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Zimmer L, Livingstone E, Krackhardt A, et al. Encorafenib, binimetinib plus pembrolizumab triplet therapy in patients with advanced BRAF. Eur J Cancer. 2021;158:72-84doi: 10.1016/j.ejca.2021.09.011.
Zimmer, L., Livingstone, E., Krackhardt, A., Schultz, E. S., Göppner, D., Assaf, C., Trebing, D., Stelter, K., Windemuth-Kieselbach, C., Ugurel, S., & Schadendorf, D. (2021). Encorafenib, binimetinib plus pembrolizumab triplet therapy in patients with advanced BRAF. European journal of cancer (Oxford, England : 1990), 15872-84. https://doi.org/10.1016/j.ejca.2021.09.011
Zimmer, Lisa, et al. "Encorafenib, binimetinib plus pembrolizumab triplet therapy in patients with advanced BRAF." European journal of cancer (Oxford, England : 1990) vol. 158 (2021): 72-84. doi: https://doi.org/10.1016/j.ejca.2021.09.011
Zimmer L, Livingstone E, Krackhardt A, Schultz ES, Göppner D, Assaf C, Trebing D, Stelter K, Windemuth-Kieselbach C, Ugurel S, Schadendorf D. Encorafenib, binimetinib plus pembrolizumab triplet therapy in patients with advanced BRAF. Eur J Cancer. 2021 Oct 13;158:72-84. doi: 10.1016/j.ejca.2021.09.011. Epub 2021 Oct 13. PMID: 34655839.
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Eur J Cancer. 2021 Oct 13;158:72-84. doi: 10.1016/j.ejca.2021.09.011. Epub 2021 Oct 13.

Encorafenib, binimetinib plus pembrolizumab triplet therapy in patients with advanced BRAF.

European journal of cancer (Oxford, England : 1990)

Lisa Zimmer, Elisabeth Livingstone, Angela Krackhardt, Erwin S Schultz, Daniela Göppner, Chalid Assaf, Dietrich Trebing, Kai Stelter, Christine Windemuth-Kieselbach, Selma Ugurel, Dirk Schadendorf

Affiliations

  1. Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner Site Essen, Germany. Electronic address: [email protected].
  2. Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner Site Essen, Germany. Electronic address: [email protected].
  3. Technische Universität München, School of Medicine, Klinik und Poliklinik Für Innere Medizin III, Klinikum Rechts der Isar, Ismaningerstr. 22, Munich 81675, Germany; German Cancer Consortium (DKTK), Technische Universität München, Partner Site Munich, Germany. Electronic address: [email protected].
  4. Department of Dermatology, University Hospital of the Paracelsus Medical Private University, Nuremberg, Germany. Electronic address: [email protected].
  5. Clinic for Dermatology and Allergology, Justus-Liebig-University, Gießen, Germany. Electronic address: [email protected].
  6. Department of Dermatology, Helios-Klinikum Krefeld, Germany. Electronic address: [email protected].
  7. Department of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical School Theodor Fontane, Dessau, Germany. Electronic address: [email protected].
  8. Department of Biostatistics, Alcedis GmbH, Giessen, Germany. Electronic address: [email protected].
  9. Department of Biostatistics, Alcedis GmbH, Giessen, Germany. Electronic address: [email protected].
  10. Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner Site Essen, Germany. Electronic address: [email protected].
  11. Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner Site Essen, Germany. Electronic address: [email protected].

PMID: 34655839 DOI: 10.1016/j.ejca.2021.09.011

Abstract

BACKGROUND: Combination of immune checkpoint inhibitors and mitogen-activated protein kinase (MAPK) pathway inhibitors (MAPKi) has been proposed to enhance the durability of anti-tumour responses induced by MAPKi. Here, we present phase I safety results from an open-label, phase I/II study of pembrolizumab (PEM), encorafenib (ENC) and binimetinib (BIN) triplet therapy in advanced, B-Raf proto-oncogene serine/threonine kinase (BRAF)

METHODS: The dose finding phase I part used a 3 + 3 design, starting with the approved doses of PEM (200 mg every three weeks), ENC (450 mg once daily [QD]) and BIN (45 mg twice daily [BID]) as dose level (DL) 0. Reduction of the ENC and BIN doses (300 mg QD and 30 mg BID at DL-1 and 200 mg QD and 30 mg BID at DL-2) was preplanned in case of ≥2 dose-limiting toxicities (DLTs). Primary objectives were to estimate the recommended phase II dose of the triplet combination, DLT and safety. As per the sponsor's decision, the study was terminated after the phase I part, as the clinical efficacy of the combination is currently being investigated in a pivotal, placebo-controlled (PEM mono), double-blinded phase III trial (STARBOARD,NCT04657991).

RESULTS: Fifteen patients were enrolled. DLTs of DL0 were creatine phosphokinase (CPK) elevation plus cytokine release syndrome (n = 1) and gamma glutamyl transferase (GGT) increase (n = 1). No DLT was observed in further 3 + 3 patients at DL-1. One (isolated GGT elevations) DLT of DL0 was questionable, as the patient had further episodes of isolated GGT elevations after treatment discontinuation. Hence, further 6 patients were enrolled at DL0: here, no DLT occurred. In total, 13 of 15 patients (87%) experienced a treatment-related adverse event (TRAE) and 8 patients (53%), a grade ≥III TRAE; there were no TRAE-related deaths. Increases in aspartate aminotransferases, GGT (6/15 patients) and CPK elevations (4/15) were the most common grade III-IV TRAE. In median, patients received triplet therapy for 24 weeks (interquartile range [IQR], 12-45). Of the 14 patients evaluable for efficacy, the overall response rate was 64% (95% confidence interval [CI], 35-87). At a median follow-up of 25 months (IQR, 9-28), progression-free survival at 12 months was 41% (95% CI, 13-68).

CONCLUSIONS: Triplet therapy with PEM, ENC and BIN as used in the study was feasible and safe and led to clinically meaningful disease control.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Keywords: Binimetinib; Encorafenib; Immunotherapy; Melanoma; Pembrolizumab; Phase I; Targeted therapy

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