Zimberelimab and Domvanalimab in Combination With Chemotherapy Versus Pembrolizumab With Chemotherapy in Patients With Untreated Metastatic Non–Small Cell Lung Cancer.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Gilead Sciences Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

1 Dec 2022 → ongoing

Decision date (initial)

2024-07-23

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Gilead Sciences Inc

External identifiers

EU CT number

2023-509825-38-00

EudraCT number

2022-000578-25

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Others, Efficacy, Safety, Therapy

To compare the effect of domvanalimab (DOM) + zimberelimab (ZIM) in combination with chemotherapy relative to pembrolizumab (PEMBRO) in combination with chemotherapy (Group A vs Group B) on overall survival (OS) in participants with positive programmed cell death ligand 1 (PD-L1) expression (≥ 1% tumor cells [SP263 scoring method] [TC])
To compare the effect of DOM+ZIM in combination with chemotherapy relative to PEMBRO in combination with chemotherapy (Group A vs Group B) on OS in all randomized participants

Secondary objectives 3

1. To compare the effect of DOM + ZIM in combination with chemotherapy relative to PEMBRO in combination with chemotherapy (Group A versus‌vs Group B) in participants with positive PD-L1 expression (≥ 1% TC) as well as in all randomized participants on:
2. Progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by blinded independent central review (BICR)
3. Overall ‌response rate (ORR) as assessed by BICR according to RECIST v1.1

Conditions and MedDRA coding

Metastatic Non–Small Cell Lung Cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 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).
2. ‌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.‌
3. ‌ECOG performance status score of 0 or 1.
4. see protocol for organ function requirement.
5. 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.
6. 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.
7. Life expectancy ≥ 3 months
8. 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).
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).‌
10. 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).
11. ‌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 20

1. 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.
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-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.
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 of the protocol
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 (> 10 mg/day prednisone equivalent). Use of topical, inhalational, intranasal, and intraocular 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 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.
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). c) New York Heart Association 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.
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 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.
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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. OS is defined as the time from the date of randomization to the date of death from any cause (both in participants with positive PD-L1 expression [≥ 1% TC] and in all randomized participants as dual primary endpoints)

Secondary endpoints 6

1. PFS is defined as the time from the date of randomization until progressive disease (PD) as assessed by BICR according to RECIST v1.1 or death from any cause, whichever comes first. ‌
2. ‌ORR is defined as the proportion of participants who have achieved a complete response (CR) or partial response (PR) that is confirmed at least 4 weeks later as assessed by BICR according to RECIST v1.1
3. DOR is defined as the time from the first response (CR or PR), to the first documented PD, as assessed by BICR according to RECIST v1.1, or death from any cause, whichever comes first.‌
4. Incidence, severity, seriousness, and relatedness of treatment-emergent adverse events (TEAEs) and incidence and severity of clinical laboratory abnormalities
5. Time to first symptom deterioration in NSCLC SAQ shortness of breath domain
6. Time to first deterioration in NSCLC-SAQ total score

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 1

Auxiliary 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Gilead Sciences Inc.

Sponsor organisation

Gilead Sciences Inc.

Address

333 Lakeside Drive

City

Foster City

Postcode

94404-1147

Country

United States

Scientific contact point

Organisation

Gilead Sciences Inc.

Contact name

EU CT Support

Public contact point

Organisation

Gilead Sciences Inc.

Contact name

EU CT Support

Third parties 6

Locations

8 EU/EEA countries · 70 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 93 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

14 submissions — initial application plus substantial / non-substantial modifications