Seven-year analysis of adjuvant pembrolizumab versus placebo in stage III melanoma in the EORTC1325 / KEYNOTE-054 trial

Eur J Cancer. 2024 Nov:211:114327. doi: 10.1016/j.ejca.2024.114327. Epub 2024 Sep 12.

Abstract

In the previously reported primary analyses of this phase 3 trial, 12 months of adjuvant pembrolizumab resulted in significantly longer recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) than placebo in patients with resected high risk stage III melanoma. Stability of these benefits when the median follow-up was 3.5 and 5 years was published. Here we report results with a longer follow-up.

Methods: We randomized 1019 patients to receive pembrolizumab 200 mg or placebo, intravenously every 3 weeks for a total of 18 doses. RFS in the overall population and in the subgroup of patients with melanoma positive for the PD-1 ligand (PD-L1) were co-primary endpoints. DMFS in these two populations was a secondary and progression/recurrence-free survival 2 (PRFS2) an exploratory endpoint.

Results: The median follow-up was 6.9 years. In the overall intention-to-treat population, RFS was longer in the pembrolizumab group than in the placebo group (HR 0.63, 95 % CI 0.53 to 0.74). RFS at 7 years was 50 % (95 % CI 46 % to 55 %) in the pembrolizumab and 36 % (95 % CI 32 % to 41 %) in the placebo group. Positive effects were present both for loco-regional recurrences and distant metastases, and across substages IIIA-IIIB-IIIC, and PD-L1 positive and PD-L1 negative as well as for BRAF mutant and BRAF wild type populations. DMFS was longer in the pembrolizumab group than in the placebo group (HR 0.64, 95 % CI 0.54 to 0.76). DMFS at 7 years was 54 % (95 % CI 50 % to 59 %) in the pembrolizumab and 42 % (95 % CI 37 % to 46 %) in the placebo group. PRFS2 was longer in the pembrolizumab group than in the placebo group (HR 0.69, 95 % CI 0.57 to 0.84). PRFS2 at 7 years was 61 % (95 % CI 57 % to 66 %) in the pembrolizumab and 53 % (95 % CI 49 % to 57 %) in the placebo group.

Conclusions: The 7-year analysis of adjuvant therapy with pembrolizumab demonstrated a sustained improvement in the long-term RFS, DMFS and PRFS2 compared with placebo in patients with resected stage III melanoma.

Keywords: Adjuvant treatment; Anti-PD1; Anti-PDL1; Clinical trial; Immune checkpoint inhibitors; Immunotherapy; Melanoma; Pembrolizumab; Phase 3.

Publication types

  • Randomized Controlled Trial
  • Clinical Trial, Phase III
  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Antibodies, Monoclonal, Humanized* / therapeutic use
  • Antineoplastic Agents, Immunological* / therapeutic use
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / metabolism
  • Chemotherapy, Adjuvant
  • Double-Blind Method
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Melanoma* / drug therapy
  • Melanoma* / mortality
  • Melanoma* / pathology
  • Middle Aged
  • Neoplasm Staging*
  • Skin Neoplasms* / drug therapy
  • Skin Neoplasms* / mortality
  • Skin Neoplasms* / pathology
  • Time Factors

Substances

  • pembrolizumab
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents, Immunological
  • B7-H1 Antigen