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

Antoni Ribas; Alain Algazi; Paolo A. Ascierto; Marcus O. Butler; Sunandana Chandra; Michael Gordon; Leonel Hernandez-Aya; Donald Lawrence; Jose Lutzky; Wilson H. Miller; Katie M. Campbell; Bruno Delafont; Shannon Marshall; Nancy Mueller; Caroline Robert

doi:10.1038/s41467-020-19810-w

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

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

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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.

Original language	English
Article number	6262
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-19810-w
Publication status	Published - 1 Dec 2020

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Ribas, A., Algazi, A., Ascierto, P. A., Butler, M. O., Chandra, S., Gordon, M., Hernandez-Aya, L., Lawrence, D., Lutzky, J., Miller, W. H., Campbell, K. M., Delafont, B., Marshall, S., Mueller, N., & Robert, C. (2020). PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma. Nature Communications, 11(1), Article 6262. https://doi.org/10.1038/s41467-020-19810-w

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title = "PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma",

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.",

author = "Antoni Ribas and Alain Algazi and Ascierto, {Paolo A.} and Butler, {Marcus O.} and Sunandana Chandra and Michael Gordon and Leonel Hernandez-Aya and Donald Lawrence and Jose Lutzky and Miller, {Wilson H.} and Campbell, {Katie M.} and Bruno Delafont and Shannon Marshall and Nancy Mueller and Caroline Robert",

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Ribas, A, Algazi, A, Ascierto, PA, Butler, MO, Chandra, S, Gordon, M, Hernandez-Aya, L, Lawrence, D, Lutzky, J, Miller, WH, Campbell, KM, Delafont, B, Marshall, S, Mueller, N & Robert, C 2020, 'PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma', Nature Communications, vol. 11, no. 1, 6262. https://doi.org/10.1038/s41467-020-19810-w

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T1 - PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma

AU - Ribas, Antoni

AU - Algazi, Alain

AU - Ascierto, Paolo A.

AU - Butler, Marcus O.

AU - Chandra, Sunandana

AU - Gordon, Michael

AU - Hernandez-Aya, Leonel

AU - Lawrence, Donald

AU - Lutzky, Jose

AU - Miller, Wilson H.

AU - Campbell, Katie M.

AU - Delafont, Bruno

AU - Marshall, Shannon

AU - Mueller, Nancy

AU - Robert, Caroline

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

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

Abstract

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