Immunotherapy Combo for Lung Cancer

(PACIFIC-8 Trial)

Recruiting at 216 trial locations

Overseen By AstraZeneca Lung Cancer Study Locator Service

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Must not be taking: Immunosuppressants

Disqualifiers: Other malignancy, Pneumonitis, Autoimmune disorders, 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: Unknown

Duration: 12 months

860 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a Phase III, randomised, double-blind, placebo-controlled, multicentre, international study assessing the efficacy and safety of durvalumab (MEDI4736) and domvanalimab (AB154) compared with durvalumab plus placebo in adults with locally advanced (Stage III), unresectable NSCLC whose disease has not progressed following definitive platinum-based cCRT.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot use immunosuppressive medication within 14 days before starting the trial.

What data supports the effectiveness of the drug combination including durvalumab for lung cancer?

Durvalumab, a part of the drug combination, has shown clinical efficacy and a manageable safety profile in advanced non-small-cell lung cancer, especially in patients with high PD-L1 expression. Additionally, in the POSEIDON study, combining durvalumab with chemotherapy significantly improved survival outcomes in metastatic non-small-cell lung cancer. ^{1 2 3 4 5}

Is the immunotherapy combo for lung cancer generally safe in humans?

Durvalumab, one of the drugs in the combo, has been shown to have a manageable safety profile in treating advanced non-small-cell lung cancer, but it can cause immune-related side effects like pneumonitis, which is a serious lung condition. ^{1 2 3 6 7}

What makes the immunotherapy combo for lung cancer unique?

The combination of domvanalimab and durvalumab is unique because it targets two different immune checkpoints, potentially enhancing the immune system's ability to fight lung cancer more effectively than using either drug alone. Durvalumab blocks PD-L1, while domvanalimab targets another pathway, which may provide a more comprehensive approach to boosting the body's immune response against cancer cells. ^{3 5 8 9 10}

Research Team

Alexander Spira, MD

Principal Investigator

Virginia Cancer Specialists Research Institute

Jinming Yu, MD

Principal Investigator

Shandong Cancer Hospital and Institute

Hidehito Horinouchi, MD, PhD

Principal Investigator

National Cancer Center Hospital

Eligibility Criteria

Adults with Stage III unresectable NSCLC who haven't progressed after platinum-based chemoradiation can join. They need a PD-L1 status ≥ 1%, adequate organ function, and no history of certain cancers or autoimmune diseases. Participants must be over 18, have completed at least two cycles of chemo with radiation, and not have used immunosuppressive drugs recently.

Inclusion Criteria

My lung cancer was confirmed by lab tests and treated with chemo and radiation for stage III.

My condition did not worsen after receiving specific chemotherapy and radiation together.

My cancer does not have mutations in the EGFR or ALK genes.

Exclusion Criteria

I haven't taken immunosuppressive drugs in the last 14 days.

I have an active Epstein-Barr virus infection.

I am getting chemoradiation for Stage III non-small cell lung cancer that can't be removed by surgery.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Durvalumab and Domvanalimab or Durvalumab and placebo as an IV infusion every 4 weeks for up to 12 months

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 years

Treatment Details

Interventions

• Domvanalimab
• Durvalumab
• Placebo

Trial Overview The study compares the effectiveness and safety of Durvalumab combined with Domvanalimab versus Durvalumab with a placebo in patients who've had concurrent chemoradiation therapy for lung cancer. It's randomized, double-blind, and includes multiple international centers.

Participant Groups

Group I: Arm A: Durvalumab + Domvanalimab Experimental Treatment 2 Interventions

Durvalumab and domvanalimab as an IV infusion q4w, starting on Day 1 for up to a maximum of 12 months

Group II: Arm B: Durvalumab + Placebo Active Control 2 Interventions

Durvalumab + placebo as an IV infusion q4w starting on Day 1 for up to a maximum of 12 months

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Arcus Biosciences, Inc.

Industry Sponsor

Trials

44

Recruited

7,500+

Findings from Research

Durvalumab, a PD-L1 blocking antibody, has shown clinical efficacy and a manageable safety profile in treating advanced non-small-cell lung cancer, especially in patients with ≥25% PD-L1 expression.

The drug is being evaluated in various treatment settings, including as a monotherapy and in combination with other therapies, showing promising results particularly after chemoradiation, although lower response rates were noted in patients with EGFR and ALK mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab in non-small-cell lung cancer patients: current developments. Mezquita, L., Planchard, D.[2018]

Durvalumab, a PD-L1 inhibitor, has been shown to be safe for patients with various solid tumors, with common side effects including pruritus and fatigue, based on a meta-analysis of 17 studies involving 1,529 patients.

Higher levels of PD-L1 expression in tumors are linked to better treatment responses to durvalumab, indicating that PD-L1 could serve as a useful biomarker for predicting the drug's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. Yang, H., Shen, K., Zhu, C., et al.[2022]

Durvalumab is an FDA-approved monoclonal antibody that enhances T-cell responses against cancer by blocking the PD-L1 pathway, specifically for patients with advanced urothelial carcinoma who have progressed after platinum-based chemotherapy.

The drug is currently being tested in phase III trials for various cancers, including lung and head and neck cancers, indicating its potential broad application in oncology beyond urothelial carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab: First Global Approval. Syed, YY.[2022]

In a phase II trial involving 116 patients with squamous non-small-cell lung cancer, durvalumab demonstrated a 16% overall response rate and a disease control rate of 54%, indicating its potential effectiveness as a treatment after platinum-based chemotherapy.

The treatment was associated with a median overall survival of 11.6 months and a median progression-free survival of 2.9 months, with 32% of patients experiencing grade ≥ 3 treatment-related adverse events, suggesting that while durvalumab is active, it also carries a risk of significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SWOG S1400A (NCT02154490): A Phase II Study of Durvalumab for Patients With Previously Treated Stage IV or Recurrent Squamous Cell Lung Cancer (Lung-MAP Sub-study). Borghaei, H., Redman, MW., Kelly, K., et al.[2022]

In the phase 3 POSEIDON study involving 1013 treatment-naïve patients with metastatic non-small-cell lung cancer (NSCLC), the combination of tremelimumab, durvalumab, and chemotherapy significantly improved overall survival and progression-free survival compared to chemotherapy alone.

Patients receiving the combination treatment also experienced a longer time to deterioration in quality of life and various symptoms, indicating better overall health status compared to those on chemotherapy, supporting its use as a first-line treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes with durvalumab, with or without tremelimumab, plus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer (POSEIDON). Garon, EB., Cho, BC., Luft, A., et al.[2023]

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 83 patients with unresectable stage III non-small cell lung cancer (NSCLC) receiving durvalumab, 25.3% experienced pneumonitis, confirming the risk associated with this treatment.

The incidence of pneumonitis observed in this real-world setting aligns with findings from the PACIFIC trial, indicating that the safety profile of durvalumab is consistent in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Incidence of Pneumonitis in Patients Receiving Durvalumab. LeClair, JN., Merl, MY., Cohenuram, M., et al.[2022]

In a phase 1b study involving 102 patients with advanced non-small cell lung cancer, the combination of durvalumab and tremelimumab demonstrated manageable safety, although 36% of patients experienced serious treatment-related adverse events, including three treatment-related deaths.

The treatment showed evidence of antitumor activity in both PD-L1-positive and PD-L1-negative tumors, with a confirmed objective response rate of 23% in the cohort receiving tremelimumab 1 mg/kg, indicating potential effectiveness regardless of PD-L1 status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Antonia, S., Goldberg, SB., Balmanoukian, A., et al.[2022]

In a pooled analysis of 1332 patients with advanced non-small-cell lung cancer (NSCLC), the combination of nivolumab and ipilimumab showed a median overall survival (OS) of 18.6 months and a 3-year OS rate of 35%, indicating significant long-term survival benefits compared to traditional chemotherapy.

The study found that patients who responded to treatment at 6 months had markedly better survival rates, with a 3-year OS of 66% for responders, highlighting the importance of early response in predicting long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis. Borghaei, H., Ciuleanu, TE., Lee, JS., et al.[2023]

In a phase I study involving 58 patients with advanced solid tumors, the combination of MEDI0562 with either durvalumab or tremelimumab showed moderate toxicity, with 74.1% and 67.7% of patients reporting treatment-related adverse events, respectively.

While three patients showed a partial response to the MEDI0562 and durvalumab combination, the study did not demonstrate clear efficacy signals, indicating that further research is needed to evaluate the effectiveness of these combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Tolerability of MEDI0562, an OX40 Agonist mAb, in Combination with Durvalumab or Tremelimumab in Adult Patients with Advanced Solid Tumors. Goldman, JW., Piha-Paul, SA., Curti, B., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Durvalumab in non-small-cell lung cancer patients: current developments. [2018]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. [2022]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Durvalumab: First Global Approval. [2022]

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

SWOG S1400A (NCT02154490): A Phase II Study of Durvalumab for Patients With Previously Treated Stage IV or Recurrent Squamous Cell Lung Cancer (Lung-MAP Sub-study). [2022]

5. Ireland pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes with durvalumab, with or without tremelimumab, plus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer (POSEIDON). [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. United States pubmed.ncbi.nlm.nih.gov

Real-World Incidence of Pneumonitis in Patients Receiving Durvalumab. [2022]

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

Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. [2022]

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

Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis. [2023]

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

Safety and Tolerability of MEDI0562, an OX40 Agonist mAb, in Combination with Durvalumab or Tremelimumab in Adult Patients with Advanced Solid Tumors. [2022]