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
Conditions
Interventions
Group 2:MK-1084+sac-TMT
Group 3:MK-1084+ cetuximab
Group 1:MK-1084+HER3-DXd
Sponsors
Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Inclusion criteria
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
Exclusion criteria
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 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Objective response rate, ORR; | — |
Secondary
| Measure | Time frame |
|---|---|
| Progression free survival;Duration of relief;PK parameters, including AUC, Cmax, and Ctrough; | — |
Countries
China
Contacts
Public ContactChongrui Xu
Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)
Outcome results
None listed