Long-term safety of pembrolizumab monotherapy and relationship with clinical outcome: A landmark analysis in patients with advanced melanoma

Eur J Cancer. 2021 Feb;144:182-191. doi: 10.1016/j.ejca.2020.11.010. Epub 2020 Dec 24.


Objective: Long-term safety of pembrolizumab in melanoma was analyzed in KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006.

Patients and methods: Analysis involved patients who received ≥1 pembrolizumab dose. Lead-time bias was addressed via landmark analyses in patients who were progression-free before day 147.

Results: Adverse events (AEs) were analyzed for 1567 patients (median follow-up, 42.4 months). Most AEs were mild/moderate; grade 3/4 treatment-related AEs occurred in 17.7% of patients. Two pembrolizumab-related deaths occurred. Any-grade immune-mediated AEs (imAEs) occurred in 23.0%, most commonly hypothyroidism (9.1%), pneumonitis (3.3%), and hyperthyroidism (3.0%); grade 3/4 imAEs occurred in 6.9% of patients. Most imAEs occurred within 16 weeks of treatment. In landmark analysis, patients who did (n = 79) versus did not (n = 384) develop imAEs had similar objective response rates (ORRs) (64.6% versus 63.0%); median time to response (TTR), 5.6 months for both; median duration of response (DOR), 20.0 versus 25.3 months; median progression-free survival (PFS), 17.0 versus 17.7 months; median overall survival (OS), not reached (NR) versus 43 months (p = 0.1104). Patients who did (n = 17) versus did not (n = 62) receive systemic corticosteroids had similar ORRs (70.6% vs. 62.9%) and median TTR (6.4 vs. 5.6 months) but numerically shorter median PFS (9.9 vs. 17.0 months); median DOR, 14.2 months versus NR; median OS, NR for both.

Conclusions: These results enhance the knowledge base for pembrolizumab in advanced melanoma, with no new toxicity signals after lengthy follow-up of a large population. In landmark analyses, pembrolizumab efficacy was similar regardless of imAEs or systemic corticosteroid use.

Clinical trial registry: NCT01295827, NCT01704287, NCT01866319.

Keywords: Advanced melanoma; Corticosteroid use; Immune-checkpoint inhibitors; Immune-related adverse events; Immunomodulating drugs; PD-1 inhibitors; Pembrolizumab.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized / adverse effects*
  • Antineoplastic Agents, Immunological / adverse effects*
  • Clinical Trials as Topic / statistics & numerical data*
  • Drug-Related Side Effects and Adverse Reactions / etiology
  • Drug-Related Side Effects and Adverse Reactions / pathology*
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Melanoma / drug therapy*
  • Melanoma / pathology
  • Meta-Analysis as Topic
  • Middle Aged
  • Prognosis
  • Young Adult


  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents, Immunological
  • pembrolizumab

Associated data

  • ClinicalTrials.gov/NCT01295827
  • ClinicalTrials.gov/NCT01866319
  • ClinicalTrials.gov/NCT01704287