| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Non–Small Cell Lung Cancer With No Epidermal Growth Factor Receptor or Anaplastic Lymphoma Kinase Genomic Tumor Aberrations |
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| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Non–Small Cell Lung Cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To compare the effect of ZIM and DOM in combination with chemotherapy relative to PEMBRO in combination with chemotherapy (Group A versus Group B) on:
•Progression-free survival (PFS) according to RECIST v1.1 as assessed by blinded independent central review (BICR)
•Overall survival (OS)
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| E.2.2 | Secondary objectives of the trial |
•To compare the effect of ZIM and DOM in combination with chemotherapy relative to PEMBRO in combination with chemotherapy (Group A vs Group B) on objective response rate (ORR) as assessed by BICR according to RECIST v1.1
•To evaluate duration of response (DOR) as assessed by BICR according to the RECIST v1.1
•To evaluate the safety and tolerability of ZIM and DOM in combination with chemotherapy versus PEMBRO in combination with chemotherapy (Group A vs Group B)
•To compare the effect of ZIM and DOM in combination with chemotherapy relative to PEMBRO in combination with chemotherapy (Group A vs Group B) on health-related quality of life (QOL) using non–small cell lung cancer Symptom Assessment Questionnaire (NSCLC-SAQ).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Members of all genders, races, and ethnic groups are eligible for this study.
Participants must meet all of the following inclusion criteria to be eligible for participation in this study (no waivers for participant eligibility will be permitted).
1)Participants assigned male at birth and participants assigned female at birth, 18 years of age or older, able to understand and give written informed consent.
2)Life expectancy ≥ 3 months.
3)Pathologically documented NSCLC that meets both of the criteria below:
a)Have documented evidence of Stage IV NSCLC disease at the time of enrollment (based on AJCC, Eighth Edition).
b)Have documented negative test results for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations.
Note:Tumor testing for EGFR or ALK mutations is required if status is unknown
4)Have no known genomic alterations in ROS proto-oncogene 1 (ROS1), neurotrophic tyrosine receptor kinase (NTRK), proto-oncogene B-raf (BRAF), RET mutations, or other actionable driver oncogenes with approved therapies (actionable genomic alteration). Testing is not required if status is unknown.
5)Provide adequate tumor tissue from locations not radiated prior to biopsy to evaluate PD-L1 status prior to randomization.
6)Have not received prior systemic treatment for metastatic NSCLC. Participants who received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 12 months prior to the start of study treatment.
7)Measurable disease by CT or MRI as per RECIST v1.1 criteria by investigator assessment.
8)ECOG PS score of 0 or 1.
9)Organ function requirement.
10)Participants assigned male at birth and participants assigned female at birth of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception.
11)Willing and able to comply with the requirements and restrictions in this protocol.
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| E.4 | Principal exclusion criteria |
Participants who meet any of the following exclusion criteria at screening/Day -1 are not eligible to be enrolled in this study (no waivers for participant eligibility will be offered or permitted):
1)Have mixed small-cell lung cancer (SCLC) and NSCLC histology.
2)Positive serum pregnancy test or participants who are breastfeeding or have plans to breastfeed during the study period and for the required duration of contraception use after the last dose of study drug.
3)Received prior treatment with any anti-PD-1, anti-PD-L1, or any other antibody targeting an immune checkpoint. Participants who received PD-(L)1 inhibitors as a part of treatment for early stage NSCLC including in neoadjuvant/adjuvant setting are not eligible.
4)Known hypersensitivity to the study drug, its metabolites, or formulation excipient.
5)Requirement for ongoing therapy with or prior use of any prohibited medications listed in Section 5.6.3.
6)Have an active second malignancy or have had an active second malignancy within 3 years prior to enrollment. Participants with a history of malignancy that has been completely treated, with no evidence of active cancer for at least 3 years prior to enrollment, or with surgically cured tumors with low risk of recurrence (eg, nonmelanoma skin cancer, histologically confirmed complete excision of carcinoma in situ, or similar) are allowed to enroll.
7)Have an active autoimmune disease that required systemic treatment in past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
8)Are receiving chronic systemic steroids. Use of topical, inhalational, intra-nasal, and intra-ocular steroids will be permitted.
9)Have significant third-space fluid retention (eg, ascites or pleural effusion) and is not amenable for required repeated drainage
10)Have known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they have stable CNS disease for at least 4 weeks prior to enrollment and all neurologic symptoms have returned to baseline, have no evidence of new or enlarging brain metastases and are not requiring use of steroids for at least 14 days prior to the start of study treatment. All participants with carcinomatous meningitis are excluded regardless of clinical stability.
11)Meet any of the following criteria for cardiac disease:
a)Myocardial infarction or unstable angina pectoris within 6 months of enrollment.
b)History of serious ventricular arrhythmia (ie, ventricular tachycardia or ventricular fibrillation), high-grade atrioventricular block, or other cardiac arrhythmias requiring antiarrhythmic medications (except for atrial fibrillation that is well controlled with antiarrhythmic medication); history of QT interval prolongation.
c)NYHA Class III or greater congestive heart failure or known left ventricular ejection fraction less than 40%.
12)Active chronic inflammatory bowel disease (ulcerative colitis, Crohn’s disease) or gastrointestinal perforation within 6 months of enrollment.
13)Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
14)Has received radiotherapy within 2 weeks prior to first dose of study intervention or radiotherapy to the lung that is > 30 Gy within 6 months of the first study treatment. Participants must have recovered to ≤ Grade 1 from all radiation-related toxicities, not requiring corticosteroids, and have not had radiation pneumonitis.
15)Has had an allogenic tissue/solid organ transplant.
16)Have received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu and COVID-19 vaccines that do not contain live virus are permitted.
17)Have active infection requiring treatment (eg, antibiotics).
18)Have known history of HIV-1 or 2 with uncontrolled viral load (ie, ≥ 200 copies/mL or CD4+ T cell count < 350 cells/µL), or taking medications that may interfere with metabolism of study drugs. No HIV testing is required unless mandated by local health authority.
19)Have known acute hepatitis B, known chronic hepatitis B infection with active untreated disease, or known active hepatitis C infection. In participants with a history of HBV or HCV, participants with detectable viral loads will be excluded. No hepatitis testing is required unless mandated by local health authority.
20)Have other concurrent medical or psychiatric conditions that, in the investigator’s opinion, may be likely to confound study interpretation or prevent completion of study procedures and follow-up examinations.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
•Primary endpoints of the study are PFS as assessed by BICR and OS
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The first interim analysis of OS will be conducted at the same time as the primary analysis of PFS when approximately 384 disease progression events as assessed by BICR or deaths have occurred among Groups A and B. The second interim analysis of OS will be conducted when approximately 357 deaths (80% of IF) have occurred in the Groups A and B. The final analysis of OS is projected to be conducted around 58 months after the first participant is randomized when approximately 446 deaths have occurred in Groups A and B.
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| E.5.2 | Secondary end point(s) |
| Key secondary endpoints are ORR as assessed by BICR and time to first symptom deterioration in NSCLC SAQ total score. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| •Time to first symptom deterioration in NSCLC-SAQ total score. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunogenicity Analysis and Biomarker Analysis |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 88 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Brazil |
| Canada |
| Chile |
| Israel |
| Korea, Democratic People's Republic of |
| Mexico |
| Singapore |
| Taiwan |
| United States |
| Austria |
| France |
| Netherlands |
| Spain |
| Germany |
| Italy |
| Belgium |
| Portugal |
| Turkey |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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