Considerations on the Role of Pembrolizumab Adjuvant Therapy in AJCC-8 Stage IIIA Melanoma
Updated results from the EORTC1325/KEYNOTE-054 trial indicate that pembrolizumab adjuvant therapy, given for 1 year, provides a sustained improvement in relapse-free survival (RFS) in patients with resected stage III melanoma (3-year RFS rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively; hazard ratio, 0.56; 95% CI, 0.47 to 0.68).1 The authors also point out that the impact of pembrolizumab on RFS was similar in subgroups according to American Joint Committee on Cancer (AJCC)-7 and AJCC-8 staging.1
The results from trials with immune checkpoint inhibitors or with targeted therapy are profoundly changing the management of melanoma patients with nodal disease. However, their benefit to patients in AJCC-8 stage IIIA deserves further discussion.1,2
Patients were stratified at random assignment according to AJCC-7.1,2 The new AJCC 8th edition redefined stage III into four substages IIIA-IIID instead of three to offer better granularity as regards prognosis.3 Notably, the new stage IIIA, according to AJCC-8, has better prognosis as it now only includes patients with 1-3 positive sentinel nodes who either have nonulcerated melanoma ≤ 2 mm or ulcerated melanoma ≤ 1 mm Breslow thickness.3 Studies have shown that about 50% of patients with AJCC-7 stage IIIA had stage migration to AJCC-8 stage IIIB or IIIC because of a tumor Breslow thickness of 2.1 to 4 mm or > 4 mm, respectively.4 A small percentage of patients with AJCC-7 stage IIIB (approximately 3%), with low-risk features (ie, patients with ulcerated thin melanoma ≤ 1 mm), moved to AJCC-8 stage IIIA.4
We previously questioned the role of dabrafenib plus trametinib combination therapy in AJCC-8 stage IIIA BRAF-mutated melanoma.5 The absolute benefit in this substage was small and decreased over time.2,5 In the most recent analysis,6 the RFS at 5 years for patients with AJCC-8 stage IIIA in the treatment group is similar to that of the placebo group, contrasting with results in the other stages IIIB, IIIC, or IIID (Supplemental Fig S2 of the report by Dummer et al).6
The situation looks different with pembrolizumab as the absolute benefit on RFS in AJCC-8 stage IIIA is about 15 points at 3 years: RFS 82.6% (95% CI, 67.0 to 91.3) versus 67.4% (95% CI, 49.1 to 80.4) for pembrolizumab versus placebo, respectively, and further increases with time (Fig 5).1 Despite this, caution is necessary. Ideally, determining the benefit from adjuvant therapy in AJCC-8 stage IIIA would require a trial where this substage is part of the stratification at random assignment, and patients are included without major restrictions. This is not the case, however. The analysis is a post hoc analysis, where patients were restratified according to the new AJCC-8, with missing information for some patients, and thus subject to potential bias. The number of patients with AJCC-8 stage IIIA included in the analysis is small and the 95 CIs wide. Notably, the RFS of AJCC-8 stage IIIA in the placebo group falls rapidly, being below 50% at 42 months, and below that of the stage IIIB placebo group (Fig 5).1 This RFS rate is also quite lower than the 4-year and 5-year RFS of 71% for the AJCC-8 stage IIIA placebo group of the dabrafenib plus trametinib trial (Supplemental Fig S2 in the work of Dummer et al).6 Longer follow-up is thus needed, as well as specific data regarding the occurrence of distant metastases in patients with AJCC-8 stage IIIA.
Importantly, current trials cannot be representative of AJCC-8 stage IIIA in clinical practice because only patients with sentinel node metastasis > 1 mm were included.1,2,7 In the AJCC database, stage IIIA represents approximately 22% of all patients with stage III (Fig 7 in the work of Gershenwald),3 whereas in the EORTC1325/KEYNOTE-054 trial, stage IIIA represented only 8.4% (82 of 979) of patients with stage III restratified according to AJCC-8 (Fig 3).1 Tumor burden is a major prognostic factor,3,8 and patients with metastasis ≤ 1 mm are expected to have much better prognosis.8 Among patients with AJCC-8 stage IIIA melanoma, the percentage of those with sentinel node metastasis > 1 mm is not well-known. Based on the findings from a multicenter trial in patients with thin (T1) melanoma,9 only 19.4% of sentinel node-positive patients had a sentinel node metastasis of > 1 mm.10
Side effects from 12 months of anti-programmed death-1 therapy with pembrolizumab should be considered as toxicity is not insignificant. Immune-related adverse events of grade 3 or higher occurred in 7.7% of the patients.1
In conclusion, it might be premature to offer pembrolizumab widely to patients with AJCC-8 stage IIIA melanoma. The opinion of the authors would be highly appreciated.
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