Encorafenib, binimetinib plus pembrolizumab triplet therapy in patients with advanced BRAFV600 mutant melanoma: safety and tolerability results from the phase I IMMU-TARGET trial. (November 2021)

• Record Type: Journal Article
• Authors: Zimmer, Lisa; Livingstone, Elisabeth; Krackhardt, Angela; Schultz, Erwin S.; Göppner, Daniela; Assaf, Chalid; Trebing, Dietrich; Stelter, Kai; Windemuth-Kieselbach, Christine; Ugurel, Selma; Schadendorf, Dirk
• Is Part Of: European journal of cancer. Volume 158(2021)
• Page Start: 72
• Page End: 84
• Publication Date: 2021-11
• Subjects: Melanoma -- Targeted therapy -- Immunotherapy -- Pembrolizumab -- Encorafenib -- Binimetinib -- Phase I; AE adverse event -- ALT alanine aminotransferase -- AST aspartate alanine aminotransferase -- BID twice daily -- BRAF B-Raf proto-oncogene serine/threonine kinase -- CI confidence interval -- CPK creatine phosphokinase -- CR complete response -- CTLA-4 cytotoxic T-lymphocyte-associated protein 4 -- DCR disease control rate -- DeCOG Dermatologic Cooperative Oncology Group (DeCOG) -- DILI drug-induced liver injury -- DL0 dose level 0 -- DL-1 dose level−1 -- DL-2 dose level−2 -- DLT dose-limiting toxicity/-ies -- FDA US Food and Drug Administration -- GGT gamma glutamyl transferase -- ICI immune checkpoint inhibitors -- IQR interquartile range -- LDH lactate dehydrogenase -- MAPK/MEK mitogen-activated protein kinase -- NCI-CTCAE (US) national cancer institute common terminology criteria for adverse events -- ORR overall response rate -- OS overall survival -- PD progressive disease -- PD-1 programmed cell death protein 1 -- PD-L1 programmed cell death ligand 1 -- QD once daily -- PFS progression-free survival -- PR partial response -- RP2D recommended phase II dose -- RP3D recommended phase III dose -- SAE serious adverse event -- SD stable disease -- TRAE treatment-related adverse event -- TT targeted therapy -- ULN upper limit of normal; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2021.09.011
• Languages: English
• ISSNs: 0959-8049

Abstract

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 ) 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. Graphical abstract: Image 1 Highlights: Phase I results combining pembrolizumab (PEM), encorafenib (ENC) and binimetinib (BIN) in BRAF V600 melanoma suggests a managable safety profile and clinical efficacy. Thirteen of 15 patients (87%) experienced a treatment-related adverse event (TRAE). There were no TRAE-related deaths. The overall response rate was 64% (95% confidence interval 35–87). Triplet therapy with pembrolizumab (200 mg Q3W), encorafenib (450 mg QD) and binimetinib (45 mg BID) was feasible and safe.