PO.CL12.01 · 临床研究

每周卡铂/紫杉醇联合cemiplimab（wCP+C）治疗晚期/转移性黏膜型头颈部鳞状细胞癌（a/mHNSCC）II期试验中疗效与生存的分子相关因素

Molecular correlates of response and survival in a phase II trial of weekly carboplatin/paclitaxel plus cemiplimab (wCP+C) in advanced/metastatic mucosal head and neck squamous cell carcinoma (a/mHNSCC)

编号 3871 展板 4 时间 4/20 02:00–05:00 区域 Section 46 主讲 Mateus Trinconi Cunha, MD

分会场 Molecular Classification and Tumor Biology in Cancer

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作者与单位 Authors & Affiliations

Mateus Trinconi Cunha¹, Fahad Rind², Priyanka Bhateja¹, Esmerina Tili³, David Konieczkowski⁴, Darrion Mitchell⁴, Sujith Baliga⁴, Sung Jun Ma⁴, Simeng Zhu⁴, Gogineni Emile⁴, John Grecula⁴, Nolan Seim⁵, Catherine Harring⁵, Lauren Miller⁵, Abberly Lott Limbach⁶, Kang Stephen⁵, James W. Rocco⁵, Christian Rolfo⁷, Dukagjin Blakaj⁴, Marcelo Bonomi⁸

¹Head and Neck Medical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH,²Clinical Trials Department, The Ohio State University Wexner Medical Center, Columbus, OH,³Anesthesiology, The Ohio State University Wexner Medical Center, Columbus, OH,⁴Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH,⁵Otolaryngology, The Ohio State University Wexner Medical Center, Columbus, OH,⁶Pathology, The Ohio State University Wexner Medical Center, Columbus, OH,⁷Medical Oncology, The Ohio State University Wexner Medical Center, Columbu, OH,⁸Head and Neck Medical Oncology, The Ohio State Universiy Wexner Medical Center, Columbus, OH

摘要 Abstract

中文摘要

背景：a/mHNSCC预后差且免疫治疗疗效有限。每周低剂量化疗可能在增强免疫原性的同时降低毒性。我们开展了一项每周低剂量化疗联合cemiplimab作为a/mHNSCC一线治疗的II期试验，并整合基因组分析以探索疗效的分子相关因素。患者接受每周卡铂（AUC 1）和紫杉醇（30 mg/m²）联合cemiplimab（350 mg 每3周一次）。2021年12月至2024年12月共入组42例患者。中位年龄68岁（范围42-81）；38/42为男性，27例（64%）为HPV阳性。中位OS（27例事件）为16.4个月（95% CI，12.6-23.9）；中位PFS（36例事件）为5.62个月（95% CI，5.0-10.3）。客观缓解率（ORR）为43%（18/42，PR或CR）。该治疗耐受性良好。这些结果曾在ESMO 2025上报告。我们旨在展示该队列中致病性基因组突变的探索性分析及其与ORR、PFS和OS的相关性。方法：在42例入组患者中，29例进行了基因组分析（Tempus xT/xF）。对4种最常见的致病性改变分别进行分析，同时将所有检测到致病性改变的基因按通路或功能组进行分组分析，采用Kaplan-Meier法和log-rank检验评估至事件时间结局，并在适当时使用Cox模型。缓解组（CR/PR对比PD，即ORR）与极端PFS组（<3个月对比>12个月）之间的肿瘤突变患病率采用比值比进行分析。P值<0.05被认为具有统计学意义。鉴于本报告的假设生成性质，未对多重检验进行p值校正。结果：致病性改变包括TP53（N=14）、CDKN2A（N=11）、TERT启动子（N=8）和FGF3/FGF4拷贝数增加（CNG；N=17）。NOTCH通路基因（NOTCH1/3、FBXW7；N=7）的突变在原发性进展患者（p = 0.02）以及PFS <3个月对比>12个月的患者（p = 0.03）中富集。NOTCH改变与较差的PFS（HR 3.6；95% CI，1.4-9.3；p < 0.01）和OS（HR 2.9；95% CI，1.05-8.0；p = 0.04）相关。TERT启动子突变与较差的OS相关（HR 4.9；95% CI，1.7-14.5；p < 0.01），并呈现出较差PFS的趋势（HR 2.2；95% CI，0.9-5.2；p = 0.08）。FGF3/FGF4 CNG也呈现出较差PFS的趋势（HR 2.6；95% CI，0.9-7.4；p = 0.08），并与较差的OS相关（HR 2.5；95% CI，1.0-6.6；p = 0.04）。结论：每周低剂量化疗联合cemiplimab在a/mHNSCC中显示出有前景的活性。探索性基因组分析提示NOTCH通路突变可能是不良预后和耐药的标志物。TERT和FGF3/4改变也可能导致较差的结局，值得进一步研究。

查看英文原文 English abstract

Background: a/mHNSCC exhibits poor prognosis and limited immunotherapy efficacy. Weekly low-dose chemotherapy may enhance immunogenicity while reducing toxicity. We conducted a phase II trial of weekly low-dose chemotherapy plus cemiplimab as first-line treatment in a/mHNSCC, with integrated genomic profiling to explore molecular correlates of outcome. Patients received weekly carboplatin (AUC 1) and paclitaxel (30 mg/m²) plus cemiplimab (350 mg q3w). Forty-two patients were enrolled from Dec 2021-Dec 2024. Median age was 68 (range 42-81); 38/42 were male, and 27 (64%) were HPV-positive. Median OS (27 events) was 16.4 months (95% CI, 12.6-23.9); median PFS (36 events) was 5.62 months (95% CI, 5.0-10.3). Objective response rate (ORR) was 43% (18/42, PR or CR). The treatment was well-tolerated. These results were previously presented at ESMO 2025. We aim to present an exploratory analysis of pathogenic genomic mutations in this cohort and their correlation with ORR, PFS, and OS. Methods: Of the 42 enrolled patients, genomic analysis (Tempus xT/xF) was performed in 29. The 4 most prevalent pathogenic alterations were analyzed separately, while all genes with detected pathogenic alterations were grouped and analyzed by pathway or functional group, with time-to-event outcomes assessed via Kaplan-Meier and log-rank, and Cox models when appropriate. Prevalence of tumor mutations between responder groups (CR/PR versus PD as ORR) and extreme PFS groups (<3 versus >12 months) was performed with odds ratio. P-values< 0.05 were deemed statistically significant. Due to the hypothesis-generating nature of this report, p-value adjustments for multiple tests were not performed. Results: Pathogenic alterations included TP53 (N=14), CDKN2A (N=11), TERT promoter (N=8), and FGF3/FGF4 copy number gains (CNG; N=17). Mutations in NOTCH pathway genes (NOTCH1/3, FBXW7; N=7) were enriched in patients with primary progression (p = 0.02) and those with PFS <3 months versus >12 months (p = 0.03). NOTCH alterations conferred inferior PFS (HR 3.6; 95% CI, 1.4-9.3; p < 0.01) and OS (HR 2.9; 95% CI, 1.05-8.0; p = 0.04). TERT promoter mutations were associated with worse OS (HR 4.9; 95% CI, 1.7-14.5; p < 0.01) and trended toward poor PFS (HR 2.2; 95% CI, 0.9-5.2; p = 0.08). FGF3/FGF4 CNGs also trended toward inferior PFS (HR 2.6; 95% CI, 0.9-7.4; p = 0.08) and were associated with worse OS (HR 2.5; 95% CI, 1.0-6.6; p = 0.04). Conclusions: Weekly low-dose chemotherapy plus cemiplimab shows promising activity in a/mHNSCC. Exploratory genomic profiling suggests NOTCH pathway mutations may be markers of poor prognosis and resistance. TERT and FGF3/4 alterations may also confer inferior outcomes and warrant further study.

利益披露 Disclosure

M. Trinconi Cunha, None.. F. Rind, None.. P. Bhateja, None.. E. Tili, None.. D. Konieczkowski, None.. D. Mitchell, None.. S. Baliga, None.. S. Ma, None.. S. Zhu, None.. G. Emile, None.. J. Grecula, None.. N. Seim, None.. C. Harring, None.. L. Miller, None.. A. Lott Limbach, None.. K. Stephen, None.. J. W. Rocco, None.. C. Rolfo, None.. D. Blakaj, None.. M. Bonomi, None.

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