NRAS突变型晚期黑色素瘤的治疗进展

doi:10.19401/j.cnki.1007-3639.2023.10.006

摘要/Abstract

摘要：

黑色素瘤的发生、发展与多种癌基因的激活密切相关。15%~20%的黑色素瘤患者存在NRAS基因的激活突变，携带该突变基因的黑色素瘤具有更强的侵袭性，治疗难度大。由于RAS蛋白突变位点属于弱药物靶标，目前尚缺乏有效的靶向抑制剂，因此临床上多以免疫检查点抑制剂作为NRAS突变型晚期黑色素瘤的一线治疗方案，然而治疗反应率较低。近年来，在NRAS突变亚型中靶向治疗方案的探索主要集中在NRAS下游丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）通路，但结果不一：新型MEK1/2抑制剂tunlametinib，在晚期NRAS突变患者中总体客观缓解率（objective response rate，ORR）达到34.7%，较既往的binimetinib显著提高；然而泛RAF抑制剂belvarafenib和ERK抑制剂ulixertinib的Ⅰ期临床试验却未能展示出该药明显的优势。此外，以MEK抑制剂为基础的联合治疗也取得一定进展，现有证据表明，分子抑制剂类药物较免疫检查点抑制剂显示出更多的优势：选择性BRAF/CRAF抑制剂naporafenib（LXH254）与MEK抑制剂trametinib联合治疗NRAS突变型黑色素瘤的Ⅰb期临床试验中ORR达到46.7%；细胞周期蛋白依赖性激酶4/6（cyclin-dependent kinase4/6，CDK4/6）抑制剂ribociclib和binimetinib联合治疗在携带NRAS突变同时合并细胞周期蛋白基因异常的人群中可达32.5%；黏着斑激酶（focal adhesion kinase，FAK）抑制剂IN10018联合cobimetinib的研究结果也表现出较好的ORR（38.5%）；但免疫检查点抑制剂程序性死亡[蛋白]配体-1（programmed death ligand-1，PD-L1）单抗durvalumab联合trametinib方案仅使27.2%的患者达到部分缓解（3/11）。与此同时，部分临床前研究结果也显示出一些转化潜质：如热激蛋白90（heat shock protein 90，HSP90）抑制剂XL888和丝氨酸/苏氨酸蛋白激酶19（serine/threonine protein kinase 19，STK19）抑制剂均在动物模型中表现出显著抑制NRAS突变型黑色素瘤细胞生长的能力。本文综述了NRAS突变型黑色素瘤的致癌机制及近年来治疗领域的研究进展，旨在展示该亚型患者的治疗现状，对多种新型治疗方法的临床研究结果进行总结和归纳，为当前临床实践和未来联合治疗方案提供依据。

关键词: NRAS基因突变, 黑色素瘤, 致癌机制, 靶向治疗

Abstract:

Oncogenic mutations are responsible for a majority of the malignancy of melanoma. Activating mutations of NRAS gene are found in 15%-20% melanoma cases, endowing the tumor cells with more aggressive phenotypes and greater difficulty to treat. The development of targeted inhibitor of mutant NRAS remains a big challenge since the mutation sites could hardly be druggable. Therefore, immune checkpoint inhibitors are currently recommended as the first-line therapy for NRAS mutant advanced melanoma albeit the response rate is still far from satisfaction. In recent years, the exploration of targeted therapy regimens has focused on the downstream pathway of NRAS, the mitogen-activated protein kinase (MAPK) pathway. A novel MEK1/2 inhibitor tunlametinib was reported to achieve an objective response rate (ORR) of 34.7% which is higher than the ORR of binimetinib in previous report. However, the phase Ⅰ trial of the pan-RAF inhibitor belvarafenib and the ERK inhibitor ulixertinib failed to show marked benefits. In the meanwhile, MEK inhibitor-based combination therapy has also achieved some progress: it was reported in the phase Ⅰb trial of the selective BRAF/CRAF inhibitor naporafenib (LXH254) combined with Trametinib in NRAS mutant melanoma that the ORR was 46.7%. The ORR of binetinib plus the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, ribociclib, was 32.5% in patients with NRAS mutation with concurrent alterations of CDKN2A, CDK4, or CCND1. The response rate of the combination of focal adhesion kinase (FAK) inhibitor, IN10018, and cobimetinib was 38.5%. On the other hand, only 27.2% of patients carrying NRAS mutation responded partially to the combined regimen of immune checkpoint inhibitor programmed death ligand-1 (PD-L1) monoclonal antibody durvalumab+trametinib. In addition, some preclinical findings have also shown translational potentials: for example, heat shock protein 90 (HSP90) inhibitor XL888 and serine/threonine protein kinase 19 (STK19) inhibitors were found to inhibit the growth of NRAS mutant melanoma in animal models. This article reviewed the oncogenic roles of NRAS mutation in melanoma and the cutting-edge clinical trials for the treatment of NRAS mutant melanoma, aiming to provide alterative treatment options for clinical practice and inspire novel combination regimen.

Key words: NRAS mutation, Melanoma, Carcinogenesis, Targeted therapy

中图分类号:

R739.5

赵博伦, 朱冠男. NRAS突变型晚期黑色素瘤的治疗进展[J]. 中国癌症杂志, 2023, 33(10): 936-944.

ZHAO Bolun, ZHU Guannan. Advances in the treatment of advanced melanoma with NRAS gene mutation[J]. China Oncology, 2023, 33(10): 936-944.

图/表 2

图1

表1

针对NRAS突变型黑色素瘤的临床试验"

Identifier	Target	Study design	NRAS-mutant mlanoma patients	Efficacy	Time frame
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

表1

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