Durvalumab + Oleclumab/Monalizumab for Lung Cancer

(PACIFIC-9 Trial)

Recruiting at 182 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

999 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop using immunosuppressive medications (drugs that lower the body's ability to fight infections) within 14 days before starting the study treatment. Other medications are not specifically mentioned, so it's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination Durvalumab, Oleclumab, and Monalizumab for lung cancer?

Research shows that combining Durvalumab with Oleclumab or Monalizumab improves the response rate in lung cancer patients compared to using Durvalumab alone. This combination leads to better immune system activation against tumors, which is promising for treating lung cancer. ^{1 2 3 4 5}

What safety data exists for Durvalumab and related treatments in humans?

Durvalumab, also known as Imfinzi, has been studied for safety in various cancers. In the PACIFIC trial for lung cancer, about 25% of patients experienced immune-related side effects, with serious cases in 3.4% of patients. Other studies show that combining Durvalumab with another drug, Tremelimumab, increases the risk of serious side effects compared to using Durvalumab alone. ^{4 6 7 8 9}

How is the drug combination of Durvalumab, Oleclumab, and Monalizumab unique for lung cancer?

This drug combination is unique because it builds on the standard treatment of durvalumab, an immune checkpoint inhibitor, by adding oleclumab and monalizumab, which target different immune pathways to potentially enhance the immune response against cancer cells in patients with stage III non-small cell lung cancer. ^{2 3 4 10 11}

What is the purpose of this trial?

This trial is testing two drug combinations to help the immune system fight advanced lung cancer that can't be surgically removed. The patients have already had previous treatment without their disease getting worse. The drugs aim to boost the immune response to better identify and kill cancer cells.

Research Team

Fabrice Barlesi, MD

Principal Investigator

Gustave Roussy, Cancer Campus, Grand Paris

Eligibility Criteria

Adults over 18 with Stage III unresectable Non-Small Cell Lung Cancer (NSCLC) who haven't worsened after platinum-based chemoradiation. They must have normal organ function, no history of certain autoimmune diseases or other cancers within the last 5 years, and not be on immunosuppressants.

Inclusion Criteria

I have provided a tumor tissue sample before starting CRT.

My organs and bone marrow are working well.

Your tumor has been tested for PD-L1 status by a central laboratory.

Exclusion Criteria

My lung cancer is a mix of small cell and non-small cell types.

My Stage III NSCLC has worsened despite platinum-based treatments.

I don't have lasting side effects from previous cancer treatments, except for hair loss.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Durvalumab in combination with Oleclumab or Monalizumab, or Durvalumab with placebo, administered in 28-day cycles for up to 12 months

12 months

Monthly visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, including progression-free survival and overall survival assessments

Up to 9 years

Treatment Details

Interventions

• Durvalumab
• Monalizumab
• Oleclumab

Trial Overview The study is testing Durvalumab in combination with either Oleclumab or Monalizumab against a placebo to see if they improve outcomes for NSCLC patients post-chemoradiation. It's randomized and double-blind, meaning neither doctors nor patients know who gets which treatment.

Participant Groups

Group I: Arm B: Durvalumab and Monalizumab Experimental Treatment 3 Interventions

Durvalumab + Monalizumab on Day 1 of each 28-day cycle for up to 12 months. Placebo infusion will be administered on Day 15 of cycles 1 and 2 only

Group II: Arm A: Durvalumab and Oleclumab Experimental Treatment 2 Interventions

Durvalumab on Day 1 of each 28-day cycle + Oleclumab on Days 1 and 15 of cycles 1 and 2, then on Day 1 of each subsequent 28-day cycle for up to 12 months

Group III: Arm C: Durvalumab and Placebo Active Control 2 Interventions

Durvalumab on Day 1 of each 28-day cycle + Placebo on Days 1 and 15 of cycles 1 and 2, then on Day 1 of each subsequent 28-day cycle for up to 12 months

Durvalumab is already approved in European Union, United States, Japan for the following indications:

Approved in European Union as Imfinzi for:

• Locally advanced, unresectable non-small cell lung cancer (NSCLC)

Approved in United States as Imfinzi for:

• Extensive-stage small cell lung cancer (ES-SCLC)
• Limited-stage small cell lung cancer (LS-SCLC)
• Locally advanced or metastatic urothelial carcinoma

Approved in Japan as Imfinzi for:

• Not specified in provided sources

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

Findings from Research

In the NeoCOAST trial involving 83 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant chemoimmunotherapy using combinations of durvalumab with oleclumab or monalizumab significantly improved major pathologic response (MPR) rates compared to durvalumab alone.

The safety profiles of the combination therapies were comparable to durvalumab alone, and enhanced immune responses were observed in patients receiving the combinations, indicating a promising approach for improving treatment outcomes in NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant Durvalumab Alone or Combined with Novel Immuno-Oncology Agents in Resectable Lung Cancer: The Phase II NeoCOAST Platform Trial. Cascone, T., Kar, G., Spicer, JD., et al.[2023]

In a phase II study involving 189 patients with unresectable stage III non-small-cell lung cancer, combining durvalumab with either oleclumab or monalizumab significantly improved the overall response rate (ORR) and progression-free survival (PFS) compared to durvalumab alone.

The safety profile of the combination therapies was similar to durvalumab alone, with no new significant safety concerns, indicating that these combinations could be promising options for further investigation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

COAST: An Open-Label, Phase II, Multidrug Platform Study of Durvalumab Alone or in Combination With Oleclumab or Monalizumab in Patients With Unresectable, Stage III Non-Small-Cell Lung Cancer. Herbst, RS., Majem, M., Barlesi, F., et al.[2022]

Immune checkpoint inhibitors (ICIs), particularly durvalumab, have significantly improved treatment outcomes for patients with advanced non-small cell lung cancer (NSCLC), establishing them as the standard of care either alone or with chemotherapy.

Durvalumab is specifically approved as a consolidation treatment after chemo-radiotherapy for stage III NSCLC, highlighting its role in enhancing patient prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on Targeted Therapies for Advanced Non-Small Cell Lung Cancer: Durvalumab in Context. Gullapalli, S., Remon, J., Hendriks, LEL., et al.[2020]

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 the phase III PACIFIC trial, durvalumab significantly improved overall survival (OS) and progression-free survival (PFS) in patients with unresectable stage III non-small-cell lung cancer after chemoradiotherapy, with a 5-year OS rate of 42.9% compared to 33.4% for placebo.

The updated analyses, with a median follow-up of 34.2 months, showed that durvalumab continues to provide durable benefits, establishing a new standard of care for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Five-Year Survival Outcomes From the PACIFIC Trial: Durvalumab After Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. Spigel, DR., Faivre-Finn, C., Gray, JE., et al.[2022]

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]

In the phase III PACIFIC trial, durvalumab treatment led to a low incidence of immune-mediated adverse events (imAEs), with any-grade immune-mediated pneumonitis occurring in 9.4% of patients and grade 3/4 imAEs in only 3.4%.

Despite the occurrence of imAEs being more common with durvalumab compared to placebo, these events were generally manageable with treatments like corticosteroids, indicating that the benefits of the PACIFIC regimen outweigh the risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterizing immune-mediated adverse events with durvalumab in patients with unresectable stage III NSCLC: A post-hoc analysis of the PACIFIC trial. Naidoo, J., Vansteenkiste, JF., Faivre-Finn, C., et al.[2022]

The combination of durvalumab and tremelimumab in cancer treatment is associated with a higher incidence of severe adverse events (32.6%) compared to durvalumab alone (23.8%), indicating increased safety concerns with the combination therapy.

Patients receiving the combination therapy also experienced higher rates of specific side effects such as diarrhea (15.6% vs. 8.1%), rash (11.1% vs. 6.5%), and treatment discontinuation (18% vs. 3%), highlighting the need for careful monitoring and patient counseling regarding these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. Fahmy, O., Ahmed, OAA., Khairul-Asri, MG., et al.[2023]

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 study of 121 patients with stage III non-small cell lung cancer treated with durvalumab, those with over 50% PD-L1 expression had significantly better outcomes, with a 1-year survival rate of 97% compared to 73% and 78% for lower expression groups.

Higher PD-L1 expression (>50%) was strongly associated with improved progression-free survival and overall survival, indicating that PD-L1 levels could be a key factor in predicting the effectiveness of durvalumab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor PD-L1 expression is associated with outcomes in stage III non-small cell lung cancer (NSCLC) patients treated with consolidation durvalumab. Jazieh, K., Gad, M., Saad, A., et al.[2022]

Durvalumab, an immune checkpoint inhibitor, has shown promising efficacy in treating advanced non-small cell lung cancer (NSCLC) in early phase trials, demonstrating a good safety profile.

The PACIFIC trial has successfully met its primary endpoint, indicating that durvalumab may be an important part of future treatment strategies for NSCLC, with ongoing studies potentially confirming its superiority over current therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MEDI 4736 (durvalumab) in non-small cell lung cancer. Jeanson, A., Barlesi, F.[2021]

References

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

Neoadjuvant Durvalumab Alone or Combined with Novel Immuno-Oncology Agents in Resectable Lung Cancer: The Phase II NeoCOAST Platform Trial. [2023]

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

COAST: An Open-Label, Phase II, Multidrug Platform Study of Durvalumab Alone or in Combination With Oleclumab or Monalizumab in Patients With Unresectable, Stage III Non-Small-Cell Lung Cancer. [2022]

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

Update on Targeted Therapies for Advanced Non-Small Cell Lung Cancer: Durvalumab in Context. [2020]

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

Durvalumab: First Global Approval. [2022]

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

Five-Year Survival Outcomes From the PACIFIC Trial: Durvalumab After Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. [2022]

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

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

7. Ireland pubmed.ncbi.nlm.nih.gov

Characterizing immune-mediated adverse events with durvalumab in patients with unresectable stage III NSCLC: A post-hoc analysis of the PACIFIC trial. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. [2023]

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

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

10. China pubmed.ncbi.nlm.nih.gov

Tumor PD-L1 expression is associated with outcomes in stage III non-small cell lung cancer (NSCLC) patients treated with consolidation durvalumab. [2022]

11. England pubmed.ncbi.nlm.nih.gov

MEDI 4736 (durvalumab) in non-small cell lung cancer. [2021]