Immunotherapy + Chemotherapy for Non-Small Cell Lung Cancer

(STAR-121 Trial)

Recruiting at 240 trial locations

Overseen By Gilead Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Gilead Sciences

Must not be taking: Chronic steroids, Immunosuppressants

Disqualifiers: Active malignancy, Autoimmune disease, CNS metastases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: Up to 68 months

1069 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how two new drugs, zimberelimab (ZIM) and domvanalimab (DOM), combined with chemotherapy, affect survival in people with advanced non-small cell lung cancer that hasn't been treated and lacks specific genetic changes. It compares this combination to the existing treatment of pembrolizumab (PEMBRO), an immunotherapy drug, with chemotherapy. The goal is to determine which treatment helps patients live longer. Suitable participants have advanced lung cancer that hasn't been treated and lacks certain genetic features. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on chronic systemic steroids or have an active autoimmune disease requiring treatment, you may not be eligible to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that using zimberelimab and domvanalimab together is generally safe, with side effects that are usually mild and manageable. Studies have found no new safety issues when domvanalimab is added to zimberelimab, indicating no unexpected problems arise from their combination.

For zimberelimab alone, past research suggests it is well tolerated, with no new safety concerns when combined with other cancer treatments.

Pembrolizumab, another treatment in the study, is already approved for lung cancer, so its side effects are well understood by doctors.

Overall, these treatments are in a late-stage study, which typically means good safety information is already available. Always consult a doctor to understand what this might mean personally. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they introduce novel immunotherapy combinations for non-small cell lung cancer. Zimberelimab and Domvanalimab are promising because they work by enhancing the body's immune response against cancer cells, which is different from standard chemotherapy that directly kills cancer cells. Additionally, Zimberelimab, used with or without Domvanalimab, offers a new way to potentially boost the effectiveness of traditional chemotherapy drugs. These combinations aim to improve outcomes by harnessing the immune system alongside established chemotherapy regimens, making them a compelling advancement over existing treatments like pembrolizumab, which is also part of the trial as a comparator.

What evidence suggests that this trial's treatments could be effective for non-small cell lung cancer?

Research shows that combining zimberelimab with domvanalimab, which participants in this trial may receive, holds promise for treating non-small cell lung cancer. Studies have found that this combination improved overall survival, reducing the risk of death by 36% compared to zimberelimab alone. This suggests that adding domvanalimab could enhance zimberelimab's effectiveness.

Zimberelimab alone, another treatment option in this trial, appears effective because it helps the immune system attack cancer cells. As an anti-PD-1 agent, it aids the body's defenses in targeting cancer. Another treatment option, pembrolizumab, is well-known and has proven effective with chemotherapy, improving survival rates in lung cancer patients. Both zimberelimab and pembrolizumab help the immune system identify and destroy cancer cells. ^{1 4 5 6 7}

Who Is on the Research Team?

Gilead Study Director

Principal Investigator

Gilead Sciences

Are You a Good Fit for This Trial?

This trial is for adults with untreated metastatic non-small cell lung cancer without certain genetic mutations. Participants should have a good performance status, no prior treatments targeting immune checkpoints, and no history of severe lung conditions or active autoimmune diseases. Pregnant or breastfeeding individuals are excluded.

Inclusion Criteria

You are expected to live for at least 3 more months.

My lung cancer is at stage IV.

My organs are working well.

Exclusion Criteria

Known hypersensitivity to the study drug, its metabolites, or formulation excipient

I have not received a live-virus vaccine in the last 30 days.

I have or had lung inflammation that needed steroids.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Zimberelimab and Domvanalimab in combination with chemotherapy or Pembrolizumab with chemotherapy every 3 weeks for up to 35 doses

Up to 68 months

Every 3 weeks

Follow-up

Participants are monitored for overall survival and progression-free survival

Up to 68 months

What Are the Treatments Tested in This Trial?

Interventions

• Carboplatin
• Cisplatin
• Domvanalimab
• Nab-paclitaxel
• Paclitaxel
• Pembrolizumab
• Pemetrexed
• Zimberelimab

Trial Overview The study compares the effectiveness of two immunotherapy drugs (Zimberelimab and Domvanalimab) combined with chemotherapy against Pembrolizumab with chemotherapy in extending life and delaying cancer progression in patients.

How Is the Trial Designed?

Group I: Zimberelimab (ZIM) +Domvanalimab (DOM) + Chemotherapy Experimental Treatment 7 Interventions

Participants will receive ZIM 360 mg + DOM 1200 mg (up to 35 doses) with chemotherapy every 3 weeks (Q3W) on Day 1 of each 21-day cycle. Choice of chemotherapy is dependent on histology. * Participants with nonsquamous histology will receive cisplatin 75 mg/m\^2 or carboplatin area under the concentration versus time curve (AUC)5 + pemetrexed 500 mg/m\^2 Q3W for first 4 cycles. After the completion of the first 4 cycles, participants with nonsquamous histology may continue with maintenance pemetrexed 500 mg/m\^2 Q3W until disease progression or intolerable toxicities. * Participants with squamous histology will receive carboplatin AUC 6 Q3W with paclitaxel 200 mg/m\^2 Q3W or nab-paclitaxel 100 mg/m\^2 weekly (QW) for first 4 cycles.

Group II: Zimberelimab (ZIM) + Chemotherapy Experimental Treatment 6 Interventions

Participants will receive ZIM 360 mg (up to 35 doses) with chemotherapy Q3W on Day 1 of each 21-day cycle. Choice of chemotherapy is dependent on histology. * Participants with nonsquamous histology will receive cisplatin 75 mg/m\^2 or carboplatin AUC 5 + pemetrexed 500 mg/m\^2 Q3W for first 4 cycles After the completion of the first 4 cycles, participants with nonsquamous histology may continue with maintenance pemetrexed 500 mg/m\^2 Q3W until disease progression or intolerable toxicities. * Participants with squamous histology will receive carboplatin AUC 6 Q3W with paclitaxel 200 mg/m\^2 Q3W or nab-paclitaxel 100 mg/m\^2 weekly (QW) for first 4 cycles.

Group III: Pembrolizumab (PEMBRO) + Chemotherapy Active Control 6 Interventions

Participants will receive PEMBRO 200 mg (up to 35 doses) with chemotherapy Q3W on Day 1 of each 21-day cycle. Choice of chemotherapy is dependent on histology. * Participants with nonsquamous histology will receive cisplatin 75 mg/m\^2 or carboplatin AUC 5 + pemetrexed 500 mg/m\^2 Q3W for first 4 cycles. After the completion of the first 4 cycles, participants with nonsquamous histology may continue with maintenance pemetrexed 500 mg/m\^2 Q3W until disease progression or intolerable toxicities. * Participants with squamous histology will receive carboplatin AUC 6 Q3W with paclitaxel 200 mg/m\^2 Q3W or nab-paclitaxel 100 mg/m\^2 weekly (QW) for first 4 cycles.

Carboplatin is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

Gilead Sciences

Lead Sponsor

Trials

1,150

Recruited

878,000+

Daniel O'Day

Gilead Sciences

Chief Executive Officer since 2019

MBA from Columbia University

Dietmar Berger

Gilead Sciences

Chief Medical Officer

MD and PhD from Albert-Ludwigs University School of Medicine

Arcus Biosciences, Inc.

Industry Sponsor

Trials

44

Recruited

7,500+

Published Research Related to This Trial

In a trial involving 84 patients with advanced non-small-cell lung cancer, the efficacy of weekly nab-paclitaxel plus cisplatin was found to be similar to that of gemcitabine plus cisplatin, with median progression-free survival of 4.8 months for nab-TP and 5.2 months for GP.

Nab-paclitaxel showed improved overall survival in patients with EGFR mutations (26.7 months) and those with a performance status of 0 (23.5 months) compared to gemcitabine, indicating potential benefits in specific patient subgroups while maintaining comparable safety profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Weekly albumin-bound paclitaxel/cisplatin versus gemcitabine/cisplatin as first-line therapy for patients with advanced non-small-cell lung cancer: A phase II open-label clinical study. Qin, S., Yu, H., Wu, X., et al.[2022]

A phase I/II trial involving 46 patients with untreated advanced non-small cell lung cancer (NSCLC) demonstrated that the combination of carboplatin, nab-paclitaxel, and pembrolizumab is a safe and effective treatment, achieving a median overall survival of 15.4 months.

The study found a 35% overall response rate and a median progression-free survival of 5.6 months, indicating that this regimen can provide a durable benefit for patients, regardless of their PD-L1 status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II Trial of Carboplatin, Nab-paclitaxel, and Pembrolizumab for Advanced Non-Small Cell Lung Cancer: Hoosier Cancer Research Network LUN13-175. Gentzler, RD., Mohindra, NA., Jalal, SI., et al.[2023]

This study is the first to evaluate the combination of necitumumab with pembrolizumab and platinum-based chemotherapy in patients with untreated squamous cell lung cancer (SqCLC), aiming to enhance tumor immunity and therapeutic effects.

The trial will assess safety and efficacy, with 42 patients enrolled in phase II to determine the overall response rate and other important outcomes like progression-free survival and overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I/II Study of Necitumumab Plus Pembrolizumab, Nab-Paclitaxel, and Carboplatin for Previously Untreated Advanced Squamous Non-Small Cell Lung Cancer Study: (NEJ048A/NEXUS). Miyanaga, A., Asahina, H., Watanabe, S., et al.[2023]

In a study of 124 patients with treatment-naïve, metastatic nonsquamous PD-L1-positive non-small cell lung cancer, the combination of atezolizumab with carboplatin and nab-paclitaxel showed significantly improved overall survival (19.9 months) and progression-free survival (8.5 months) compared to carboplatin and nab-paclitaxel alone (14.8 months and 5.1 months, respectively).

While the combination therapy had a higher incidence of manageable adverse events like neutropenia and anemia, it still demonstrated a tolerable safety profile, suggesting it could be an effective first-line treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin and nab-paclitaxel chemotherapy with or without atezolizumab as front-line management for treatment-naïve metastatic nonsquamous non-small cell lung cancer with PD-L1 staining: a retrospective study. Xu, B., Cheng, H., Li, K., et al.[2023]

In a study involving 812 patients with malignant pleural mesothelioma (MPM), single-agent pemetrexed showed promising efficacy, with a median time to progressive disease of 6.0 months for chemonaïve patients and an overall response rate of 10.5%.

The treatment was well-tolerated, exhibiting mild hematologic toxicity, primarily neutropenia, in less than 18% of patients, indicating a favorable safety profile for pemetrexed in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-agent pemetrexed for chemonaïve and pretreated patients with malignant pleural mesothelioma: results of an International Expanded Access Program. Taylor, P., Castagneto, B., Dark, G., et al.[2015]

The combination of paclitaxel and carboplatin has shown promising results in treating advanced non-small-cell lung cancer (NSCLC), with reported 1-year survival rates as high as 54%, making it a widely used regimen in clinical practice.

This combination therapy has been effective without additional toxicity, allowing for full doses of both drugs to be administered, and is currently being evaluated in ongoing studies for earlier stages of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel/carboplatin in the treatment of non-small-cell lung cancer. Belani, CP.[2015]

In a real-life study of 121 patients with advanced non-squamous non-small cell lung cancer, the combination of pembrolizumab and chemotherapy resulted in a median progression-free survival of 9 months and overall survival of 20.6 months, demonstrating its efficacy as a first-line treatment.

The treatment was generally well-tolerated, with manageable side effects; however, 17.5% of patients experienced grade 3-4 adverse events, and there were two treatment-related deaths, indicating the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus pemetrexed-carboplatin combination in first-line treatment of advanced non-squamous non-small cell lung cancer: a multicenter real-life study (CAP29). Renaud, E., Ricordel, C., Corre, R., et al.[2023]

In a study involving 74 patients with advanced non-small-cell lung cancer, the combination of pembrolizumab with platinum-based chemotherapy showed promising antitumor activity, with objective response rates of 48% to 75% across different treatment cohorts.

The treatment was generally well-tolerated, with no dose-limiting toxicities reported, although 40% to 46% of patients experienced grade 3/4 adverse events, which aligns with the known side effects of platinum-based chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab and platinum-based chemotherapy as first-line therapy for advanced non-small-cell lung cancer: Phase 1 cohorts from the KEYNOTE-021 study. Gadgeel, SM., Stevenson, JP., Langer, CJ., et al.[2019]

In a study involving 180 patients with advanced non-small cell lung cancer (NSCLC), pemetrexed-carboplatin did not show superior efficacy compared to paclitaxel-carboplatin, with similar progression-free survival (PFS) rates and overall survival after a median follow-up of 17 months.

While both treatment regimens had comparable overall toxicities, the paclitaxel-carboplatin group experienced higher rates of alopecia and peripheral neuropathy, indicating a difference in side effects between the two treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Open-Label Randomized Controlled Trial Comparing the Efficacy and Safety of Pemetrexed-Carboplatin versus (Weekly) Paclitaxel-Carboplatin as First-Line Chemotherapy in Advanced Non-Squamous Non-Small Cell Lung Cancer. Yadav, A., Malik, PS., Khurana, S., et al.[2021]

In a phase II trial involving 32 elderly patients with untreated advanced non-small cell lung cancer, the combination of weekly nanoparticle albumin-bound-paclitaxel and carboplatin showed a 50% overall response rate and a median overall survival of 17.5 months, indicating significant efficacy.

The treatment was well tolerated, with no treatment-related deaths or febrile neutropenia reported, and it resulted in less neuropathic toxicity compared to traditional regimens, making it a promising option for elderly patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Modified Carboplatin Plus Weekly Nab-Paclitaxel in Elderly Patients with Non-Small Cell Lung Cancer: North Japan Lung Cancer Study Group Trial 1301. Miyauchi, E., Inoue, A., Usui, K., et al.[2018]

In a phase III trial involving 1,052 patients with advanced non-small-cell lung cancer, nab-paclitaxel plus carboplatin showed a significantly higher overall response rate (33%) compared to solvent-based paclitaxel plus carboplatin (25%), indicating greater efficacy in treatment.

Nab-paclitaxel was associated with fewer severe side effects, such as neuropathy and neutropenia, compared to solvent-based paclitaxel, suggesting it may be a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. Socinski, MA., Bondarenko, I., Karaseva, NA., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04736173

NCT04736173 | Study Evaluating Effectiveness and Safety ... Study Evaluating Effectiveness and Safety of Zimberelimab and Domvanalimab in Lung Cancer (ARC-10). ClinicalTrials.gov ID NCT04736173. Sponsor Arcus ...

2. investors.arcusbio.com investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2024/Arcus-Biosciences-Announces-that-Domvanalimab-Plus-Zimberelimab-Improved-Overall-Survival-in-ARC-10-a-Randomized-Study-in-Patients-with-PD-L1-High-Non-Small-Cell-Lung-Cancer/default.aspx

Press Release Details Domvanalimab plus zimberelimab demonstrated a meaningful improvement in overall survival compared to zimberelimab alone, with a 36% reduction in risk of death.

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38310035/

STAR-121: A Phase III Randomized Study of ... The STAR-121 (NCT05502237) phase III, global, randomized, open-label study will investigate first-line domvanalimab (anti-TIGIT) and zimberelimab (anti-PD-1) ...

4. jitc.bmj.com jitc.bmj.com/content/12/Suppl_3/A1690

1461 Phase 2 randomized study of domvanalimab ... Background Although PD-(L)1 inhibitors demonstrated survival benefits vs chemotherapy in PD–(L)1–high NSCLC, <50% of patients will respond ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.36_suppl.397600

ARC-7: Randomized phase 2 study of domvanalimab + ... ARC-7 evaluates whether inhibition of TIGIT and adenosine pathways augments activity of zimberelimab (Z) (anti-PD-1 mAb) in pts with PD-L1-high NSCLC.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04791839

Study Details | NCT04791839 | Safety and Efficacy of ... Histologically confirmed metastatic squamous or non-squamous non-small cell lung cancer. Previously treated with at least one line of therapy including an ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.4_suppl.409

Zimberelimab platform study: Safety and efficacy of ... The combination of Zim, Futi, and chemotherapy has a manageable safety profile without new safety signals and shows promising antitumor activity in pts with ...