these patients, the similar magnitude of benefit seen with pembrolizumab supports immunotherapy as an appropriate choice regardless of BRAF status.
One area that requires further research is the optimal duration of adjuvant therapy. This study used a 1-year treatment course, but it's unclear if longer durations might provide additional benefit or if shorter courses could maintain efficacy while reducing toxicity and costs. Additionally, biomarker studies to better identify which patients derive the most benefit from adjuvant immunotherapy are needed.
The lack of mature overall survival data is a limitation, as this is ultimately the most critical endpoint. However, given the strong correlation between RFS/DMFS and overall survival in melanoma, a survival benefit is anticipated. The planned analysis at 10 years or 380 deaths will be crucial to confirm this.
In conclusion, this long-term follow-up of the EORTC 1325/KEYNOTE-054 trial provides robust evidence for the sustained efficacy of adjuvant pembrolizumab in high-risk stage III melanoma. The consistent benefits across subgroups and endpoints support its use as a standard of care option in this setting. However, ongoing research into neoadjuvant approaches and biomarker-guided patient selection may further refine treatment strategies. As the melanoma treatment landscape continues to evolve rapidly, these data provide an important benchmark for long-term outcomes with adjuvant anti-PD-1 therapy.
References
Eggermont AM, Kicinski M, Blank CU, et al. Seven-year analysis of adjuvant pembrolizumab versus placebo in stage III melanoma in the EORTC1325 / KEYNOTE-054 trial. Eur J Cancer. 2024;211:114327. doi:10.1016/j.ejca.2024.114327
