Tipifarnib in Head and Neck Squamous Cell Carcinoma With HRAS Mutations.
Tipifarnib in Head and Neck Squamous Cell Carcinoma With HRAS Mutations.
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DOI：
10.1200/jco.20.02903
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发表时间：
2021-06-10
期刊：
影响因子：
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通讯作者：
Gualberto A
中科院分区：
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作者：
Ho AL;Brana I;Haddad R;Bauman J;Bible K;Oosting S;Wong DJ;Ahn MJ;Boni V;Even C;Fayette J;Flor MJ;Harrington K;Kim SB;Licitra L;Nixon I;Saba NF;Hackenberg S;Specenier P;Worden F;Balsara B;Leoni M;Martell B;Scholz C;Gualberto A
HRAS（mHRAS）原癌基因突变发生在4%-8%的复发性和/或转移性（R/M）头颈部鳞状细胞癌（HNSCC）患者中。Tipifarnib是一种法尼基转移酶抑制剂，可破坏HRAS功能。我们评估了替吡法尼在R/M mHRAS HNSCC患者中的疗效。我们在替吡法尼治疗mHRAS恶性肿瘤的单臂、开放标签II期试验中招募了30例R/M HNSCC患者;另外1例患者接受了扩大治疗计划。对前16例具有mHRAS变异等位基因频率（VAF）数据的HNSCC患者进行专门分析后，入组仅限于mHRAS VAF ≥ 20%（高VAF）的患者。主要终点为客观缓解率。次要终点包括评估安全性和耐受性。患者在28天周期的第1-7天和第15-21天口服tipifarnib 600或900 mg，每日两次。在22例伴有高VAF的HNSCC患者中，20例在数据截止时可评价缓解。可评价的高VAF HNSCC患者的客观缓解率为55%（95% CI，31.5 - 76.9）。tipifarnib组的中位无进展生存期为5.6个月（95%CI，3.6至16.4），而最后一次既往治疗组为3.6个月（95%CI，1.3至5.2）。中位总生存期为15.4个月（95% CI，7.0 - 29.7）。30例HNSCC患者中最常见的治疗后出现的不良事件是贫血（37%）和淋巴细胞减少症（13%）。替吡法尼在具有HRAS突变的R/M HNSCC患者中表现出令人鼓舞的疗效，对于这些患者，存在有限的治疗选择（NCT 02383927）。
Mutations in the HRAS (mHRAS) proto-oncogene occur in 4%-8% of patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Tipifarnib is a farnesyltransferase inhibitor that disrupts HRAS function. We evaluated the efficacy of tipifarnib in patients with R/M mHRAS HNSCC. We enrolled 30 patients with R/M HNSCC in a single-arm, open-label phase II trial of tipifarnib for mHRAS malignancies; one additional patient was treated on an expanded access program. After an ad hoc analysis of the first 16 patients with HNSCC with mHRAS variant allele frequency (VAF) data, enrollment was limited to those with a mHRAS VAF of ≥ 20% (high VAF). The primary end point was objective response rate. Secondary end points included assessing safety and tolerability. Patients received tipifarnib 600 or 900 mg orally twice daily on days 1-7 and 15-21 of 28-day cycles. Of the 22 patients with HNSCC with high VAF, 20 were evaluable for response at the time of data cutoff. Objective response rate for evaluable patients with high-VAF HNSCC was 55% (95% CI, 31.5 to 76.9). Median progression-free survival on tipifarnib was 5.6 months (95% CI, 3.6 to 16.4) versus 3.6 months (95% CI, 1.3 to 5.2) on last prior therapy. Median overall survival was 15.4 months (95% CI, 7.0 to 29.7). The most frequent treatment-emergent adverse events among the 30 patients with HNSCC were anemia (37%) and lymphopenia (13%). Tipifarnib demonstrated encouraging efficacy in patients with R/M HNSCC with HRAS mutations for whom limited therapeutic options exist (NCT02383927).