Cetuximab and Nivolumab in Recurrent/Metastatic Head and Neck Cancer

A multi-center, non-randomized, open label, phase I/II study was conducted at Moffitt Cancer Center, Ohio State University and Emory University. Early results of the clinical trial in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) has been previously published, showing that the combination of cetuximab and nivolumab has manageable toxicities and is more efficacious compared to the response rate of historical cetuximab or anti-PD-1 monotherapy (Chung et al., Cancers 2021, Chung et al., Clin Cancer Res 2022). Additional exploratory correlative studies were also conducted using the clinical specimens including formalin fixed paraffin embedded (FFPE) tumors and serially collected plasma cell free DNA (cfDNA; pre-treatment, on-treatment, and time of disease progression/end of treatment). These biomarker results were correlated with the clinical data obtained from the trial patients. Evaluated molecular biomarkers include DNA and RNA-sequencing and multiple immunohistochemistry markers. Altogether, our findings indicate that p16-negative R/M HNSCC patients may have greater benefit from the combination of cetuximab and nivolumab compared to patients with p16-positive HNSCC. It is anticipated that this resource will facilitate researchers to advance the therapeutic development by further understanding of HNSCC biology and provide tools to improve the clinical outcomes in incurable R/M HNSCC. ]]>
Inclusion Criteria: • Participants must have histologically or cytologically confirmed squamous cell carcinoma of oral cavity, oropharynx, paranasal sinuses, nasal cavity, hypopharynx, or larynx. Squamous cell carcinoma of unknown primary in cervical lymph node can be included only if p16 status is positive. • Must have recurrent or metastatic HNSCC stage III/IV that is not amenable to local therapy with curative intent (surgery or radiation therapy with or without chemotherapy).Patients with persistent disease following radiation therapy administered with a chemotherapy sensitizer may also be included. • Must have progressed on at least one prior line of chemotherapy, targeted therapy, palliative radiation, and/or biological therapy regimen for their recurrent and/or metastatic HNSCC. However, if patients are likely to be intolerant to standard first-line systemic chemotherapy, the patients are eligible to enroll to this study as the first-line therapy. Additionally, patients with persistent disease or platinum-refractory recurrent disease may enroll in this study as a first-line therapy. • Must NOT have any systemic therapy for recurrent and/or metastatic disease except if given as a part of a multimodality treatment (i.e. re-irradiation and systemic therapy for curable intent of locally recurrent disease). • Must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as outlined in RECIST version 1.1. • Must be ≥ 18 years of age. • Life expectancy of greater than 3 months. • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. • Must have normal organ function: Absolute neutrophil count > 1,500/μL; Hemoglobin > 9 g/dLPlatelets > 100,000/μLTotal bilirubin ≤ 1.5 mg/dL X institutional upper limits of normal (ULN)AST (SGOT)/ALT (SGPT) < 3 X institutional ULN (or 5.0 X the ULN in the setting of liver metastasis)Serum creatinine of ≤ 1.5 X ULN or creatinine clearance > 40 mL/minute (using Cockcroft/Gault formula): Female creatinine clearance = (140 - age in years) x weight in kg x 0.8572 x serum creatinine in mg/ dLMale creatinine clearance = (140 - age in years) x weight in kg x 1.0072 x serum creatinine in mg/dL.• Participants, if sexually active, must be postmenopausal, surgically sterile, or using effective contraception (hormonal or barrier methods). Female participants of childbearing potential must have a negative serum pregnancy test within 7 days prior to enrollment. • Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: • Have experienced grade 3 or above skin toxicity from prior Epidermal growth factor receptor (EGFR) inhibiting therapy. • Have experienced grade 3 or above toxicity from prior anti-PD1 therapy. • Have p16 negative squamous cell carcinoma of unknown primary in cervical lymph node. • Patients with primary nasopharynx or salivary gland cancers. • Patients who have had chemotherapy, biological therapy or definitive radiation within 4 weeks of the study enrollment or those who have not recovered from adverse events to ≤ Grade 1 due to agents administered more than 4 weeks earlier. • Had undergone any major surgery within 4 weeks of study enrollment. • Had undergone any palliative radiation within 2 weeks of study enrollment. • Have had other investigational agents within 4 weeks or 5 half-lives, whichever is shorter, of the study enrollment. • Have known leptomeningeal metastases or untreated or symptomatic brain metastases. Treated, asymptomatic brain metastasis can be included. • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, autoimmune disease requiring systemic steroids, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. • Have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. • Have clinically relevant coronary artery disease or history of myocardial infarction in the last 12 months or high risk of uncontrolled arrhythmia or uncontrolled cardiac insufficiency. • Have uncontrolled or poorly controlled hypertension (>180 mmHg systolic or > 130 mmHg diastolic) at the time of enrollment. • Prior treatment with a combination of cetuximab and a PD-1/PD-L1 inhibitor. Prior treatment with cetuximab or a PD-1/PD-L1 inhibitor is allowed as long as not previously given in combination. • A history of allergic reactions attributed to compounds of chemical or biologic composition similar to those of cetuximab and/or nivolumab. • Pregnant or breast-feeding. • Known active HIV, Hep B, or Hep C infection. If not clinically indicated, the patients do not need to be tested. ]]>

本研究为多中心、非随机、开放标签的I/II期临床试验，由莫菲特癌症中心（Moffitt Cancer Center）、俄亥俄州立大学（Ohio State University）及埃默里大学（Emory University）共同开展。该项针对复发/转移性（recurrent and/or metastatic, R/M）头颈部鳞状细胞癌（head and neck squamous cell carcinoma, HNSCC）的临床试验早期结果已既往发表，结果显示西妥昔单抗（cetuximab）联合纳武利尤单抗（nivolumab）的毒性反应可控，且相较于历史队列中西妥昔单抗单药或抗PD-1单药治疗的应答率，联合疗法展现出更优的疗效（Chung等，《Cancers》2021；Chung等，《Clinical Cancer Research》2022）。

本研究同时利用临床标本开展了额外的探索性关联分析，标本包括福尔马林固定石蜡包埋（formalin fixed paraffin embedded, FFPE）肿瘤组织及连续采集的血浆无细胞DNA（cell free DNA, cfDNA；采集节点包括治疗前、治疗中及疾病进展/治疗结束时）。将上述生物标志物结果与试验患者的临床数据进行关联分析，评估的分子生物标志物包括DNA与RNA测序、多种免疫组化标志物。综上，本研究结果提示，相较于p16阳性HNSCC患者，p16阴性的R/M HNSCC患者或可从西妥昔单抗联合纳武利尤单抗的治疗方案中获得更大获益。预计本数据集将助力研究者进一步阐明HNSCC的生物学特性，推动治疗研发，并为改善不可治愈R/M HNSCC的临床结局提供工具。

### 纳入标准
• 受试者需经组织学或细胞学确认患有口腔、口咽、鼻窦、鼻腔、下咽或喉部的鳞状细胞癌；宫颈淋巴结不明原发灶鳞状细胞癌仅在p16状态为阳性时可纳入本研究。
• 患有复发/转移性III/IV期HNSCC，且无法接受根治性局部治疗（手术或放疗±化疗）；接受过化疗增敏放疗后仍存在持续性疾病的患者亦可纳入。
• 针对其复发/转移性HNSCC，已接受至少一线化疗、靶向治疗、姑息放疗及/或生物治疗后出现疾病进展；但若患者对标准一线系统性化疗不耐受，则可作为一线治疗入组本研究。此外，存在持续性疾病或铂类难治性复发疾病的患者，亦可作为一线治疗入组本研究。
• 未接受过针对复发/转移性疾病的系统性治疗，但若为多模式治疗的一部分（即针对局部复发性疾病的再放疗联合系统性治疗，以达到根治目的）则除外。
• 存在可测量病灶，即至少存在一个可通过至少一个维度（记录最长直径）准确测量的病灶，符合实体瘤疗效评价标准1.1版（Response Evaluation Criteria in Solid Tumors version 1.1, RECIST 1.1）。
• 年龄≥18周岁。
• 预期生存期≥3个月。
• 东部肿瘤协作组（Eastern Cooperative Oncology Group, ECOG）体能状态评分≤2分。
• 器官功能正常：中性粒细胞绝对计数>1500/μL；血红蛋白>9g/dL；血小板计数>100000/μL；总胆红素≤1.5×机构正常上限（upper limits of normal, ULN）；天冬氨酸氨基转移酶（AST/SGOT）/丙氨酸氨基转移酶（ALT/SGPT）<3×ULN（若存在肝转移则可放宽至5.0×ULN）；血清肌酐≤1.5×ULN或肌酐清除率>40mL/min（采用Cockcroft-Gault公式计算：女性肌酐清除率=(140-年龄)×体重(kg)×0.8572/血清肌酐(mg/dL)；男性肌酐清除率=(140-年龄)×体重(kg)×1.0072/血清肌酐(mg/dL)）。
• 若有性生活，女性受试者需为绝经后、手术绝育或采用有效的避孕措施（激素避孕或屏障避孕）；育龄期女性受试者需在入组前7天内血清妊娠试验结果为阴性。
• 能够理解并自愿签署书面知情同意书。

### 排除标准
• 既往接受表皮生长因子受体（Epidermal growth factor receptor, EGFR）抑制剂治疗后出现≥3级皮肤毒性反应。
• 既往接受抗PD-1治疗后出现≥3级毒性反应。
• 宫颈淋巴结不明原发灶且p16阴性的鳞状细胞癌。
• 原发性鼻咽癌或涎腺腺癌患者。
• 在研究入组前4周内接受过化疗、生物治疗或根治性放疗，或在入组前4周以上接受的治疗导致的不良反应未恢复至≤1级者。
• 研究入组前4周内接受过任何大型手术。
• 研究入组前2周内接受过任何姑息性放疗。
• 研究入组前4周内或5个半衰期（以较短者为准）内接受过其他试验性药物治疗。
• 已知存在软脑膜转移，或未经治疗、有症状的脑转移；经治疗且无症状的脑转移患者可纳入。
• 存在未控制的间发性疾病，包括但不限于：活动性或持续性感染、需要系统性糖皮质激素治疗的自身免疫性疾病、症状性充血性心力衰竭、不稳定型心绞痛、心律失常，或会影响研究依从性的精神疾病/社会状况。
• 研究药物给药前14天内需要接受系统性糖皮质激素治疗（每日泼尼松等效剂量>10mg）或其他免疫抑制药物治疗；若不存在活动性自身免疫性疾病，吸入性或局部用糖皮质激素、每日泼尼松等效剂量≤10mg的肾上腺替代治疗是允许的。
• 近12个月内有临床相关冠状动脉疾病史或心肌梗死史，或存在未控制的心律失常风险或未控制的心功能不全。
• 入组时存在未控制或控制不佳的高血压（收缩压>180mmHg或舒张压>130mmHg）。
• 既往接受过西妥昔单抗与PD-1/PD-L1抑制剂的联合治疗；既往单独接受西妥昔单抗或PD-1/PD-L1抑制剂治疗是允许的，前提是未联合使用。
• 有针对西妥昔单抗和/或纳武利尤单抗化学结构或生物组成类似化合物的过敏反应史。
• 妊娠或哺乳期女性。
• 已知现症HIV、乙型肝炎（Hep B）或丙型肝炎（Hep C）感染；若无临床指征，无需对患者进行相关检测。