Reference Detail

Ref Type

PMID

Authors

Lisa Zimmer, Angela Krackhardt, Erwin S. Schultz, Daniela Goeppner, Chalid Assaf, Dietrich Trebing, Elisabeth Livingstone, Dirk Schadendorf

Title

Triplet therapy with pembrolizumab (PEM), encorafenib (ENC) and binimetinib (BIN) in advanced, BRAF V600 mutant melanoma: Final results from the dose-finding phase I part of the IMMU-Target trial.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of Clinical Oncology	39	no. 15_suppl	May 20, 2021

URL

https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.9532

Abstract Text

Background: Survival of BRAF-mutated melanoma profoundly improved since the introduction of immune checkpoint inhibitors (ICI) and MAPK pathway inhibitors (MAPKi). Response kinetics of ICI and MAPKi are complementary, mechanistic evidence indicates that MAPKi may affect the tumor immune microenvironment. Combined use of both drug classes may further enhance clinical benefit. IMMU-Target was set-up as a prospective, open-label, phase I/II trial, with a safety phase I part followed by a randomized phase II part, to study the tolerability and clinical activity of PEM, ENC and BIN triplet therapy. Methods: Treatment naïve adult patients (pts) with stage IIIB-IV (AJCC 2017), BRAF V600 mutant melanoma with measurable disease but no active brain metastasis were eligible. The dose finding part used a 3+3 design, starting with a dose level (DL) 0 applying the clinically recommended doses of PEM (200 mg Q3W), ENC (450 mg QD) and BIN (45 mg BID). In case of ≥2 dose-limiting toxicities (DLT), a reduction of the ENC and BIN doses (300 mg QD and 30 mg BID at DL-1, 200 mg QD and 30 mg BID at DL -2) was foreseen. Primary endpoints of the phase I part were safety and tolerability. Results: From April 2018 until May 2020, 14 pts with BRAF V600 mutations were enrolled. 2 of 3 pts at DL 0 developed DLT (creatine phosphokinase (CPK) elevations grade 3 plus cytokine release syndrome grade 4; gamma glutamyl transferase (GGT) elevations grade 3), and had to stop therapy early. Therefore, 3+3 further pts at DL -1 were included with no DLT observed in these 6 pts. One (isolated GGT elevations grade 3) of the 2 DLT observed in the 3 pts of DL 0 enrolled initially was questionable as DLT, as the patient had further episodes of isolated GGT elevations without therapy. As a result, further 5 pts were enrolled at DL 0: here no DLT-matching treatment-related adverse event (TRAE) occurred. In total, 12 out of 14 pts (86%) experienced a TRAE and 7 (50%) experienced a grade ≥3 TRAE; there were no fatal AE or TRAE-related deaths. Increases in alanine and in aspartate aminotransferases, GGT and CPK elevations (6 of 14 pts) were the most common grade 3-4 TRAE. In median, pts at DL 0 (n=8) received triplet therapy for 18 weeks (IQR 7.5-29), at DL-1 (n=6) for 46 weeks (IQR 27-102). The overall response rate was 64% (95% CI=35-87). At a median follow-up of 10.0 months at DL 0 and 27.0 months at DL-1, progression-free survival at 12 months was 37.5% (95% CI 9- 67) and 60% (95% CI 13-88), respectively. Conclusions: Triplet therapy was feasible and safe at both dose levels leading to clinically meaningful disease control. The phase II part was not initiated, since the clinical efficacy of PEM plus ENC and BIN is currently investigated in STARBOARD (NCT04657991), a prospective, randomized, placebo-controlled (PEM mono), double-blinded phase III trial. Clinical trial information: NCT02902042.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600X	melanoma	predicted - sensitive	Binimetinib + Encorafenib + Pembrolizumab	Phase I	Actionable	In a Phase I trial (IMMU-Target), Mektovi (binimetinib), Braftovi (encorafenib), and Keytruda (pembrolizumab) demonstrated safety and preliminary efficacy in treatment naive patients with advanced melanoma harboring BRAF V600 mutations, resulting in an overall response rate of 64% (9/14), with a 12-month progression-free survival rate of 37.5% (n=8) and 60% (n=6) at the two tested dose levels, respectively (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 9532; NCT02902042).	detail...