Purpose: No targeted therapy has been approved for NRAS-mutant melanoma. We evaluated the safety and tolerability and determined the recommended phase 2 dose (RP2D) of FCN-159, a selective MEK1/2 inhibitor, in patients with NRAS-mutant advanced melanoma.

Methods: This single-arm, open-label, dose-escalation, phase 1A study in China (NCT03932253) enrolled patients with unresectable stage III/IV melanoma harboring NRAS mutations. Patients received FCN-159 in doses escalating from 0.2 mg until the maximum tolerated dose (MTD). Oral FCN-159 was given once in the single-dose period and once daily (QD) in 28-day cycles in the continuous-dose period. The primary endpoint was the incidence of dose-limiting toxicity (DLT).

Results: As of September 16, 2021, 33 patients were enrolled and received 0.2-15 mg FCN-159. All patients had received systemic treatments. One DLT event (grade 3 folliculitis) occurred in the 15 mg group, and no DLT occurred at other dose levels; MTD was defined as 15 mg QD. Grade ≥3 treatment-emergent adverse events (TEAEs) deemed related to FCN-159 were reported in 5 (15.2%) patients across dose levels; stomatitis (2; 6.1%) was the most common. No FCN-159-related TEAEs were serious or led to treatment discontinuation. Among 21 patients assigned to doses ≥6 mg, 4 had investigator-confirmed objective responses (objective response rate, 19.0%; 95% confidence interval [CI], 5.4-41.9); all were partial responses (Table). Median DOR was 4.8 months (95% CI, 2.8-NE). Seven patients had SD (CBR, 52.4%; 95% CI, 29.8-74.3). Median progression-free survival was 3.8 months (95% CI, 1.8-5.6). FCN-159 12 mg QD was determined to be the RP2D per assessment of safety, antitumor activity, and pharmacokinetic data.

Conclusion: FCN-159 was well tolerated and showed antitumor activity in patients with NRAS-mutant advanced melanoma. FCN-159 12 mg QD as a treatment for NRAS-mutant advanced melanoma warrants future investigation.

Tumor response was assessed by the investigators according to Response Evaluation Criteria in Solid Tumors version 1.1.BOR, best overall response; CBR, clinical benefit rate; CR, complete response; DOR, duration of response; NA, not applicable; NE, not evaluable; NR, not reached; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.

Table. Confirmed best overall response

6 mg(n = 5)8 mg(n = 4)12 mg(n = 6)15 mg(n = 6)Total(N = 21)
Confirmed BOR, n (%)      
CR 
PR 2 (40.0) 1 (25.0) 1 (16.7) 4 (19.0) 
SD 1 (20.0) 1 (25.0) 3 (50.0) 2 (33.3) 7 (33.3) 
PD 2 (40.0) 2 (50.0) 1 (16.7) 2 (33.3) 7 (33.3) 
NE 2 (33.3) 1 (16.7) 3 (14.3) 
ORR, n (%), 95% CI 2 (40.0), 5.3–85.3 1 (25.0), 0.6–80.6 1 (16.7), 0.4–64.1 4 (19.0), 5.4–41.9 
CBR, n (%), 95% CI 3 (60.0), 14.7–94.7 2 (50.0), 6.8–93.2 3 (50.0), 11.8–88.2 3 (50.0), 11.8–88.2 11 (52.4), 29.8–74.3 
Median DOR (95% CI), months 4.8 (2.8–NE) NR (NE–NE) NA NR (NE–NE) 4.8 (2.8–NE) 
6 mg(n = 5)8 mg(n = 4)12 mg(n = 6)15 mg(n = 6)Total(N = 21)
Confirmed BOR, n (%)      
CR 
PR 2 (40.0) 1 (25.0) 1 (16.7) 4 (19.0) 
SD 1 (20.0) 1 (25.0) 3 (50.0) 2 (33.3) 7 (33.3) 
PD 2 (40.0) 2 (50.0) 1 (16.7) 2 (33.3) 7 (33.3) 
NE 2 (33.3) 1 (16.7) 3 (14.3) 
ORR, n (%), 95% CI 2 (40.0), 5.3–85.3 1 (25.0), 0.6–80.6 1 (16.7), 0.4–64.1 4 (19.0), 5.4–41.9 
CBR, n (%), 95% CI 3 (60.0), 14.7–94.7 2 (50.0), 6.8–93.2 3 (50.0), 11.8–88.2 3 (50.0), 11.8–88.2 11 (52.4), 29.8–74.3 
Median DOR (95% CI), months 4.8 (2.8–NE) NR (NE–NE) NA NR (NE–NE) 4.8 (2.8–NE) 

Citation Format: Lili Mao, Jun Guo, Lingjun Zhu, Yu Jiang, Wangjun Yan, Jian Zhang, Ai-min Hui, Zhuli Wu, Yuchen Yang, Han Zhao, Yiqian Jiang, Lu Si. FCN-159, a MEK1/2 inhibitor, in patients with advanced melanoma harboring NRAS mutations: A phase 1A dose-escalation study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT519.