Prospective registration

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

KEYMAKER-U01 Substudy 01F

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

Rui Kuang 

Chongrui Xu 

A.Level 36, Tower A, THREE ITC No. 183 Hongqiao Road, Xuhui District, Shanghai 200030, China

No.106 Zhongshan Er Road, Guangzhou, China

Merck Sharp & Dohme LLC

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

Yes

Ethics Review Committee of Guangdong Provincial People's Hospital

Bai Sheng

No.106 Zhongshan Er Road, Guangzhou, China

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

No.106 Zhongshan Er Road, Guangzhou, China

Merck Sharp & Dohme LLC

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

Interventional study

1-2

Non randomized control 

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

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;

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.

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.

Open-label study

NA

EDC