| NCT03013101, NCT02821000, NCT02738489, CTR20160872[25] | PD-1 antiboby | Clinical data from four clinical trials in patients with advanced melanoma treated with anti-PD-1 monoclonal antibodies between 2016 and 2019 were analyzed. The efficacy of immunotherapy in patients with cutaneous and non-cutaneous NRAS mutant melanoma was analyzed separately. | A total of 206 patients were assessed, including 12 patients with NRAS-mutated cutaneous melanoma and 21 patients with NRAS-mutated non-cutaneous melanoma | In cutaneous melanoma, patients with NRAS mutations had a lower overall response rate (ORR) than patients without NRAS mutations (9.5% vs 23.9%). In non-cutaneous melanoma, response rates were 0% and 13.7%, median progression-free survival (mPFS) was 3.6 months and 4.3 months (P=0.015), and median survival time (mOS) was 10.8 months and 15.3 months (P=0.025) in NRAS mutant and wild-type patients, respectively | 2016-2019 |
| NCT01763164[27] | MEKi binimetinib | Phase Ⅲ randomized, multicenter, open-label clinical trial. Patients with advanced, unresectable stage ⅢC-Ⅳ NRAS mutated melanoma who were previously untreated or progressed following prior immunotherapy were randomized (2:1) to receive binimetinib 45 mg orally twice daily or dacarbazine 1 000 mg/m2 intravenously every 3 weeks. | A total of 402 patients with NRAS-mutated melanoma were enrolled, 269 treated with binimetinib and 233 treated with dacarbazine (1:2) | In the binimetinib arm mPFS was 2.8 months and 1.5 months in the dacarbazine arm | 2013-2015 |
| NCT01693068[28] | MEKi pmasertib | Phase Ⅱ multicenter, open-label clinical trial. Patients with unresectable stage Ⅲc/ⅣM1 NRAS-mutated cutaneous melanoma were randomized 2:1 to receive pmasertib (60 mg orally twice daily) or DTIC
(1 000 mg/m2 intravenously). Primary endpoint: investigator-assessed PFS; secondary endpoints: OS, ORR, quality of life (QoL), and safety. | 191 patients with NRAS mutated cutaneous melanoma, 191 treated (pimasertib n=130, DTIC n=61) | PFS and 6-month PFS rates were significantly improved in the pimasertib arm compared with the DTIC arm: 13 weeks versus 7 weeks, 17% vs 9%. Investigator-assessed ORR was 27% in the pimasertib arm and 14% in the DTIC arm. However, there was no difference in OS between patients treated with pimasertib and DTIC (mOS 9 and 11 months, respectively; HR=0.89, 95% CI: 0.61-1.30) | 2012-2014 |
| NCT00060125[30] | Farnesyltransferase inhibitor (FTI) | Three-stage trial design, up to 40 patients, stopped early if first 14 patients did not respond, or first 28 patients had less than 2 responders | 14 patients with NRAS mutated melanoma | 2 patients presented with grade 3 toxicity and all patients had no clinical response and the trial was prematurely discontinued | 2003-2006 |
| Identifier | Target | Study design | NRAS-mutant mlanoma patients | Efficacy | Time frame |
| NCT03118817[36] | RAFi belvarafenib | Single-arm, open-label, multicenter, phase Ⅰ extension study | 9 NRAS mutated melanoma patients | ORR 11%, mPFS 25 weeks | 2017-2020 |
| NCT03973151[37] | MEKi HL-085 | Phase Ⅰ/Ⅱ, single-arm, dose-escalation and cohort expansion study | 42 patients with NRAS mutated melanoma | HL-085 was published in 2023 confirming an ORR of 34.7% | 2019-2023 |
| NCT02974725[42] | BRAF/CRAF protein kinases inhibitor Naporafenib(LXH254) + MEKi trametinib | Phase Ⅰb escalation/expansion study | 30 patients with NRAS mutated melanoma | The ORR was 46.7%, the median DOR was 3.75 and the overall median PFS was 5.52 months in patients treated with naporafenib 200 mg twice a day plus trametinib 1 mg once daily. | 2017-2023 |
| NCT01449058[44] | PI3Kαinhibitor BYL719 +MEKi binimetinib | Phase Ⅰb open-label, multicenter, dose escalation and expansion study | 5 NRAS mutated melanoma patients | ORR 20% | 2011-2017 |
| NCT01941927[45] | MEKi trametinib +AKT inhibitor GSK2141795 | Phase Ⅱ non-randomized, multicenter, open-label clinical trial | Efficacy and safety of MEK inhibitors combined with AKT inhibitors in 10 patients with NRAS-mutated melanoma and 10 patients with BRAFWT/NRASWT melanoma | The mPFS and mOS of the 10 NRAS-mutated melanoma patients were only 2.3 and 4.0 months. Median PFS and OS for the wild-type cohort were 2.8 months and 3.5 months, respectively. No objective responses were identified in either cohort. The combination of Trametinib and GSK2141795 has no significant clinical activity in NRAS mutants or BRAFWT/NRASWT melanomas | 2013-2020 |
| NCT03932253 | MEKi FCN-159 | Phase Ⅰa/Ⅰb, open-label, dose escalation and dose expansion study | 33 patients with NRAS mutated melanoma were enrolled | The ORR and clinical benefit rates were 19.0% and 52.4%, respectively. Median duration of response and progression-free survival were 4.8 months and 3.8 months (1.8-5.6 months), respectively. | 2019-2023 |
| NCT03284502 | MEKi cobimetinib + RAFi HM95573 | Phase Ⅰb, open-label, multicenter dose escalation study | 9 NRAS mutated melanoma patients | Available data published ORR of 40% | 2017-2023 |
| NCT03979651 | MEKi trametinib+autophagy inhibitor hydroxychloroquine | Phase Ⅰb/Ⅱ non-randomized, open-label clinical trial | 29 NRAS mutated melanoma patients | Results to be further published | 2019-2022 |
| NCT04109456 | MEKi cobimetinib | Phase Ⅰb open-label clinical study | Estimated enrollment is 120 patients with NRAS mutated melanoma | Results to be further published | 2019-2023 |
