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

Caroline Robert*, Wen Jen Hwu, Omid Hamid, Antoni Ribas, Jeffrey S. Weber, Adil I. Daud, F. Stephen Hodi, Jedd D. Wolchok, Tara C. Mitchell, Peter Hersey, Roxana Dronca, Richard W. Joseph, Celine Boutros, Le Min, Georgina V. Long, Jacob Schachter, Igor Puzanov, Reinhard Dummer, Jianxin Lin, Nageatte IbrahimScott J. Diede, Matteo S. Carlino, Anthony M. Joshua

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)182-191
Number of pages10
JournalEuropean Journal of Cancer
StatePublished - Feb 2021
Externally publishedYes


  • Advanced melanoma
  • Corticosteroid use
  • Immune-checkpoint inhibitors
  • Immune-related adverse events
  • Immunomodulating drugs
  • PD-1 inhibitors
  • Pembrolizumab


Dive into the research topics of 'Long-term safety of pembrolizumab monotherapy and relationship with clinical outcome: A landmark analysis in patients with advanced melanoma'. Together they form a unique fingerprint.

Cite this