Durvalumab/Osimertinib + SBRT for Lung Cancer

(PACIFIC-4 Trial)

Recruiting at 195 trial locations

Overseen By AstraZeneca Lung Cancer Study Locator Service

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Must not be taking: CYP3A4 inducers

Disqualifiers: EGFR mutation, QTc prolongation, others

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: Up to 36 months for Osimertinib cohort, up to 26 cycles for Durvalumab cohort

724 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a Phase III, randomized, placebo-controlled, double-blind, multi-center study assessing the efficacy and safety of durvalumab with SoC SBRT versus placebo with SoC SBRT in patients with unresected clinical Stage I/II lymph node-negative (T1 to T3N0M0) NSCLC. An additional cohort will assess Osimertinib following SBRT in patients with early stage unresected T1 to T3N0M0 NSCLC harbouring an EGFR mutation.

Will I have to stop taking my current medications?

The trial requires that you stop taking medications or herbal supplements known to be potent inducers of CYP3A4 before starting the study treatment. If you're on such medications, you may need to discuss alternatives with your doctor.

What data supports the effectiveness of the treatment Durvalumab/Osimertinib + SBRT for Lung Cancer?

Research shows that combining durvalumab with radiotherapy can improve survival in patients with non-small cell lung cancer (NSCLC), as seen in the PACIFIC trial. Additionally, stereotactic body radiotherapy (SBRT) has been found to enhance the immune response when used with durvalumab, potentially improving outcomes in lung cancer. ^{1 2 3 4 5}

Is the combination of Durvalumab and Osimertinib generally safe for humans?

Durvalumab has been associated with an increased risk of immune-related side effects, such as pneumonitis (lung inflammation), which can be serious. In a study with advanced gastric cancer patients, Durvalumab combined with chemotherapy showed a high rate of severe side effects, but these were mostly related to the chemotherapy. Safety data for Osimertinib is not provided in the articles. ^{6 7 8 9 10}

How is the treatment with Durvalumab/Osimertinib + SBRT for lung cancer different from other treatments?

This treatment combines Durvalumab and Osimertinib with Stereotactic Body Radiation Therapy (SBRT), which is unique because it integrates targeted therapy (Osimertinib) and immunotherapy (Durvalumab) with precise radiation (SBRT) to potentially enhance effectiveness and reduce side effects compared to traditional chemoradiotherapy. ^{2 4 11 12 13}

Eligibility Criteria

This trial is for adults over 18 with early-stage, unresected non-small cell lung cancer without lymph node involvement. Participants must weigh more than 30 kg and have good organ function. Those with certain EGFR mutations can join an additional cohort. Contraception is required during the study.

Inclusion Criteria

I can take care of myself and perform daily activities.

I have had lung cancer more than once or at the same time, with some exceptions.

You are expected to live for at least 12 more weeks.

Exclusion Criteria

Your heart's electrical activity is too slow, as shown by multiple ECG tests.

I have previously received EGFR TKI therapy before or after surgery.

My cancer does not have the EGFR mutation according to tests.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Durvalumab with SoC SBRT or placebo with SoC SBRT. In the Osimertinib cohort, participants receive Osimertinib following SBRT.

Up to 36 months for Osimertinib cohort, up to 26 cycles for Durvalumab cohort

Follow-up

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

Up to 7 years

Open-label extension (optional)

Participants in the Osimertinib cohort may continue treatment until progression or up to 36 months.

Long-term

Treatment Details

Interventions

• Durvalumab
• Osimertinib
• Placebo
• SBRT

Trial Overview The trial tests if durvalumab combined with standard-of-care stereotactic body radiation therapy (SBRT) improves outcomes compared to placebo plus SBRT in one group, while another group receives osimertinib following SBRT if they have specific EGFR mutations.

Participant Groups

Group I: SoC SBRT + Osimertinib Therapy (Osimertinib cohort, single-arm, open-label separate cohort) Experimental Treatment 1 Intervention

SBRT Osimertinib 80mg every day \[qd\] for oral administration up to 36 months or until progression. Osimertinib treatment should start within 7 to 14 days after completion of SBRT

Group II: SoC SBRT + Durvalumab Therapy (Main Cohort) Experimental Treatment 1 Intervention

SBRT Durvalumab (PD-L1 monoclonal antibody) 1500 mg every 4 weeks \[q4w\] intravenously \[iv\] for up to 26 cycles or until progression or other discontinuation criteria are met.

Group III: SoC SBRT + Placebo Therapy (Main Cohort) Placebo Group 1 Intervention

SBRT Placebo (matching placebo for infusion) every 4 weeks iv for up to 26 cycles or until progression or other discontinuation criteria are met.

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

This phase II trial aims to evaluate whether combining stereotactic body radiotherapy (SBRT) with the immune checkpoint inhibitor durvalumab can improve progression-free survival in patients with oligometastatic hormone-sensitive prostate cancer, compared to SBRT alone.

The study will involve 96 patients over 3 years, focusing on not only progression-free survival but also other important outcomes like quality of life and immune response, with the expectation that the combination treatment will be effective and have manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II trial in prostate cancer with hormone-sensitive OligometaSTatic relapse: Combining stereotactic ablative radiotherapy and durvalumab (POSTCARD GETUG P13): Study protocol. Rogé, M., Pointreau, Y., Sargos, P., et al.[2023]

Patients with locally advanced non-small cell lung cancer (LA-NSCLC) who received concurrent chemoradiotherapy (CCRT) and durvalumab had a significantly higher 1-year local control rate (89%) compared to those who received CCRT alone (47%), indicating that adding durvalumab may enhance local tumor control.

While the addition of durvalumab improved local control, it was associated with a slightly higher incidence of grade 2 pneumonitis (50% in the durvalumab cohort vs. 41% in the CCRT-alone cohort), highlighting the importance of monitoring for respiratory side effects in patients undergoing this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the Efficacy and Toxicity of Concurrent Chemoradiotherapy and Durvalumab and Concurrent Chemoradiotherapy Alone for Locally Advanced Non-small Cell Lung Cancer With N3 Lymph Node Metastasis. Abe, T., Iino, M., Saito, S., et al.[2023]

The DUART trial is a Phase II study investigating the safety and tolerability of durvalumab in patients with unresectable, stage III non-small-cell lung cancer (NSCLC) who cannot undergo chemotherapy due to poor performance status or other health issues.

This study aims to evaluate whether durvalumab can improve survival outcomes for these patients compared to the current standard of care, which is radiotherapy alone, based on promising results from the PACIFIC trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DUART: durvalumab after radiotherapy in patients with unresectable, stage III NSCLC who are ineligible for chemotherapy. Filippi, AR., Dziadziuszko, R., García Campelo, MR., 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]

The DEDALUS phase 2 trial is investigating a new treatment approach for 45 patients with unresectable stage III non-small cell lung cancer (NSCLC), combining induction chemo-immunotherapy with de-intensified radiotherapy and the immunotherapy drug durvalumab.

The primary focus of the study is to assess safety by monitoring severe adverse events within 6 months, while secondary goals include evaluating progression-free survival (PFS) and overall survival (OS), indicating a comprehensive approach to understanding both the safety and effectiveness of this treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and Design of a Single-Arm, Phase 2, Multi-Center Study of Chemo-Immunotherapy Followed by Hypo-Fractionated RT and Maintenance Immunotherapy in Patients With Unresectable Stage III NSCLC: The DEDALUS Trial. Filippi, AR., Agustoni, F., Arcangeli, S., et al.[2023]

In a randomized phase II trial involving 60 patients with resectable non-small cell lung cancer, the addition of sub-ablative radiation to neoadjuvant durvalumab did not increase mortality or major complications compared to durvalumab alone, indicating a safe combination treatment approach.

Both treatment groups experienced similar rates of grade 3/4 adverse events (38% each), with anemia and hypotension being the most common, suggesting that the safety profile of durvalumab remains consistent regardless of the addition of radiation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Surgical resection after neoadjuvant durvalumab and radiation is feasible and safe in non-small cell lung cancer: Results from a randomized trial. Lee, B., Mynard, N., Nasar, A., et al.[2022]

In a study involving 10 patients receiving palliative radiotherapy (RT) combined with durvalumab, the treatment was well tolerated, with only 50% experiencing mild to moderate adverse events, primarily G2 mucositis, and no severe adverse events reported.

The treatment showed promising efficacy, with a 60% objective response rate in evaluable lesions and a significant decrease in tumor growth rate after RT, indicating that durvalumab combined with RT may effectively reduce tumor size in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent irradiation with the anti-programmed cell death ligand-1 immune checkpoint blocker durvalumab: Single centre subset analysis from a phase 1/2 trial. Levy, A., Massard, C., Soria, JC., et al.[2022]

In a safety run-in phase of the DURIGAST PRODIGE 59 study involving 11 patients with advanced gastric or gastro-oesophageal junction adenocarcinoma, 63.6% experienced significant adverse events, primarily neutropenia, indicating a notable safety concern with the treatment combination.

The combination of FOLFIRI with Durvalumab and/or Tremelimumab showed an expected safety profile, allowing progression to the randomized phase II study, although careful monitoring for serious adverse events is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of FOLFIRI + Durvalumab +/- Tremelimumab in Second Line of Patients with Advanced Gastric Cancer: A Safety Run-In from the Randomized Phase II Study DURIGAST PRODIGE 59. Evrard, C., Aparicio, T., Soularue, E., et al.[2022]

In a study of 1006 veterans with stage III non-small cell lung cancer (NSCLC), the addition of durvalumab after chemoradiotherapy significantly improved progression-free survival (PFS) and overall survival (OS), with hazard ratios of 0.62 and 0.57 respectively, indicating a strong benefit from the treatment.

While durvalumab improved OS in veterans compared to those who received only chemoradiotherapy, their survival rates were still lower than those observed in the PACIFIC clinical trial population, suggesting that real-world outcomes may differ from clinical trial results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real World Outcomes versus Clinical Trial Results of Durvalumab Maintenance in Veterans with Stage III Non-Small Cell Lung Cancer. Sankar, K., Bryant, AK., Strohbehn, GW., et al.[2022]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Randomized phase II trial in prostate cancer with hormone-sensitive OligometaSTatic relapse: Combining stereotactic ablative radiotherapy and durvalumab (POSTCARD GETUG P13): Study protocol. [2023]

2. Greece pubmed.ncbi.nlm.nih.gov

Comparison of the Efficacy and Toxicity of Concurrent Chemoradiotherapy and Durvalumab and Concurrent Chemoradiotherapy Alone for Locally Advanced Non-small Cell Lung Cancer With N3 Lymph Node Metastasis. [2023]

3. England pubmed.ncbi.nlm.nih.gov

DUART: durvalumab after radiotherapy in patients with unresectable, stage III NSCLC who are ineligible for chemotherapy. [2022]

4. Singapore pubmed.ncbi.nlm.nih.gov

Effect of durvalumab on local control after concurrent chemoradiotherapy for locally advanced non-small cell lung cancer in comparison with chemoradiotherapy alone. [2022]

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

Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial. [2021]

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

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

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

Rationale and Design of a Single-Arm, Phase 2, Multi-Center Study of Chemo-Immunotherapy Followed by Hypo-Fractionated RT and Maintenance Immunotherapy in Patients With Unresectable Stage III NSCLC: The DEDALUS Trial. [2023]

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

Surgical resection after neoadjuvant durvalumab and radiation is feasible and safe in non-small cell lung cancer: Results from a randomized trial. [2022]

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

Concurrent irradiation with the anti-programmed cell death ligand-1 immune checkpoint blocker durvalumab: Single centre subset analysis from a phase 1/2 trial. [2022]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Safety of FOLFIRI + Durvalumab +/- Tremelimumab in Second Line of Patients with Advanced Gastric Cancer: A Safety Run-In from the Randomized Phase II Study DURIGAST PRODIGE 59. [2022]

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

Neoadjuvant Osimertinib Followed by Sequential Definitive Radiation Therapy and/or Surgery in Stage III Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer: An Open-Label, Single-Arm, Phase 2 Study. [2023]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Real World Outcomes versus Clinical Trial Results of Durvalumab Maintenance in Veterans with Stage III Non-Small Cell Lung Cancer. [2022]

13. England pubmed.ncbi.nlm.nih.gov

A phase 2 trial of durvalumab treatment following radiation monotherapy in patients with non-small cell lung cancer ineligible for stage III chemoradiotherapy: The SPIRAL-RT study. [2023]