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.
This open-label, dual-stratum, single-center phase 2 clinical trial investigated 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.
Between Jan and Dec 2019, 9 pts initiated T monotherapy and 8 pts initiated T + 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 developed 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 + 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. TRAE in ≥2 pts
TRAE G1-2 (n[%]) G3-4 (n[%]) CPK increase 10 (59) 0 Diarrhea 5 (29) 0 AST increase 4 (24) 1 (6) Lipase increase 4 (24) 0 Arterial hypertension 4 (24) 0 Hyponatremia 2 (12) 2 (12) ALT increase 3 (18) 1 (6) Fatigue 2 (12) 1 (6) Anemia 3 (18) 0 Chills 3 (18) 0 Nausea 3 (18) 0 Central serous retinopathy 3 (18) 0 Syncope 0 2 (12) Acute kidney injury 2 (12) 0 Thrombocytopenia 2 (12) 0 Fever 2 (12) 0
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 increase tolerance of and optimize exposure to T.
NCT04059224; EudraCT 2018-004003-39.
Universitair Ziekenhuis Brussel.
Novartis, Stichting tegen Kanker.
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; Advisory/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; Advisory/Consultancy, Speaker Bureau/Expert testimony: CryoStorage; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Merck Serono. All other authors have declared no conflicts of interest.