中国临床试验注册中心 - 世界卫生组织国际临床试验注册平台一级注册机构

注册号： Registration number：	ChiCTR2600124257
最近更新日期： Date of Last Refreshed on：	2026-05-09 11:47:30
注册时间： Date of Registration：	2026-05-09 00:00:00
注册号状态：	预注册
Registration Status：	Prospective registration
注册题目：	KEYMAKER-U01子研究01F：一项在既往接受过治疗的KRAS G12C突变晚期或转移性非鳞状非小细胞肺癌（NSCLC）受试者中评估试验药物的滚动臂、Ib/II期、伞式研究
Public title：	KEYMAKER-U01 Substudy 01F: A Phase 1b/2 Umbrella Study With Rolling Arms of Investigational Agents for Previously Treated Participants With Advanced or Metastatic Nonsquamous Non-small Cell Lung Cancer (NSCLC) With KRAS G12C Mutations
注册题目简写：
English Acronym：	KEYMAKER-U01 Substudy 01F
研究课题的正式科学名称：	KEYMAKER-U01子研究01F：一项在既往接受过治疗的KRAS G12C突变晚期或转移性非鳞状非小细胞肺癌（NSCLC）受试者中评估试验药物的滚动臂、Ib/II期、伞式研究
Scientific title：	KEYMAKER-U01 Substudy 01F: A Phase 1b/2 Umbrella Study With Rolling Arms of Investigational Agents for Previously Treated Participants With Advanced or Metastatic Nonsquamous Non-small Cell Lung Cancer (NSCLC) With KRAS G12C Mutations
研究课题代号(代码)： Study subject ID：
在二级注册机构或其它机构的注册号： The registration number of the Partner Registry or other register：

申请注册联系人：	匡芮	研究负责人：	徐崇锐
Applicant：	Rui Kuang	Study leader：	Chongrui Xu
申请注册联系人电话： Applicant telephone：	+86 15618528998	研究负责人电话： Study leader's telephone：	+86 20 8382 7812
申请注册联系人传真： Applicant Fax：		研究负责人传真： Study leader's fax：
申请注册联系人电子邮件： Applicant E-mail：	rui.kuang@msd.com	研究负责人电子邮件： Study leader's E-mail：	xucr001@gmail.com
申请单位网址(自愿提供)： Applicant website(voluntary supply)：		研究负责人网址(自愿提供)： Study leader's website(voluntary supply)：
申请注册联系人通讯地址：	中国上海市徐汇区虹桥路183号徐家汇中心三期A座36层	研究负责人通讯地址：	广州市中山二路106号
Applicant address：	A.Level 36, Tower A, THREE ITC No. 183 Hongqiao Road, Xuhui District, Shanghai 200030, China	Study leader's address：	No.106 Zhongshan Er Road, Guangzhou, China
申请注册联系人邮政编码： Applicant postcode：		研究负责人邮政编码： Study leader's postcode：
申请人所在单位：	默沙东研发（中国）有限公司
Applicant's institution：	Merck Sharp & Dohme LLC
研究负责人所在单位：	广东省人民医院（广东省医学科学院）
Affiliation of the Leader：	Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)

是否获伦理委员会批准：	是
Approved by ethic committee：	Yes
伦理委员会批件文号： Approved No. of ethic committee：	YW2025-195-03	伦理委员会批件附件： Approved file of Ethical Committee：	查看附件View
批准本研究的伦理委员会名称：	广东省人民医院注册临床试验伦理审查委员会
Name of the ethic committee：	Ethics Review Committee of Guangdong Provincial People's Hospital
伦理委员会批准日期： Date of approved by ethic committee：	2026-01-30 00:00:00
伦理委员会联系人：	白胜
Contact Name of the ethic committee：	Bai Sheng
伦理委员会联系地址：	广州市中山二路106号
Contact Address of the ethic committee：	No.106 Zhongshan Er Road, Guangzhou, China
伦理委员会联系人电话： Contact phone of the ethic committee：	+86 20 83525173	伦理委员会联系人邮箱： Contact email of the ethic committee：	gdghospital_ec@gdph.org.cn

研究实施负责（组长）单位：

广东省人民医院（广东省医学科学院）

Primary sponsor：

Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)

研究实施负责（组长）单位地址：

广州市中山二路106号

Primary sponsor's address：

No.106 Zhongshan Er Road, Guangzhou, China

试验主办单位(项目批准或申办者)：

Secondary sponsor：

国家：	中国	省(直辖市)：	广东省	市(区县)：
Country：	China	Province：	Guangdong	City：
单位(医院)：	广东省人民医院（广东省医学科学院）	具体地址：	广州市中山二路106号
Institution hospital：	Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)	Address：	No.106 Zhongshan Er Road, Guangzhou, China

经费或物资来源：

默沙东研发（中国）有限公司

Source(s) of funding：

Merck Sharp & Dohme LLC

研究疾病：

接受过1-2线抗PD-1/PD-L1治疗及含铂化疗、未接受过KRAS抑制剂治疗的KRAS G12C突变晚期或转移性非鳞状NSCLC

Target disease：

with advanced or metastatic nonsquamous NSCLC with KRAS G12C mutations, whohave received 1-2 lines of prior anti-PD-1/PD-L1 therapy and platinum-based chemotherapywithout prior KRAS inhibitor therapy

研究疾病代码：

Target disease code：

研究类型：

干预性研究

Study type：

Interventional study

研究所处阶段：

I期+II期

Study phase：

1-2

研究设计：

非随机对照试验

Study design：

Non randomized control

研究目的：

1、评价试验药物联合治疗的安全性和耐受性 2、评价ORR

Objectives of Study：

1. To evaluate the safety and tolerability ofinvestigational agent combinations 2. To evaluate ORR

药物成份或治疗方案详述：

Description for medicine or protocol of treatment in detail：

纳入标准：

1. 经组织学或细胞学确诊的晚期或转移性非鳞状NSCLC（根据AJCC分期手册第8版确认的III期（不适合根治性切除或放化疗）或IV期 [M1a、M1b或M1c]）。注：混合性肿瘤将通过主要细胞类型（鳞状或非鳞状）进行分类；但不允许存在小细胞成分。
2. 当地实验室评估证实存在KRAS G12C突变的肿瘤组织或ctDNA。  注：必须在分配/随机分组前评估是否存在KRAS G12C突变。
3. 根据当地治疗标准接受抗PD-1/PD-L1治疗和含铂化疗（联合治疗或序贯治疗）后记录到根据RECIST 1.1评估的疾病进展。如果是联合治疗，则既往治疗线数不得超过1线。如果是序贯治疗，则既往治疗线数不得超过2线。   注：如果依次给予抗PD-1/PD-L1治疗和含铂化疗，则合格受试者应在各线治疗后记录到疾病进展。  注：受试者应接受过至少2个周期的抗PD-1/PD-L1治疗和至少2个周期的含铂化疗。  注：对于作为非转移性NSCLC新辅助或辅助治疗的一部分或作为根治性放化疗的一部分既往接受的抗PD-1/PD-L1治疗和/或含铂化疗，如果在晚期或转移性NSCLC诊断前12个月完成治疗，则视为1线治疗。
4. 由研究者根据RECIST 1.1评估并经BICR确认的可测量病灶。位于既往放疗照射区域的病灶，如果已经出现进展，则认为该病灶是可测量的。
5. 预期寿命至少为3个月。
6. 分配/随机分组前7天内评估的ECOG体能状态评分为0或1分。
7. 具有下表（表2 ）所定义的充分的器官功能。样本必须在研究干预开始前10天内采集。
8. 在提供知情同意书时（如适用），为性别不限的、年龄≥18岁的个体。如当地法规要求可同意参与研究的法定年龄需大于18岁，请遵循当地的规定。
9. 如果受试者能够产生精子，同意在干预期间和至少在研究干预末次给药后消除每种研究干预所需的时间内遵守以下要求。每种研究干预所需的持续避孕时长如下：  - MK-1084：10天  - HER3-DXd：120天  - 芦康沙妥珠单抗：120天  - 西妥昔单抗：无需男性避孕措施  • 禁止捐精  方案标识号：MK-3475 研究编号：01F-01 •与当前未妊娠且有生育能力的非受试者进行阴茎-阴道性交时使用阴茎套/外用避孕套，且伴侣使用额外避孕措施（参见第10.5.3节），因为避孕套可能破裂或泄漏使用的避孕措施应符合当地法规对临床研究受试者的避孕措施的要求。如果任何研究干预药物当地说明书的避孕要求比上述要求更严格，则应遵循当地说明书要求。 注：如果受试者无精子（输精管结扎或继发于医学原因，由研究中心工作人员通过审查受试者病历、医学检查或病史询问后进行书面记录），则无需避孕。
10.如果在研究干预期间和研究干预末次给药后至少10天（MK-1084）、30天（HER3-DXd）、15天（芦康沙妥珠单抗）或60天（西妥昔单抗）内不进行哺乳，则出生时性别指定为女性的受试者符合入组条件。
11.如果POCBP未发生妊娠且在研究干预首次给药前24小时（尿液检测）或72小时（血清检测）内高灵敏度妊娠试验（根据当地法规要求，进行尿液或血清试验）的结果为阴性，则符合入组条件。如果通过尿液检测不能确定结果为阴性（例如结果不能明确提示是否妊娠），则需要进行血清妊娠试验。研究干预期间和研究干预后对妊娠试验的其他要求参见第8.3.7节。
12.如附录5所述，如果POCBP在研究干预期间以及研究干预末次给药后消除每种研究干预所需的最短时间内，使用高效的（每年失败率＜1%）且使用者依赖性低的避孕措施，或者在首选和日常生活方式中坚持无阴茎-阴道性交（长期和持续禁欲），则有资格参与研究。此外，受试者同意在此期间不得以生殖为目的向他人捐赠卵子（卵细胞、卵母细胞），或者冷冻/储存卵子。每种研究干预所需的继续采取避孕措施的时长如下：◦MK-1084：10天◦HER3-DXd：210天◦芦康沙妥珠单抗：210天◦西妥昔单抗：60天注：研究者应评价可能的避孕措施失败（即不依从、近期才开始使用）与研究干预首次给药之间的关系。POCBP使用的避孕措施应符合当地法规对临床研究受试者的避孕措施的要求。如果任何研究干预药物当地说明书的避孕要求比上述要求更严格，则应遵循当地说明书要求。研究者应审查病史、月经史和近期性行为，以降低伴有未检出的早期妊娠的POCBP被纳入研究的风险。
13.受试者（或法律上接受的代理人）已提供本研究的知情同意书。
14. 已提供既往未接受过放疗的肿瘤病灶的存档肿瘤组织样本（定义为在开始抗PD-1/PD-L1治疗和含铂化疗前）。关于肿瘤组织提交的详细信息参见实验室手册。  注：优先选择诊断为晚期或转移性疾病后采集的肿瘤组织。
15. 在治疗随机分组前提供符合以下要求的组织：从既往未接受过放疗的肿瘤病灶新获得的活检组织（定义为完成抗PD-1/PD-L1治疗和含铂化疗后）。关于肿瘤组织提交的详细信息参见实验室手册。   注：从新采集活检组织到研究干预开始前的这段时间里，不得接受系统性抗肿瘤治疗。必须在分配/随机分组前将组织样本运送至中心实验室。FFPE组织蜡块优于切片。不接受细针抽吸的样本。
16. 因既往抗肿瘤治疗而发生AE的受试者必须已恢复至≤1级或基线水平。发生内分泌相关AE且充分接受激素替代治疗的受试者或发生≤2级神经病的受试者有资格参加研究。
17. HIV感染的受试者必须在ART治疗后HIV得到良好控制，定义为：  a. 在筛选时，接受ART的受试者CD4+ T细胞计数必须≥350个细胞/mm3。  b. 接受ART的受试者达到并维持病毒学抑制，定义为：在筛选时和筛选前至少12周，经当地可及的检测方法确认HIV RNA水平低于50或低于其检测下限（LLOQ）。  c. 如果受试者在过去12个月内发生任何AIDS定义的机会性感染，则不建议纳入。  d. 接受ART的受试者在进入研究（第1天）前必须已接受稳定ART方案至少4周，无药物变化或剂量调整，并同意在整个研究期间继续接受ART。  e. ART联合治疗方案中不得包含第6.5节中描述的任何禁用药物。
18. HBsAg阳性的受试者如果在分配/随机分组前已接受至少4周的HBV抗病毒治疗并且HBV病毒载量不可检出，则符合入组条件。   注：受试者应在整个研究干预期间继续接受抗病毒治疗，并在完成研究干预后遵循当地HBV抗病毒治疗指南。  筛选期不要求进行乙型肝炎检测，除非：  - 已知有HBV感染史  - 当地指南强制要求；
19. 对于有HCV感染史的受试者，如果在过去4周内未接受抗病毒治疗的情况下，HCV病毒载量低于检测水平，则有资格参加研究。   注：受试者必须在分配/随机分组前至少4周完成根治性抗病毒治疗。此外，受试者必须有正常转氨酶值，或者，如果存在肝转移，存在转氨酶异常（结果为AST/ALT < 3×ULN，且不能归因于HCV感染）。  筛选期不要求进行丙型肝炎检测，除非：  - 已知有HCV感染史  - 当地指南强制要求；

Inclusion criteria

1. Histologically or cytologically confirmed diagnosis of advanced or metastatic nonsquamous NSCLC (Stage III, not eligible for curative resection or chemoradiation, or Stage IV [M1a, M1b, or M1c]) per AJCC Staging Manual, Version 8 Note: Mixed tumors will be characterized by the predominant cell type (squamous or nonsquamous); however, small cell elements are not permitted.
2. Tumor tissue or ctDNA that demonstrates the presence of KRAS G12C mutations as assessed at a local laboratory. Note: Assessment of presence of KRAS G12C mutations must be made before allocation/randomization.
3. Documented disease progression per RECIST 1.1 after receiving anti-PD-1/PD-L1 treatment and platinum-based chemotherapy (administered concurrently or sequentially) per local standard of care. If treatments were concurrent, no more than 1 prior line of treatment is allowed. If treatments were sequential, no more than 2 prior lines of treatment are allowed. Note: If anti-PD-1/PD-L1 treatment and platinum-based chemotherapy were administered sequentially, eligible participants should have documented disease progression after each line of therapy. Note: Participants should have received at least 2 cycles of an anti-PD-1/PD-L1 therapy and at least 2 cycles of platinum-based chemotherapy. Note: Prior anti-PD-1/PD-L1 treatment and/or platinum-based chemotherapy as part of neoadjuvant or adjuvant therapy or as part of definitive chemoradiation treatment for nonmetastatic NSCLC will be considered as 1 line of therapy if completed within 12 months before diagnosis of advanced or metastatic NSCLC.
4. Measurable disease per RECIST 1.1 as assessed by investigator and verified by BICR. Lesions situated in a previously irradiated area are considered measurable if progression has been shown in such lesions.
5. Life expectancy of at least 3 months.
6. ECOG performance status of 0 or 1 assessed within 7 days before allocation/randomization.
7. Adequate organ function as defined in the following table (Table 2). Specimens must be collected within 10 days before the start of study intervention.
8. Is an individual of any sex/gender, who is at least 18 years of age at the time of providing the informed consent or assent, as applicable. Follow local regulatory requirements if the legal age of consent for participation is >18 years of age.
9. If capable of producing sperm, the participant agrees to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is: - MK-1084: 10 days - HER3-DXd: 120 days - Sacituzumab tirumotecan: 120 days - Cetuximab: no male contraception measures are required • Refrains from donating sperm • Uses a penile/external condom when having penile-vaginal intercourse with a nonparticipant of childbearing potential who is not currently pregnant PLUS partner use of an additional contraceptive method (refer to Section 10.5.3), as a condom may break or leak Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions are more stringent than the requirements above, the local label requirements are to be followed. Note: If the participant is azoospermic (vasectomized or secondary to medical cause, documented from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview), no contraception is required.
10. A participant assigned female sex at birth is eligible to participate if not breastfeeding during the study intervention period and for at least 10 (MK-1084), 30 (HER3-DXd), 15 (sacituzumab tirumotecan), or 60 (cetuximab) days after the last dose of study intervention.
11. A POCBP is eligible to participate if not pregnant and if a negative highly sensitive pregnancy test (urine or serum), as required by local regulations, has been obtained within 24 hours (for a urine test) or 72 hours (for a serum test) before the first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. Additional requirements for pregnancy testing during and after study intervention are in Section 8.3.7.
12. A POCBP is eligible to participate if they use a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or if they adhere to penile-vaginal intercourse abstinence as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), as described in Appendix 5, during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. In addition, the participant agrees not to donate eggs (ova, oocytes) to others or freeze/store eggs during this period for the purpose of intervention is: ◦ MK-1084: 10 days ◦ HER3-DXd: 210 days ◦ Sacituzumab tirumotecan: 210 days ◦ Cetuximab: 60 days Note: The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recent initiation) in relationship to the first dose of study intervention. Contraceptive use by POCBPs should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the local contraception requirements for any of the study interventions are more stringent than the requirements above, the local label requirements are to be followed. Medical history, menstrual history, and recent sexual activity should be reviewed by the investigator to decrease the risk for inclusion of a POCBP with an early undetected pregnancy.
13. The participant (or legally acceptable representative) has provided documented informed consent for the study.
14. Archival tumor tissue sample (defined as before the initiation of anti-PD-1/PD-L1 therapy and platinum-based chemotherapy) of a tumor lesion not previously irradiated has been provided. Details pertaining to tumor tissue submission can be found in the Laboratory Manual. Note: Tumor tissue from after diagnosis of advanced or metastatic disease is preferred.
15. Provided tissue prior to treatment allocation/randomization from a newly obtained biopsy (defined as after completion of anti-PD-1/PD-L1 therapy and platinum-based chemotherapy) of a tumor lesion not previously irradiated. Details pertaining to tumor tissue submission can be found in the Laboratory Manual. Note: No systemic anticancer therapy may be administered between the newly obtained biopsy and initiation of study intervention. The tissue sample must be shipped to the central vendor before allocation/randomization. FFPE tissue blocks are preferred to slides. Fine-needle aspirates are not acceptable.
16. Participants who have AEs due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement or participants who have <=Grade 2 neuropathy are eligible.
17. Participants with HIV infection must have well-controlled HIV on ART, defined as: a. Participants b. Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening. c. It is advised that participants must not have had any AIDS-defining opportunistic infections within the past 12 months. d. Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before study entry (Day 1) and agree to continue ART throughout the study. e. The combination ART regimen must not contain any of the prohibited medications described in Section 6.5. on ART must have a CD4+ T-cell count >=350 cells/mm3 at the time of screening.
18. Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to allocation/randomization. Note: Participants should remain on antiviral therapy throughout study intervention and follow local guidelines for HBV antiviral therapy after completion of study intervention. Hepatitis B screening tests are not required unless: - Known history of HBV infection - As mandated by local guidelines;
19. Participants with history of HCV infection are eligible if HCV viral load is below the level of detection in the absence of antiviral therapy during the previous 4 weeks. Note: Participants must have completed curative antiviral therapy at least 4 weeks prior to allocation/randomization. In addition, participants must have normal transaminase values, or, if liver metastases are present, abnormal transaminases with a result of AST/ALT <3 × ULN, which are not attributable to HCV infection. Hepatitis C screening tests are not required unless: - Known history of HCV infection - As mandated by local guidelines;

排除标准：

1. 诊断为小细胞肺癌或存在小细胞成分的混合性肿瘤。
2. 因肺部并发症导致的临床严重肺部损害，包括但不限于：任何基础肺部疾病（即，治疗分配/随机分组前3个月内患肺栓塞，重度哮喘，重度慢性阻塞性肺疾病，限制性肺疾病，胸腔积液等），或任何自身免疫、结缔组织或炎症性疾病伴累及肺部的情况（即类风湿关节炎、舍格林综合征、结节病等），或既往全肺切除术。
3. 已知有活动性的CNS转移和/或癌性脑膜炎。既往接受过脑转移治疗的受试者可以参与研究，但前提是研究筛选期间经重复影像学检查证实，受试者在至少4周内处于影像学稳定状态（即没有疾病进展的证据），临床稳定并且在研究干预首次给药前至少14天内不需要使用类固醇治疗。基于上述定义的稳定脑转移应在研究干预首次给药前确定。已知患有未经治疗的无症状脑转移的受试者（即无神经系统症状、不需要皮质类固醇激素、无或极轻微周围水肿、无病灶＞1.5 cm）可参与研究。
4. 患有需要免疫抑制药物治疗的活动性炎症性肠病，或有炎症性肠病既往史（例如，克罗恩病、溃疡性结肠炎或慢性腹泻）。
5. 存在任何软脑膜疾病的证据。
6. 分配/随机分组前存在不受控制的或重大心血管疾病或脑血管疾病，包括： a. QTcF间期延长 > 450 ms b. LVEF≤45% c. 静息收缩压＞180 mmHg或舒张压＞110 mmHg d. 6个月内发生过心肌梗死 e. NYHA 3级或4级充血性心力衰竭 f. 6个月内发生过不受控制的心绞痛 g. 需要持续接受抗心律失常治疗的心律失常 h. 确诊或疑似为长QT综合征，或已知有长QT综合征家族史 i. 有临床意义的室性心律失常病史，如室性心动过速、室颤或尖端扭转型室速 j. 心动过缓，心率＜50 bpm，除非受试者植入起搏器 k. 有二度或三度心脏传导阻滞病史。有心脏传导阻滞病史的受试者，如果目前已植入起搏器、并且植入起搏器后未出现过昏厥或有临床意义的心律失常，则可能有资格参加研究。 l. 6个月内接受过冠状动脉/外周动脉搭桥术 m. 完全左束支传导阻滞 n. 6个月内有其他严重心脑血管疾病；
7.以下一种或多种眼科检查结果/状况：a.存在具有临床意义的角膜疾病 b.有记录的重度干眼征、重度睑板腺疾病和/或睑缘炎病史；
8.无法吞咽口服药物或患有影响吸收的胃肠道疾病。
9.有卡波西肉瘤和/或多中心型Castleman病病史的HIV感染者。
10.既往已接受过一种靶向KRAS的药物治疗。
11.既往接受过拓扑异构酶I抑制剂（如伊立替康）或抗HER3抗体治疗和/或含拓扑异构酶I抑制剂exatecan衍生物的ADC（如德曲妥珠单抗）治疗。
12.既往接受过靶向TROP2的ADC治疗。
13.分配/随机分组前洗脱不充分，定义为：a.在分配/随机分组前4周或5个半衰期（以较短者为准）内接受过既往全身性抗肿瘤治疗（包括试验药物），且尚未从抗肿瘤治疗相关AE中恢复至≤1级或基线。 b.在研究干预开始前2周内接受过放疗，或出现需要皮质类固醇治疗的放射相关毒性。注：允许针对非CNS疾病进行≤2周的姑息性放疗。末次姑息性放疗必须在研究干预首次给药前至少7天完成。 c.接受的放射治疗范围超过30%的骨髓或广野照射＜28天或姑息性放疗＜7天。 d.在研究干预开始前6个月内接受＞30 Gy的肺部放疗。 e.既往IO药物以外的mAb（如贝伐珠单抗[抗VEGF治疗]和西妥昔单抗[抗EGFR治疗]）治疗＜28天。f.接受氯喹或羟氯喹治疗≤14天。
14.在研究干预首次给药前30天内接种过活疫苗或减毒活疫苗。允许接种灭活疫苗。
15.无法依从第6.5节所述的禁用药物和洗脱时间要求。
16.在研究干预给药前4周内接受过试验药物治疗或使用过试验用器械。
17.被诊断为免疫缺陷，或在研究干预首次给药前7天内正在接受长期系统性类固醇治疗（超过10mg/天泼尼松或等效剂量）或任何其他形式的免疫抑制治疗。
18.已知患有正在进展或在过去3年内需要积极治疗的其他恶性肿瘤。注：已接受潜在根治性治疗的皮肤基底细胞癌、皮肤鳞状细胞癌或原位癌（不包括膀胱原位癌）受试者无需被排除。宫颈上皮内细胞癌充分治疗或患有低危组早期前列腺癌（ T1-T2a，Gleason评分≤6，PSA＜10 ng/mL）的受试者，如果已经接受了根治性治疗，或者疾病状态稳定未接受治疗并正在接受主动监测，则不被排除。
19. 有需要类固醇治疗的（非感染性）肺部炎症/ILD史，或当前患有肺部炎症/ILD，或筛选时无法通过标准诊断性评估排除的疑似ILD/肺部炎症。注：NSCLC的淋巴管扩散不予以排除。
20. 有需要全身治疗的活动性感染，第5.1节允许的情况除外。
21. 研究者认为，既往或当前存在任何可能混淆研究结果或干扰受试者配合研究要求的能力的状况、治疗、实验室检查异常或其他情况，在这些情况下参与研究不符合受试者的最佳利益。
22. 对研究干预、其任何辅料和/或某一生物制剂治疗有已知重度超敏反应（≥3级）。
23.受试者尚未从大手术中充分恢复或有持续的手术并发症。

Exclusion criteria：

1. Diagnosis of small cell lung cancer or, for mixed tumors, presence of small cell elements. 2. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (ie, pulmonary emboli within 3 months before treatment allocation/randomization, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, etc), or any autoimmune, connective tissue, or inflammatory disorders with pulmonary involvement (ie, rheumatoid arthritis, Sjogren’s syndrome, sarcoidosis, etc), or prior complete pneumonectomy. 3. Known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable (ie, without evidence of progression) for at least 4 weeks as confirmed by repeat imaging performed during study screening, are clinically stable, and have not required steroid treatment for at least 14 days before the first dose of study intervention. Stable brain metastases by this definition should be established prior to the first dose of study intervention. Participants with known untreated, asymptomatic brain metastases (ie, no neurological symptoms, no requirements for corticosteroids, no or minimal surrounding edema, and no lesion >1.5 cm) may participate. 4. Active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease (eg, Crohn’s disease, ulcerative colitis, or chronic diarrhea). 5. Evidence of any leptomeningeal disease. 6. Uncontrolled or significant cardiovascular disorder or cerebrovascular disease prior to allocation/randomization, including: a. QTcF prolongation interval >450 ms b. LVEF <=45% c. Resting systolic blood pressure >180 mm Hg or diastolic blood pressure >110 mm Hg) d. Myocardial infarction within 6 months e. NYHA Classes 3 or 4 congestive heart failure f. Uncontrolled angina pectoris within 6 months g. Cardiac arrhythmia requiring ongoing antiarrhythmic treatment h. Diagnosed or suspected long QT syndrome, or known family history of long QT syndrome i. History of clinically relevant ventricular arrhythmias, such as ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes j. Bradycardia of less than 50 bpm unless the participant has a pacemaker k. History of second or third degree heart block. Candidates with a history of heart block may be eligible if they currently have pacemakers and have no history of fainting or clinically relevant arrhythmia with pacemakers. l. Coronary/peripheral artery bypass graft within 6 months m. Complete left bundle branch block n. Other serious cardiovascular and cerebrovascular diseases within 6 months; 7. One or more of the following ophthalmological findings/conditions: a. Clinically significant corneal disease b. History of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis; 8. Unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption. 9. HIV-infected participants with a history of Kaposi’s sarcoma and/or Multicentric Castleman’s Disease. 10. Received previous treatment with an agent targeting KRAS. 11. Received prior treatment with a topoisomerase 1 inhibitor (eg, irinotecan) or an anti-HER3 antibody and/or ADC that consists of an exatecan derivative that is a topoisomerase 1 inhibitor (eg, trastuzumab deruxtecan). 12. Received prior treatment with a TROP2-targeted ADC. 13. Inadequate washout period before allocation/randomization, defined as: a. Received prior systemic anticancer therapy including investigational agents within 4 weeks or 5 half-lives, whichever is shorter, and has not recovered to Grade <=1 or baseline from AE associated with anticancer therapy before allocation/randomization. b. Received prior radiotherapy within 2 weeks of start of study intervention, or radiation-related toxicities, requiring corticosteroids. Note: Two weeks or fewer of palliative radiotherapy for non-CNS disease is permitted. The last palliative radiotherapy treatment must have been performed at least 7 days before the first dose of study intervention. c. Received radiotherapy treatment to more than 30% of the bone marrow or wide field radiation <28 days or palliative radiation therapy <7 days. d. Received radiation therapy to the lung that is >30 Gray within 6 months of start of study intervention. e. Received mAbs other than IO agents, such as bevacizumab (anti-VEGF) and cetuximab (anti-EGFR), <28 days. f. Received chloroquine or hydroxychloroquine <=14 days. 14. Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed. 15. Unable to adhere to the prohibited medications and washout times as per Section 6.5. 16. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration. 17. Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention. 18. Known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded. Participants with adequately treated intraepithelial carcinoma of the cervix or with low-risk early-stage prostate cancer (T1-T2a, Gleason score <=6, and PSA <10 ng/mL) either treated with definitive intent or untreated in active surveillance with stable disease are not excluded. 19. History of (noninfectious) pneumonitis/ILD that required steroids or has current pneumonitis/ILD, or where suspected ILD/pneumonitis cannot be ruled out by standard diagnostic assessments at screening. Note: Lymphangitic spread of the NSCLC is not exclusionary. 20. Active infection requiring systemic therapy other than those permitted in Section 5.1. 21. History or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant’s ability to cooperate with the requirements of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator. 22. Known severe hypersensitivity (≥Grade 3) to study intervention, any of its excipients, and/or to a biologic therapy; 23. Participants who have not adequately recovered from major surgery or have ongoing surgical complications.

研究实施时间：

Study execute time：

从 From 2026-05-15 00:00:00至 To 2038-05-15 00:00:00

征募观察对象时间：

Recruiting time：

从 From 2026-05-15 00:00:00 至 To 2029-05-15 00:00:00

干预措施：

Interventions：

组别：	第2组	样本量：	75
Group：	Group 2	Sample size：	75
干预措施：	MK-1084+sac-TMT	干预措施代码：
Intervention：	MK-1084+sac-TMT	Intervention code：

组别：	第3组	样本量：	40
Group：	Group 3	Sample size：	40
干预措施：	MK-1084+ 西妥昔单抗	干预措施代码：
Intervention：	MK-1084+ cetuximab	Intervention code：

组别：	第1组	样本量：	75
Group：	Group 1	Sample size：	75
干预措施：	MK-1084+HER3-DXd	干预措施代码：
Intervention：	MK-1084+HER3-DXd	Intervention code：

研究实施地点：

Countries of recruitment and research settings：

国家：	中国	省(直辖市)：	广东省	市(区县)：
Country：	China	Province：	Guangdong	City：
单位(医院)：	广东省人民医院（广东省医学科学院）	单位级别：	三级甲等
Institution hospital：	Guangdong Provincial People's Hospital(Guangdong Academy of Medical Sciences)	Level of the institution：	Tertiary A

国家：	中国	省(直辖市)：	上海	市(区县)：
Country：	China	Province：	Shanghai	City：
单位(医院)：	复旦大学附属中山医院	单位级别：	三级甲等
Institution hospital：	Zhongshan Hospital Affiliated to Fudan University	Level of the institution：	Tertiary A

国家：	中国	省(直辖市)：	山西	市(区县)：
Country：	China	Province：	Shanxi	City：
单位(医院)：	山西省肿瘤医院	单位级别：	三级甲等
Institution hospital：	Shanxi Cancer Hospital	Level of the institution：	Tertiary A

国家：	中国	省(直辖市)：	南京	市(区县)：
Country：	China	Province：	Nanjing	City：
单位(医院)：	南京大学医学院附属鼓楼医院	单位级别：	三级甲等
Institution hospital：	Drum Tower Hospital Affiliated to Nanjing University School of Medicine	Level of the institution：	Tertiary A

国家：	中国	省(直辖市)：	广西	市(区县)：
Country：	China	Province：	Guangxi	City：
单位(医院)：	柳州市人民医院	单位级别：	三级甲等
Institution hospital：	Liuzhou People's Hospital	Level of the institution：	Tertiary A

国家：	中国	省(直辖市)：	四川	市(区县)：
Country：	China	Province：	Sichuan	City：
单位(医院)：	四川大学华西医院	单位级别：	三级甲等
Institution hospital：	West China Hospital of Sichuan University	Level of the institution：	Tertiary A

国家：	中国	省(直辖市)：	云南	市(区县)：
Country：	China	Province：	Yunnan	City：
单位(医院)：	云南省肿瘤医院	单位级别：	三级甲等
Institution hospital：	Yunnan Provincial Cancer Hospital	Level of the institution：	Tertiary A

国家：	中国	省(直辖市)：	福建	市(区县)：
Country：	China	Province：	Fujian	City：
单位(医院)：	福建省肿瘤医院	单位级别：	三级甲等
Institution hospital：	Fujian Provincial Cancer Hospital	Level of the institution：	Tertiary A

国家：	中国	省(直辖市)：	浙江	市(区县)：
Country：	China	Province：	Zhejiang	City：
单位(医院)：	温州医科大学附属第一医院	单位级别：	三级甲等
Institution hospital：	The First Affiliated Hospital of Wenzhou Medical University	Level of the institution：	Tertiary A

国家：	中国	省(直辖市)：	河南	市(区县)：
Country：	China	Province：	Henan	City：
单位(医院)：	河南省肿瘤医院	单位级别：	三级甲等
Institution hospital：	Henan Provincial Cancer Hospital	Level of the institution：	Tertiary A

国家：	中国	省(直辖市)：	浙江	市(区县)：
Country：	China	Province：	Zhejiang	City：
单位(医院)：	浙江大学医学院附属邵逸夫医院	单位级别：	三级甲等
Institution hospital：	Shaw Hospital Affiliated to Zhejiang University School of Medicine	Level of the institution：	Tertiary A

测量指标：

Outcomes：

指标中文名：	客观缓解率	指标类型：	主要指标
Outcome：	Objective response rate, ORR	Type：	Primary indicator
测量时间点：		测量方法：	胸部、腹部和盆腔CT（或MRI）
Measure time point of outcome：		Measure method：	Tumor scan(chest,abdomen, andpelvis)

指标中文名：	无进展生存期	指标类型：	次要指标
Outcome：	Progression free survival	Type：	Secondary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	缓解持续时间	指标类型：	次要指标
Outcome：	Duration of relief	Type：	Secondary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	PK 参数，包括 AUC、 Cmax 和 Ctrough	指标类型：	次要指标
Outcome：	PK parameters, including AUC, Cmax, and Ctrough	Type：	Secondary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

采集人体标本：

Collecting sample(s)
from participants：

标本中文名：	血液	组织：
Sample Name：	Blood	Tissue：
人体标本去向	其它	说明
Fate of sample：	0thers	Note：

征募研究对象情况：

Recruiting status：

尚未开始

Not yet recruiting

年龄范围：

Participant age：

最小 Min age	18	岁 years
最大 Max age		岁 years

性别：

男女均可

Gender：

Both

随机方法（请说明由何人用什么方法产生随机序列）：

在剂量递增（Ib期）期间，将通过非随机方式对受试者进行分配。当II期阶段的治疗组开放入组时，将使用IRT集中进行随机分组。

Randomization Procedure (please state who generates the random number sequence and by what method)：

During dose escalation (Phase 1b), participants will be allocated by nonrandom assignment.When treatment arms open for enrollment during Phase 2, treatment randomization will occur centrally using IRT.

是否公开试验完成后的统计结果:

Calculated Results after the Study Completed public access:

不公开/Private

盲法：	开放标签
Blinding：	Open-label study

是否共享原始数据： IPD sharing	否No
共享原始数据的方式（说明：请填入公开原始数据日期和方式，如采用网络平台，需填该网络平台名称和网址）：	暂无
The way of sharing IPD”(include metadata and protocol, If use web-based public database, please provide the url)：	NA
数据采集和管理（说明：数据采集和管理由两部分组成，一为病例记录表(Case Record Form, CRF)，二为电子采集和管理系统(Electronic Data Capture, EDC)，如ResMan即为一种基于互联网的EDC：	EDC
Data collection and Management (A standard data collection and management system include a CRF and an electronic data capture：	EDC
数据与安全监察委员会： Data and Safety Monitoring Committee：	有/Yes
注册人： Name of Registration：	2026-05-09 11:46:51