Phase 3 Randomized Study of Zimberelimab and Domvanalimab with Chemotherapy vs. Pembrolizumab with Chemotherapy in Metastatic NSCLC without EGFR/ALK Aberrations
- Trial ID
- 2023-509825-38-00
- Protocol
- GS-US-626-6216
- Sponsor
- Gilead Sciences Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the effect of **domvanalimab** (DOM) and **zimberelimab** (ZIM) in combination with chemotherapy relative to **pembrolizumab** (PEMBRO) in combination with chemotherapy on overall survival (OS) in participants with metastatic non-small cell lung cancer (NSCLC) who have positive programmed cell death ligand 1 (PD-L1) expression (≥ 1% tumor cells). This comparison is also extended to all randomized participants, regardless of PD-L1 expression. The clinical relevance of this objective lies in determining the potential superiority or equivalence of DOM and ZIM as a first-line treatment option, which could influence treatment protocols for NSCLC, a condition with significant morbidity and mortality.
Secondary objectives include:
- Comparing the effect of DOM + ZIM in combination with chemotherapy relative to PEMBRO in combination with chemotherapy in participants with positive PD-L1 expression (≥ 1% TC) as well as in all randomized participants.
- Evaluating progression-free survival (PFS) according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, as assessed by blinded independent central review (BICR).
- Assessing the overall response rate (ORR) as evaluated by BICR according to RECIST v1.1.
Participants
The clinical trial involves a total of **398 participants** diagnosed with **Metastatic Non–Small Cell Lung Cancer**. The study population includes individuals of all genders, races, and ethnic groups, aged 18 years and older. Participants are required to have a life expectancy of at least three months and an **ECOG performance status** score of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population was selected based on specific inclusion criteria, including the provision of adequate tumor tissue for PD-L1 expression evaluation and the absence of prior systemic treatment for metastatic NSCLC. Participants must not have actionable genomic alterations with approved frontline therapies. Lifestyle considerations such as diet and physical activity are not specified, but participants must agree to use protocol-specified contraception methods if applicable. The trial includes a vulnerable population, ensuring comprehensive representation across different demographic groups.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, Phase 3 study to evaluate the efficacy of **zimberelimab** and **domvanalimab** in combination with chemotherapy compared to **pembrolizumab** with chemotherapy for the first-line treatment of patients with **metastatic non-small cell lung cancer** (NSCLC) without epidermal growth factor receptor or anaplastic lymphoma kinase genomic tumor aberrations. The trial aims to assess overall survival (OS) as the primary endpoint, with secondary endpoints including progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), and the incidence of treatment-emergent adverse events (TEAEs). The study is expected to run from December 2022 to September 2027, with participants involved for a maximum treatment period of 84 weeks.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as measurable disease per RECIST v1.1 criteria, ECOG performance status score of 0 or 1, and life expectancy of at least 3 months. Adequate tumor tissue must be provided for central evaluation of PD-L1 expression. Follow-up visits will be conducted to monitor treatment response and safety, with assessments including imaging studies and laboratory tests. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
Participants may be withdrawn from the study early due to reasons such as disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision. The trial will ensure that all participants receive treatment via **intravenous use**, with the investigational products being administered as solutions or dispersions for infusion. The study will adhere to rigorous scientific and ethical standards, ensuring the collection of high-quality data to evaluate the therapeutic potential of the investigational treatments in the specified patient population.
Treatment
The clinical trial involves the administration of several experimental and non-experimental treatments for the first-line treatment of patients with metastatic **non-small cell lung cancer**. The experimental medication **Zimberelimab** is a concentrate for solution for infusion, administered intravenously. It is a biological product of biotechnological origin, specifically a human IgG4 lambda monoclonal antibody against programmed death cell 1. The dosing schedule and frequency are determined by the study protocol, with a maximum treatment period of 1 unit of time as defined in the trial.
**Domvanalimab** is another experimental treatment used in the trial. It is also a concentrate for solution for infusion, administered intravenously. Domvanalimab is a humanized IgG1 monoclonal antibody targeting TIGIT, and like Zimberelimab, it is of biological origin. The dosing schedule is consistent with the study protocol, with a maximum treatment period of 1 unit of time.
**Pembrolizumab**, marketed as Keytruda, is used as a comparator treatment in the study. It is a 25 mg/mL concentrate for solution for infusion, administered intravenously. Pembrolizumab is a protein-based biological product, and its administration follows the dosing schedule outlined in the study protocol, with a maximum treatment period of 1 unit of time.
**Pemetrexed**, marketed as Alimta, is a non-experimental treatment used in combination with other therapies. It is a 500 mg powder for concentrate for solution for infusion, administered intravenously. Pemetrexed is a chemical substance, and its dosing is based on body surface area (mg/m²), with a maximum treatment period of 1 unit of time.
**Paclitaxel** is another non-experimental treatment, administered as a solution for infusion intravenously. It is a chemical substance, and the dosing is based on body surface area (mg/m²), with a maximum treatment period of 1 unit of time.
**Carboplatin** is used as a non-experimental treatment, administered intravenously. It is a chemical substance, and the dosing is based on body surface area (mg/m²), with a maximum treatment period of 84 units of time.
**Paclitaxel albumin-bound**, marketed as Abraxane, is a non-experimental treatment used in the study. It is a 5 mg/mL powder for dispersion for infusion, administered intravenously. This formulation is a specified substance group 1, and the dosing is based on body surface area (mg/m²), with a maximum treatment period of 1 unit of time.
**Cisplatin** is another non-experimental treatment, administered intravenously. It is a chemical substance, and the dosing is based on body surface area (mg/m²), with a maximum treatment period of 84 units of time.
All treatments are administered intravenously, and participant compliance is monitored according to the study protocol. The trial aims to evaluate the efficacy of Zimberelimab and Domvanalimab in combination with chemotherapy compared to Pembrolizumab with chemotherapy, focusing on overall survival in patients with positive programmed cell death ligand 1 expression.
Efficacy
The efficacy of the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is **Overall Survival (OS)**, defined as the time from the date of randomization to the date of death from any cause. This will be evaluated in participants with positive programmed cell death ligand 1 (PD-L1) expression (≥ 1% tumor cells) and in all randomized participants. Secondary endpoints include **Progression-Free Survival (PFS)**, which is the time from randomization until progressive disease or death from any cause, as assessed by Blinded Independent Central Review (BICR) according to RECIST v1.1. **Objective Response Rate (ORR)** is defined as the proportion of participants achieving a complete or partial response confirmed at least 4 weeks later, also assessed by BICR. **Duration of Response (DOR)** is the time from the first response to the first documented progression or death. Additional secondary endpoints include the incidence, severity, seriousness, and relatedness of treatment-emergent adverse events (TEAEs), as well as the incidence and severity of clinical laboratory abnormalities. Patient-reported outcomes will be measured by the time to first symptom deterioration in the NSCLC Symptom Assessment Questionnaire (SAQ) shortness of breath domain and the time to first deterioration in the NSCLC-SAQ total score.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Members of all genders, races, and ethnic groups are eligible for this study. Participants must meet all the following inclusion criteria to be eligible for participation in this study (no waivers for participant eligibility will be permitted).
- Measurable disease per RECIST v1.1 criteria by investigator assessment (Appendix 7). Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
- ECOG performance status score of 0 or 1.
- see protocol for organ function requirement.
- 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 from screening visit until 6 months after the last dose of chemotherapy and 120 days after the last dose of DOM, ZIM, or PEMBRO (or longer according to local regulatory requirements), as described in of the study protocol.
- 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.
- Life expectancy ≥ 3 months
- Pathologically documented NSCLC that meets both 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 actionable EGFR and ALK mutations and ALK gene rearrangements. Note: tumor testing for actionable EGFR or ALK mutations or ALK gene rearrangements is not required for participants with nonsquamoussquamous NSCLC tumor histology if status is unknown (Section 6.3.9).
- Have no actionable genomic alterations such as ROS proto-oncogene 1, neurotrophic tyrosine receptor kinase, proto-oncogene B-raf, RET mutations, or other driver oncogenes with approved frontline therapies. Testing of actionable genomic alterations required by local regulations will be performed locally. Note: see Appendix Table 1 for requirements in Germany and Appendix Table 5 for requirements in Argentina (Appendix 14).
- Provide adequate tumor tissue from locations not radiated prior to biopsy to allow central evaluation of PD-L1 expression using the investigational VENTANA PD-L1 (SP263) assay prior to randomization. Bone biopsies, cytology, and fine needle aspirates are not suitable tissues. If no tissue is available, a new biopsy will need to be obtained prior to enrollment in the study (Section 6.3.9).
- Have not received prior systemic treatment for metastatic NSCLC. Participants who received chemotherapy for nonmetastatic disease are eligible if the treatment was completed at least 12 months prior to the start of study treatment.
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): Have mixed SCLC and NSCLC histology.
- 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
- Received prior treatment with any anti-programmed cell death protein 1 (anti-PD-1), anti-PD-L1, or any other antibody targeting an immune checkpoint. Participants who received programmed cell death protein 1/programmed cell death ligand PD-1/PD-L1 inhibitors as a part of treatment for early stage or locally advanced stage NSCLC are not eligible.
- Known hypersensitivity to the study drug, its metabolites, or formulation excipient.
- Requirement for ongoing therapy with or prior use of any prohibited medications listed in Section 5.6.3 of the protocol
- 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.
- 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.
- Are receiving chronic systemic steroids (> 10 mg/day prednisone equivalent). Use of topical, inhalational, intranasal, and intraocular steroids will be permitted.
- Have significant third-space fluid retention (eg, ascites or pleural effusion) and is not amenable for required repeated drainage.
- Have untreated central nervous system (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.
- 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). c) New York Heart Association Class III or greater congestive heart failure or known left ventricular ejection fraction less than 40%.
- Active chronic inflammatory bowel disease (ulcerative colitis, Crohn’s disease) or gastrointestinal perforation within 6 months of enrollment.
- Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
- 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.
- Has had an allogenic tissue/solid organ transplant.
- 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.
- Have active infection requiring treatment (eg, antibiotics).
- 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.
- 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 hepatitis B virus or hepatitis C virus, participants with detectable viral loads will be excluded. No hepatitis testing is required unless mandated by local health authority.
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 01 Dec 2022 | 14 |
 Belgium | Not Recruiting | 01 Dec 2022 | 13 |
 France | Not Recruiting | 01 Dec 2022 | 24 |
 Germany | Not Recruiting | 01 Dec 2022 | 40 |
 Italy | Not Recruiting | 01 Dec 2022 | 18 |
 The Netherlands | Not Recruiting | 01 Dec 2022 | — |
 Portugal | Not Recruiting | 01 Dec 2022 | 18 |
 Spain | Not Recruiting | 01 Dec 2022 | 188 |
| Netherlands | — | — | 7 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Abraxane 5 mg/ml powder for dispersion for infusion. | Other | POWDER FOR DISPERSION FOR INFUSION | INTRAVENOUS USE | 00 | 1 | PRD9254301 |
PACLITAXEL | Other | PHF00230MIG | INTRAVENOUS USE | 00 | 1 | SCP129816 |
CARBOPLATIN | Other | PHF00230MIG | INTRAVENOUS USE | 00 | 84 | SCP10337134 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 00 | 1 | PRD4323105 |
DOMVANALIMAB | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 00 | 1 | PRD9450051 |
ALIMTA 500 mg powder for concentrate for solution for infusion | Other | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 00 | 1 | PRD2433080 |
CISPLATIN | Other | PHF00015MIG | INTRAVENOUS USE | 00 | 84 | SCP134220 |
Zimberelimab | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 00 | 1 | PRD9450049 |