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Background: Preclinical and clinical data suggest MEK-inhibition (MEKi) to be effective in NRAS-mutant (mt) and NRAS wild-type (wt) melanoma. However, MEKi causes considerable cutaneous treatment-related adverse events (TRAE) which are less present if MEKi is combined with BRAFi. Methods: This open-label, dual-stratum, single-center phase 2 clinical trial investi- gated trametinib (T; 2 mg QD) in patients (pts) with advanced BRAFV600 wt, NRASQ61R/ K/L mt/wt melanoma who had progressed following or were ineligible for immune checkpoint inhibitors. In case of T-related cutaneous TRAE, low-dose dabrafenib (ld-D; 50 mg BID) was added to prevent further skin TRAE. The trial was amended in June 2019 to administer ld-D upfront with T. The primary endpoint was the confirmed objective response rate (ORR; per RECIST 1.1); secondary endpoints were progression- free and overall survival and safety. Results: Between Jan and Dec 2019, 9 pts initiated T monotherapy and 8 pts initiated T þ ld-D. TRAE were seen in 15 pts (29% G3-4; 29% SAE). One pt permanently interrupted T due to G3 pneumonitis. All 9 pts who initiated T monotherapy devel- oped G1-2 acneiform rash which resolved (to G0: 6 pts; to G1: 3 pts) with temporary interruption of T, local metronidazole therapy and subsequent addition of ld-D to T. One pt had a G1 recurrence of acneiform rash that was managed with local therapy. Of 8 pts who initiated T þ ld-D upfront, 1 developed G1 acneiform rash that resolved with local therapy only. Other TRAE are shown in the table. T dose was reduced in 4 pts for TRAE (1 pt with left ventricular ejection fraction decrease; 1 with central serous retinopathy; 1 with AST/ALT increase; 1 with hyponatremia and syncope). The unconfirmed ORR is 4/15 and the disease control rate is 7/15 evaluable pts. Conclusions: No unexpected toxicities were seen with T or T + ld-D. ld-D is able to prevent T-related skin toxicity. Thus, combining ld-D with T is a safe approach to in- crease tolerance of and optimize exposure to T. Clinical trial identification: NCT04059224; EudraCT 2018-004003-39. Legal entity responsible for the study: Universitair Ziekenhuis Brussel. Funding: Novartis, Stichting tegen Kanker. Disclosure: G. Awada: Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Travel/Accommodation/Expenses: Astellas; Travel/Accommodation/Expenses: Merck Sharp & Dohme; Advisory/Consultancy, Research grant/Funding (institution): Novartis. J.K. Schwarze: Travel/ Accommodation/Expenses: Amgen; Travel/Accommodation/Expenses: Merck Sharp & Dohme. S. Aspeslagh: Advisory/Consultancy, Speaker Bureau/Expert testimony: Amgen; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca; Advisory/Consultancy, Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Advi- sory/Consultancy, Speaker Bureau/Expert testimony: Merck Sharp & Dohme; Advisory/Consultancy, Speaker Bureau/Expert testimony: Sanofi; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis. B. Neyns: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck Sharp & Dohme; Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca; Advisory/Consultancy, Speaker Bureau/Expert testimony: EtheRNA; Advi- sory/Consultancy, Speaker Bureau/Expert testimony: CryoStorage; Research grant/Funding (institu- tion): Pfizer; Research grant/Funding (institution): Merck Serono. All other authors have declared no conflicts of interest. https://doi.org/10.1016/j.annonc.2020.01.039
Original languageEnglish
Pages (from-to)S10-S10
JournalAnnals of Oncology
Volume31
Issue numberS1
Publication statusPublished - 2020
EventESMO TARGETED ANTICANCER THERAPIES CONGRESS 2020 -
Duration: 2 Mar 20204 Mar 2020

ID: 49799451