PMID- 34655839 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240220 IS - 1879-0852 (Electronic) IS - 0959-8049 (Linking) VI - 158 DP - 2021 Oct 13 TI - Encorafenib, binimetinib plus pembrolizumab triplet therapy in patients with advanced BRAF(V600) mutant melanoma: safety and tolerability results from the phase I IMMU-TARGET trial. PG - 72-84 LID - S0959-8049(21)00606-7 [pii] LID - 10.1016/j.ejca.2021.09.011 [doi] AB - 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)(V600)-mutated melanoma (IMMU-TARGET, NCT02902042). 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. CI - Copyright (c) 2021 Elsevier Ltd. All rights reserved. FAU - Zimmer, Lisa AU - Zimmer L AD - Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner Site Essen, Germany. Electronic address: lisa.zimmer@uk-essen.de. FAU - Livingstone, Elisabeth AU - Livingstone E AD - Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner Site Essen, Germany. Electronic address: elisabeth.livingstone@uk-essen.de. FAU - Krackhardt, Angela AU - Krackhardt A AD - Technische Universitat Munchen, School of Medicine, Klinik und Poliklinik Fur Innere Medizin III, Klinikum Rechts der Isar, Ismaningerstr. 22, Munich 81675, Germany; German Cancer Consortium (DKTK), Technische Universitat Munchen, Partner Site Munich, Germany. Electronic address: angela.krackhardt@tum.de. FAU - Schultz, Erwin S AU - Schultz ES AD - Department of Dermatology, University Hospital of the Paracelsus Medical Private University, Nuremberg, Germany. Electronic address: erwin.schultz@klinikum-nuernberg.de. FAU - Goppner, Daniela AU - Goppner D AD - Clinic for Dermatology and Allergology, Justus-Liebig-University, Giessen, Germany. Electronic address: Daniela.Goeppner@derma.med.uni-giessen.de. FAU - Assaf, Chalid AU - Assaf C AD - Department of Dermatology, Helios-Klinikum Krefeld, Germany. Electronic address: chalid.assaf@helios-kliniken.de. FAU - Trebing, Dietrich AU - Trebing D AD - Department of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical School Theodor Fontane, Dessau, Germany. Electronic address: dietrich.trebing@klinikum-dessau.de. FAU - Stelter, Kai AU - Stelter K AD - Department of Biostatistics, Alcedis GmbH, Giessen, Germany. Electronic address: kst@alcedis.de. FAU - Windemuth-Kieselbach, Christine AU - Windemuth-Kieselbach C AD - Department of Biostatistics, Alcedis GmbH, Giessen, Germany. Electronic address: cwk@alcedis.de. FAU - Ugurel, Selma AU - Ugurel S AD - Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner Site Essen, Germany. Electronic address: selma.ugurel@uk-essen.de. FAU - Schadendorf, Dirk AU - Schadendorf D AD - Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner Site Essen, Germany. Electronic address: dirk.schadendorf@uk-essen.de. LA - eng SI - ClinicalTrials.gov/NCT04657991 SI - ClinicalTrials.gov/NCT02902042 PT - Journal Article DEP - 20211013 PL - England TA - Eur J Cancer JT - European journal of cancer (Oxford, England : 1990) JID - 9005373 SB - IM OTO - NOTNLM OT - Binimetinib OT - Encorafenib OT - Immunotherapy OT - Melanoma OT - Pembrolizumab OT - Phase I OT - Targeted therapy EDAT- 2021/10/17 06:00 MHDA- 2021/10/17 06:01 CRDT- 2021/10/16 20:15 PHST- 2021/09/09 00:00 [received] PHST- 2021/09/10 00:00 [accepted] PHST- 2021/10/17 06:01 [medline] PHST- 2021/10/17 06:00 [pubmed] PHST- 2021/10/16 20:15 [entrez] AID - S0959-8049(21)00606-7 [pii] AID - 10.1016/j.ejca.2021.09.011 [doi] PST - aheadofprint SO - Eur J Cancer. 2021 Oct 13;158:72-84. doi: 10.1016/j.ejca.2021.09.011.