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Poster display session

2369 - Phase 2 Study Comparing Pembrolizumab with Intermittent/short-term dual MAPK pathway inhibition plus Pembrolizumab(PEM) in patients harboring the BRAFV600 mutation (IMPemBra Trial).

Date

10 Sep 2017

Session

Poster display session

Presenters

Elisa Rozeman

Citation

Annals of Oncology (2017) 28 (suppl_5): v428-v448. 10.1093/annonc/mdx377

Authors

E.A. Rozeman1, M.A. Deken2, J. Gadiot3, M.H. Geukes Foppen1, L. Pronk4, J.V. Thienen1, J.B. Haanen1, C.U. Blank1

Author affiliations

  • 1 Medical Oncology Department, Het Nederlands Kanker Instituut Antoni van Leeuwenhoek (NKI-AVL), 1006 BE - Amsterdam/NL
  • 2 Molecular Oncology And Immunology, Het Nederlands Kanker Instituut Antoni van Leeuwenhoek (NKI-AVL), 1006 BE - Amsterdam/NL
  • 3 Immunology, Het Nederlands Kanker Instituut Antoni van Leeuwenhoek (NKI-AVL), 1006 BE - Amsterdam/NL
  • 4 Department Of Biometrics, Het Nederlands Kanker Instituut Antoni van Leeuwenhoek (NKI-AVL), 1006 BE - Amsterdam/NL
More

Resources

Abstract 2369

Background

Continuous combinations of targeted therapy (TT), e.g. BRAF+MEK inhibitors(BRAFi+MEKi), with immunotherapy (IT), e.g. CTLA-4 or PD-1 blockade are currently tested in several phase1/2 trials with the aim to improve response rate and response duration in melanoma patients with a BRAFV600 mutation. However, high toxicity rates have been observed, revealing PD-1 blockade currently being the only possible combination partner for TT. Recently we have published preclinical data, showing that short-time TT induces strong T cell infiltration and is synergistic with PD-1 blockade. Analysis of biopsies of patients during TT indicate that long-term TT might be counterproductive, as T cell infiltration decreases in some patients already beyond 2 weeks. This raises the question which time period of MAPK pathway inhibition is optimal for combination with anti-PD-1. The IMPemBra trial will address this question, comparing PEM monotherapy with combination schemes of intermittent/short-term BRAFi + MEKi plus PEM. The primary objective is to explore safety, feasibility and the immune-activating capacity of the different regimens.

Trial design

Stage IV BRAFV600E/K mutation positive melanoma patients, naïve for IT and TT, will start treatment with PEM 200mg q3wk. After 6 wks the patients will be randomized (stratified according their LDH level) to continue PEM for up to 2 years (cohort 1), or to one of the experimental cohorts receiving either dabrafenib 150mg BID + trametinib 2mg QD two times intermittent for 1 wk (cohort 2), two times intermittent for 2 wks (cohort 3), or continuous for 6 wks (cohort 4). All cohorts continue afterwards with PEM for up to 2 years. Each cohort will consist of 8 patients. Primary endpoints are SUSARs and adherence to the study timeline, the intra-patient alteration in intratumoral CD8+ T cells and the percentage PD1+ CD8+ T cells in the peripheral blood. Tumor biopsies and blood samples including PBMCs are taken at baseline, wk 6, 9, 12, 18 and in case of progression. Secondary endpoints are objective response rate and progression free survival. Enrollment started in May 2016, 11 patients have been included so far.

Clinical trial identification

NCT02625337

Legal entity responsible for the study

NKI-AVL

Funding

MSD

Disclosure

J.V. Thienen: Advisory board: MSD and Bristol-Myers Squib. J.B. Haanen: Advisory role: Bristol-Myers Squib. MSD, Pfizer, Roche, Novartis, Neon Therapeutics Research grants: Bristol-Myers Squib, MSD, GSK. C.U. Blank: Advisory board: Bristol-Myers Squib, MSD, Novartis, GSK, Pfizer, Lilly, Roche Research grants: Bristol-Myers Squib, Novartis. All other authors have declared no conflicts of interest.

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