Therapeutic Implications of Detecting MAPK-Activating Alterations in Cutaneous and Unknown Primary Melanomas.
Therapeutic Implications of Detecting MAPK-Activating Alterations in Cutaneous and Unknown Primary Melanomas.
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皮肤和不明原因的原发黑色素瘤中检测MAPK激活改变的治疗意义。
DOI：
10.1158/1078-0432.ccr-20-4189
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发表时间：
2021-04-15
期刊：
影响因子：
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通讯作者：
Schultz N
中科院分区：
文献类型：
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作者：
Shoushtari AN;Chatila WK;Arora A;Sanchez-Vega F;Kantheti HS;Rojas Zamalloa JA;Krieger P;Callahan MK;Betof Warner A;Postow MA;Momtaz P;Nair S;Ariyan CE;Barker CA;Brady MS;Coit DG;Rosen N;Chapman PB;Busam KJ;Solit DB;Panageas KS;Wolchok JD;Schultz N
皮肤和不明原因的原发黑色素瘤经常存在激活丝裂原活化蛋白激酶(MAPK)途径的改变。超过BRAF V600的MAPK驱动程序检测在检查点抑制剂时代是否具有临床意义尚不清楚。前瞻性地向黑色素瘤患者提供了341-468个基因的肿瘤测序。28个RTK-RAS-MAPK通路基因的致癌改变用于构建MAPK驱动组。对于接受一线PD-1单一治疗、尼伏卢单抗加ipilimumab或随后基因匹配的靶向治疗的患者，确定治疗失败时间(TTF)。使用驾驶员组和临床变量建立了TTF的COX比例风险模型。在696例测序的黑色素瘤中，670例(96%)存在致癌的rtk-ras-MAPK通路改变，33%的黑色素瘤有≥-1驱动。9组司机的临床表现和突变负担各不相同。PD-1单一治疗(N=181)的TTf因司机而异，NRASQ61和BRAFV600的结果比NF1或其他改变(中位数4.2、7.5、22和未达到；p<；0.0001)更差。司机组仍然显著独立于TMB和临床特征。尼伏单抗加ipilimumab(N=141)的TTF没有因驱动因素而改变。在检查点阻断进展的172例BRAF V600野生型黑色素瘤患者中，27例接受了基因匹配治疗，8例(30%)获得了持续6个月的≥临床受益。靶向捕获多基因测序可以检测几乎所有皮肤和未知的原发黑色素瘤中致癌的RTK-RAS-MAPK通路的改变。PD-1单一治疗失败的时间因ERK激活机制而异。致癌激酶融合可以成功地靶向免疫检查点抑制物-难治性黑色素瘤。
Cutaneous and unknown primary melanomas frequently harbor alterations that activate the Mitogen Activated Protein Kinase (MAPK) pathway. Whether MAPK driver detection beyond BRAF V600 is clinically relevant in the checkpoint inhibitor era is unknown. Patients with melanoma were prospectively offered tumor sequencing of 341–468 genes. Oncogenic alterations in 28 RTK-RAS-MAPK pathway genes were used to construct MAPK driver groups. Time to treatment failure (TTF) was determined for patients who received frontline PD-1 monotherapy, nivolumab plus ipilimumab, or subsequent genomically matched targeted therapies. A Cox proportional hazards model was constructed for TTF using driver group and clinical variables. 670 of 696 sequenced melanomas (96%) harbored an oncogenic RTK-RAS-MAPK pathway alteration; 33% had ≥1 driver. Nine driver groups varied by clinical presentation and mutational burden. TTF of PD-1 monotherapy (N=181) varied by driver, with worse outcomes for NRAS Q61 and BRAF V600 versus NF1 or other alterations (median 4.2, 7.5, 22 and not reached; p<0.0001). Driver group remained significant independent of TMB and clinical features. TTF did not vary by driver for nivolumab plus ipilimumab (N=141). Among 172 patients with BRAF V600 wild-type melanoma who progressed on checkpoint blockade, 27 were treated with genomically matched therapy, and 8 (30%) derived clinical benefit lasting ≥6 months. Targeted capture multigene sequencing can detect oncogenic RTK-RAS-MAPK pathway alterations in almost all cutaneous and unknown primary melanomas. Time to treatment failure of PD-1 monotherapy varies by mechanism of ERK activation. Oncogenic kinase fusions can be successfully targeted in immune checkpoint inhibitor-refractory melanoma.