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PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma.

  • Author(s): Ribas, Antoni
  • Algazi, Alain
  • Ascierto, Paolo A
  • Butler, Marcus O
  • Chandra, Sunandana
  • Gordon, Michael
  • Hernandez-Aya, Leonel
  • Lawrence, Donald
  • Lutzky, Jose
  • Miller, Wilson H
  • Campbell, Katie M
  • Delafont, Bruno
  • Marshall, Shannon
  • Mueller, Nancy
  • Robert, Caroline
  • et al.
Abstract

Combining PD-L1 blockade with inhibition of oncogenic mitogen-activated protein kinase (MAPK) signaling may result in long-lasting responses in patients with advanced melanoma. This phase 1, open-label, dose-escalation and -expansion study (NCT02027961) investigated safety, tolerability and preliminary efficacy of durvalumab (anti-PD-L1) combined with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for patients with BRAF-mutated melanoma (cohort A, n = 26), or durvalumab and trametinib given concomitantly (cohort B, n = 20) or sequentially (cohort C, n = 22) for patients with BRAF-wild type melanoma. Adverse events and treatment discontinuation rates were more common than previously reported for these agents given as monotherapy. Objective responses were observed in 69.2% (cohort A), 20.0% (cohort B) and 31.8% (cohort C) of patients, with evidence of improved tumor immune infiltration and durable responses in a subset of patients with available biopsy samples. In conclusion, combined MAPK inhibition and anti-PD-L1 therapy may provide treatment options for patients with advanced melanoma.

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