Triple Combination Immunotherapy for Lung Cancer

Overseen By Daniel Morgensztern

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Washington University School of Medicine

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: EGFR mutation, ALK rearrangement, others

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

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

Compensation: Varies

Number of Visits: 21

Duration: 9 months

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a combination of three drugs to help the immune system fight lung cancer. The drugs are zimberelimab, domvanalimab, and etrumadenant. They are being tested on patients who have already tried other immune-based treatments. The goal is to see if this new combination can work better.

Do I need to stop my current medications to join the trial?

The trial requires that you stop taking certain medications that interact with the study drugs, such as strong inhibitors or inducers of specific enzymes and transporters, at least 4 weeks or 5 half-lives before starting the trial. If you're on any of these medications, you may need to stop them before participating.

What data supports the effectiveness of the drug combination Domvanalimab, AB 154, GS-0154, Domvanalimab, Etrumadenant, AB928, Zimberelimab, AB122 for lung cancer?

Research shows that combining different immunotherapy drugs, like PD-1/PD-L1 and CTLA-4 inhibitors, can improve survival in lung cancer patients compared to using a single drug. This suggests that using multiple drugs together might be more effective in treating lung cancer. ^{1 2 3 4 5}

What safety data exists for the triple combination immunotherapy for lung cancer?

The safety of treatments similar to the triple combination immunotherapy, which includes drugs like Domvanalimab and Zimberelimab, has been studied in lung cancer. These treatments can cause immune-related side effects, which are reactions where the immune system attacks normal parts of the body. It's important to monitor and manage these side effects during treatment. ^{2 6 7 8 9}

What makes the triple combination immunotherapy for lung cancer unique?

The triple combination immunotherapy for lung cancer is unique because it combines three different drugs that target various immune pathways to enhance the body's ability to fight cancer. This approach is different from traditional treatments like chemotherapy, as it aims to boost the immune system's response to cancer cells, potentially leading to better outcomes. ^{1 2 4 5 10}

Research Team

Daniel Morgensztern

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

This trial is for adults with non-small cell lung cancer who've had previous treatments including immune checkpoint blockers. They must have at least one measurable tumor and cannot have more than two prior therapies in the metastatic setting. Participants need normal organ function, no severe psychiatric issues or substance abuse, not be pregnant/breastfeeding, and can't have certain other cancers or active autoimmune diseases.

Inclusion Criteria

We don't know how the study drugs might affect a developing baby in the womb.

My bone marrow and organs are functioning normally.

My cancer shows PD-L1 expression of 1% or more.

Exclusion Criteria

Pregnant and/or breastfeeding

I have not received any live vaccines in the last 28 days.

You have had allergic reactions to similar drugs as zimberelimab, domvanalimab, etrumadenant, or other drugs used in the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive zimberelimab, domvanalimab, and etrumadenant in 21-day cycles

9 months

21-day cycles with visits on Day 1

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Treatment Details

Interventions

• Domvanalimab
• Etrumadenant
• Zimberelimab

Trial Overview The study tests a combination of three drugs: Zimberelimab, Domvanalimab, and Etrumadenant on patients with non-small cell lung cancer who didn't respond well to previous treatments. It explores how these drugs work together since they target different aspects of the immune system's ability to fight cancer.

Participant Groups

Group I: Cohort B: Zimberelimab + Domvanalimab + Etrumadenant Experimental Treatment 3 Interventions

* Patients will be treated on 21-day cycles with 360 mg zimberelimab intravenously on Day 1, 15 mg/kg domvanalimab intravenously on Day 1, and 150 mg etrumadenant orally daily on Days 1 to 21. * Cohort B participants are those that have PD-L1 ≥ 50%.

Group II: Cohort A: Zimberelimab + Domvanalimab + Etrumadenant Experimental Treatment 3 Interventions

* Patients will be treated on 21-day cycles with 360 mg zimberelimab intravenously on Day 1, 15 mg/kg domvanalimab intravenously on Day 1, and 150 mg etrumadenant orally daily on Days 1 to 21. * Cohort A participants are those that have PD-L1 1-49%

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Arcus Biosciences, Inc.

Industry Sponsor

Trials

44

Recruited

7,500+

Findings from Research

The combination of platinum-based chemotherapy and immunotherapy is now the standard treatment for patients with metastatic non-small-cell lung cancer, regardless of their programmed death ligand 1 tumor proportion score.

Clinical trials have shown that this combination therapy can lead to improved and long-lasting responses by enhancing the immune system's ability to attack tumors and reducing the immunosuppressive environment that hinders immune detection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combining Immunotherapy and Chemotherapy for Non-Small Cell Lung Cancer. Judd, J., Borghaei, H.[2020]

The combination of PD-1/PD-L1 and CTLA-4 inhibitors significantly improves objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) in patients with advanced lung cancer, based on a review of six studies.

While the incidence of severe adverse events (grade ≥3) was lower than in control groups, it was still notable, indicating that while the treatment is generally tolerable, monitoring for side effects remains important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of PD-1/PD-L1 plus CTLA-4 antibodies ± other therapies in lung cancer: a systematic review and meta-analysis. Shen, X., Huang, S., Xiao, H., et al.[2023]

In a study involving 51 patients with advanced non-small-cell lung cancer (NSCLC) who had previously undergone multiple treatments, the combination of pembrolizumab and ipilimumab demonstrated an objective response rate of 30%, indicating some level of antitumor activity.

While the combination therapy showed potential benefits, it also resulted in significant toxicity, with 64% of patients experiencing treatment-related adverse events, highlighting the need for careful monitoring and management of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in combination with ipilimumab as second-line or later therapy for advanced non-small-cell lung cancer: KEYNOTE-021 cohorts D and H. Gubens, MA., Sequist, LV., Stevenson, JP., et al.[2020]

The phase III POSEIDON trial demonstrated that a three-drug regimen combining the CTLA4 inhibitor tremelimumab, the PD-L1 inhibitor durvalumab, and chemotherapy significantly improves progression-free survival and overall survival in patients with metastatic non-small cell lung cancer compared to chemotherapy alone.

This study suggests that targeting multiple immune pathways with this combination therapy may enhance treatment effectiveness for lung cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Three-Drug Regimen Bests Chemo in NSCLC. [2022]

Patients with metastatic non-small-cell lung cancer who developed immune-mediated adverse events (imAEs) while treated with durvalumab showed significantly improved overall survival compared to those without imAEs, indicating a potential link between imAE development and treatment efficacy.

A predictive model was created using machine learning to identify patients at higher risk of developing imAEs, which could help tailor treatment strategies and enhance patient outcomes in immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between immune-mediated adverse events and efficacy in metastatic non-small-cell lung cancer patients treated with durvalumab and tremelimumab. Dey, A., Austin, M., Kluger, HM., et al.[2022]

In a study of 184 patients with non-small cell lung cancer treated with immune checkpoint inhibitors, 26.6% developed immune-related adverse events (IRAEs), with certain factors like statin use and previous corticosteroid therapy increasing the risk of IRAEs.

Interestingly, patients who experienced IRAEs had significantly better progression-free survival (41 weeks vs. 9 weeks) and overall survival (89 weeks vs. 28 weeks), suggesting that the occurrence of IRAEs may be linked to improved treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of immune-related adverse events and outcomes in patients with NSCLC treated with immune-checkpoint inhibitors. Serino, M., Freitas, C., Martins, M., et al.[2022]

In a meta-analysis of 16 clinical trials involving 6208 patients with non-small cell lung cancer, the overall incidence of immune-related adverse events (irAEs) was found to be 22%, with a higher rate of severe irAEs (4%) associated with PD-1 inhibitors compared to PD-L1 inhibitors.

The most common organ-specific irAEs occurred in the endocrine system, skin, pulmonary tract, and gastrointestinal tract, with pneumonitis being the leading cause of death among the 14 patients (0.34%) who died due to irAEs, highlighting the importance of monitoring and managing these side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune-related adverse events associated with programmed cell death protein-1 and programmed cell death ligand 1 inhibitors for non-small cell lung cancer: a PRISMA systematic review and meta-analysis. Sun, X., Roudi, R., Dai, T., et al.[2020]

References

1. United States pubmed.ncbi.nlm.nih.gov

Combining Immunotherapy and Chemotherapy for Non-Small Cell Lung Cancer. [2020]

2. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of PD-1/PD-L1 plus CTLA-4 antibodies ± other therapies in lung cancer: a systematic review and meta-analysis. [2023]

3. Ireland pubmed.ncbi.nlm.nih.gov

Pembrolizumab in combination with ipilimumab as second-line or later therapy for advanced non-small-cell lung cancer: KEYNOTE-021 cohorts D and H. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Three-Drug Regimen Bests Chemo in NSCLC. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC). [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Association between immune-mediated adverse events and efficacy in metastatic non-small-cell lung cancer patients treated with durvalumab and tremelimumab. [2022]

7. Spain pubmed.ncbi.nlm.nih.gov

Predictors of immune-related adverse events and outcomes in patients with NSCLC treated with immune-checkpoint inhibitors. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Different associations between organ-specific immune-related adverse event and survival in non-small cell lung cancer patients treated with programmed death-1 inhibitors-based combination therapy. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Immune-related adverse events associated with programmed cell death protein-1 and programmed cell death ligand 1 inhibitors for non-small cell lung cancer: a PRISMA systematic review and meta-analysis. [2020]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Double immune checkpoint blockade in advanced NSCLC. [2020]