IMPemBra: a phase 2 study comparing pembrolizumab with intermittent/short-term dual MAPK pathway inhibition plus pembrolizumab in patients with melanoma harboring the BRAFV600 mutation
Journal for ImmunoTherapy of Cancer, vol. 11, pp. e006821
Abstract
BACKGROUND: -mutated melanoma. Short-term MAPKi induces T-cell infiltration in patients and is synergistic with anti-programmed death-1 (PD-1) in a preclinical melanoma mouse model. The aim of this phase 2b trial was to identify an optimal regimen of short-term MAPKi with dabrafenib plus trametinib in combination with pembrolizumab. METHODS: -mutant advanced melanoma started pembrolizumab 200 mg every 3 weeks. In week 6, patients were randomized to continue pembrolizumab only (cohort 1), or to receive, in addition, intermittent dabrafenib 150 mg two times per day plus trametinib 2 mg one time per day for two cycles of 1 week (cohort 2), two cycles of 2 weeks (cohort 3), or continuously for 6 weeks (cohort 4). All cohorts continued pembrolizumab for up to 2 years. Primary endpoints were safety and treatment-adherence. Secondary endpoints were objective response rate (ORR) at week 6, 12, 18 and PFS. RESULTS: Between June 2016 and August 2018, 33 patients with advanced melanoma have been included and 32 were randomized. Grade 3-4 TRAE were observed in 12%, 12%, 50%, and 63% of patients in cohort 1, 2, 3, and 4, respectively. All planned targeted therapy was given in 88%, 63%, and 38% of patients in cohort 2, 3, and 4. ORR at week 6, 12, and 18 were 38%, 63%, and 63% in cohort 1; 25%, 63%, and 75% in cohort 2; 25%, 50%, and 75% in cohort 3; and 0%, 63%, and 50% in cohort 4. After a median follow-up of 43.5 months, median PFS was 10.6 months for pembrolizumab monotherapy and not reached for patients treated with pembrolizumab and intermittent dabrafenib and trametinib (p=0.17). The 2-year and 3-year landmark PFS were both 25% for cohort 1, both 63% for cohort 2, 50% and 38% for cohort 3 and 75% and 60% for cohort 4. CONCLUSIONS: The combination of pembrolizumab plus intermittent dabrafenib and trametinib seems more feasible and tolerable than continuous triple therapy. The efficacy is promising and appears to be favorable over pembrolizumab monotherapy. TRIAL REGISTRATION NUMBER: NCT02625337.
Authors 21
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The Netherlands Cancer Institute
Affiliation as printed
Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Department of Radiology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Department of Radiology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Department of Laboratory Medicine, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Core Facility and Biobanking, Netherlands Cancer Institute, Amsterdam, The Netherlands
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Affiliation as printed
Isala Oncology Center, Isala, Zwolle, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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Leiden University Medical Center · The Netherlands Cancer Institute
Affiliation as printed
Department of Medical Oncology, Leiden University Medical center, Leiden, The Netherlands
Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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