Local Consolidative Therapy + Durvalumab for Lung Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Immunosuppressants, Live vaccines

Disqualifiers: Autoimmune disorders, Uncontrolled illness, Active infection, 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

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 28 days per cycle

51 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial finds out the effect of local consolidative therapy and durvalumab in treating patients with stage III non-small cell lung cancer that has 3 or fewer lesions of progression (oligoprogressive) and greater than 3 lesions of progression (polyprogressive) after chemoradiation and anti-PD-l1 therapy. Local consolidative therapy, such as surgery and/or radiation, after initial treatment may kill any remaining tumor cells. Immunotherapy with durvalumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving local consolidative therapy and durvalumab may help to control the disease.

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

The trial protocol does not specify if you need to stop taking your current medications. However, there is a 28-day washout period (time without taking certain medications) required for most anticancer therapies before starting the study drug, except for durvalumab. It's best to discuss your specific medications with the study team.

What data supports the effectiveness of the drug Durvalumab for lung cancer?

Research shows that adding Durvalumab to chemoradiation improves survival and disease control in patients with locally advanced non-small cell lung cancer. The PACIFIC trial demonstrated significant improvements in overall survival and progression-free survival with Durvalumab compared to a placebo. ^{1 2 3 4 5}

Is durvalumab (Imfinzi) safe for humans?

Durvalumab (also known as Imfinzi or MEDI4736) has been shown to have manageable safety in patients with non-small cell lung cancer (NSCLC) after chemoradiotherapy, with adverse events documented in clinical studies. It is generally considered to have acceptable tolerability, although treatment-related side effects are an important consideration. ^{1 5 6 7 8}

What makes the drug Durvalumab unique for lung cancer treatment?

Durvalumab is unique because it is an immunotherapy drug that boosts the immune system to fight cancer by blocking a protein called PD-L1, and it is used after chemoradiotherapy to improve survival in patients with locally advanced non-small cell lung cancer. ^{3 4 9 10 11}

Research Team

Joe Y Chang, MD,MS,PHD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with stage III non-small cell lung cancer who've had chemoradiation and anti-PD-L1 therapy but still have up to 3 progressing lesions (oligoprogressive) or more than 3 (polyprogressive). They should be fit for radiation, have a life expectancy of at least 12 weeks, and their major organs must function within certain limits. People with certain genetic mutations or unresolved severe side effects from previous treatments can't join.

Inclusion Criteria

I have stage III lung cancer, treated with chemoradiation and durvalumab, but my cancer either worsened or didn't fully respond.

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

My cancer has spread, but only to 3 or fewer places.

Exclusion Criteria

I haven't had any live vaccines in the last 30 days.

I have had cancer before, but it was a different type.

I have or had an autoimmune or inflammatory disorder.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Local Consolidative Therapy (LCT)

Patients undergo LCT consisting of radiation therapy and/or surgery

4 weeks

1 visit (in-person)

Treatment

Patients receive durvalumab IV over 1 hour on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity

28 days per cycle

1 visit per cycle (in-person)

Chemotherapy (Cohort B only)

Patients receive chemotherapy options such as carboplatin and paclitaxel, carboplatin and nab-paclitaxel, or carboplatin and gemcitabine. Treatment repeats every 21 days for 4 cycles

12 weeks

1 visit per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 12 weeks for 2 years

1 visit every 12 weeks (in-person)

Treatment Details

Interventions

• Durvalumab
• Local Consolidation Therapy

Trial Overview The trial tests if adding local consolidative therapy (like surgery/radiation) to durvalumab immunotherapy helps control the disease better in patients whose cancer has progressed after initial treatments. It aims to see if this combination can kill remaining tumor cells and boost the immune system's ability to fight cancer.

Participant Groups

Group I: Cohort B (polyprogressive) Experimental Treatment 9 Interventions

Patients undergo LCT consisting of radiation therapy and/or surgery, then receive durvalumab IV over 1 hour on day 1. Patients also receive one of the following chemotherapy options: carboplatin and paclitaxel on day 1, carboplatin on day 1 and nab-paclitaxel on days 1, 8, 15, or carboplatin on day 1 and gemcitabine on days 1 and 8. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients with non-squamous histology receive pemetrexed on day 1 every 21 days for cycles 1-4, pemetrexed and durvalumab IV on day 1 every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Cohort A (oligoprogressive) Experimental Treatment 4 Interventions

Patients undergo LCT consisting of radiation therapy and/or surgery, then receive durvalumab IV over 1 hour on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Findings from Research

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, 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]

In a study of 34 patients with locally advanced non-small cell lung cancer (LA-NSCLC) treated with chemoradiotherapy followed by durvalumab, 26.5% experienced symptomatic pneumonitis, but this did not negatively affect their overall survival or progression-free survival.

The management of pneumonitis included steroid treatment, and 70% of patients were able to safely resume durvalumab after recovery, indicating that re-challenging with durvalumab is feasible even after pneumonitis occurs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Implications of pneumonitis after chemoradiation and durvalumab for locally advanced non-small cell lung cancer. Hassanzadeh, C., Sita, T., Savoor, R., et al.[2022]

In a study of 81 patients with unresectable locally advanced non-small cell lung cancer (NSCLC), those with high tumor mutational burden (TMB-high) showed significantly better outcomes, including lower local-regional failure rates (9% vs 51%) and improved progression-free survival (66% vs 27%) compared to TMB-low patients.

The study suggests that TMB status could be a valuable biomarker for personalizing treatment strategies, as it was the only factor significantly associated with local-regional failure and progression-free survival after treatment with chemoradiation and adjuvant durvalumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of Tumor Mutational Burden, Progression-Free Survival, and Local-Regional Control in Patents with Locally Advanced Non-Small Cell Lung Cancer Treated With Chemoradiation and Durvalumab. Lebow, ES., Shepherd, A., Eichholz, JE., et al.[2023]

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]

In a study of 442 patients with unresectable stage III non-small cell lung cancer (NSCLC) who received platinum-based chemoradiotherapy, 50.3% were found eligible for durvalumab consolidation immunotherapy (CIT) according to PACIFIC trial criteria.

Despite only half of the patients meeting eligibility criteria, 85.6% of those eligible received CIT within a year of the drug's approval, with the main reasons for ineligibility being disease progression and low PD-L1 tumor proportion scores.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Consolidation Immunotherapy After Platinum-Based Chemoradiotherapy in Patients With Unresectable Stage III Non-Small Cell Lung Cancer-Cross-Sectional Study of Eligibility and Administration Rates. Eichkorn, T., Bozorgmehr, F., Regnery, S., et al.[2022]

Durvalumab, an immunotherapy drug for non-small cell lung cancer (NSCLC), has shown significant activity and acceptable tolerability, especially in patients with at least 25% PD-L1 tumor expression, and has been established as a standard treatment following chemoradiation based on the PACIFIC study results.

While durvalumab is effective in wild-type EGFR and ALK patients, its efficacy is lower in those with EGFR mutations or ALK-positive status, highlighting the need for ongoing research into combination therapies and the management of treatment-related toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab for the treatment of non-small cell lung cancer. Mezquita, L., Planchard, D.[2019]

Durvalumab has been approved for use in patients with locally advanced PD-L1-positive non-small cell lung cancer (NSCLC) after chemoradiotherapy, based on its efficacy demonstrated in the PACIFIC trial and subsequent analysis of 211 patients in the Expanded Access Program (EAP).

In the EAP, 126 patients who received durvalumab were included, some of whom had oligometastatic disease and a history of autoimmune conditions, indicating that durvalumab may be effective and safe for a broader patient population than previously studied.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab after definitive chemoradiotherapy in locally advanced NSCLC: Data of the German EAP. Faehling, M., Schumann, C., Christopoulos, P., et al.[2020]

In a study involving 576 patients with unresectable stage III non-small cell lung cancer (NSCLC), the PD-L1 inhibitor durvalumab showed a favorable safety profile, with only 22.7% of patients experiencing adverse events, primarily mild esophagitis.

Durvalumab treatment after concurrent chemoradiotherapy (cCRT) resulted in consistent outcomes across both PD-L1 positive and negative patients, indicating its potential as a standard care option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nationwide Real-Life Safety and Treatment Exposure Data on Durvalumab After Concurrent Chemoradiotherapy in Unresectable Stage III, Locally Advanced, Non-small Cell Lung Cancer: Analysis of Patients Enrolled in the French Early Access Program. Avrillon, V., Daniel, C., Boisselier, P., et al.[2022]

In a study of 104 patients with unresectable locally advanced non-small cell lung cancer (NSCLC), those with driver variations experienced significantly shorter progression-free survival (PFS) times (8.4 months) compared to those without driver variations (40.1 months), indicating that these mutations may limit the effectiveness of the PACIFIC regimen.

Despite the shorter PFS, there was no significant difference in overall survival (OS) between patients with and without driver variations, suggesting that while the initial treatment may be less effective for some, it does not necessarily impact long-term survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Driver Oncogene Variations With Outcomes in Patients With Locally Advanced Non-Small Cell Lung Cancer Treated With Chemoradiation and Consolidative Durvalumab. Liu, Y., Zhang, Z., Rinsurongkawong, W., et al.[2023]

In a study of 158 patients with stage III NSCLC receiving durvalumab after chemoradiotherapy, those who developed grade two or greater pneumonitis had significantly worse overall survival compared to those with other immune-related adverse events.

Multivariate analysis indicated that both grade two or greater pneumonitis and squamous histology were independent factors associated with poorer survival outcomes, highlighting the need for careful monitoring of pneumonitis in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pneumonitis During Durvalumab Consolidation Therapy Affects Survival in Stage III NSCLC. Kinehara, Y., Shiroyama, T., Tamiya, A., et al.[2023]

References

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

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

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

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

3. China pubmed.ncbi.nlm.nih.gov

Implications of pneumonitis after chemoradiation and durvalumab for locally advanced non-small cell lung cancer. [2022]

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

Analysis of Tumor Mutational Burden, Progression-Free Survival, and Local-Regional Control in Patents with Locally Advanced Non-Small Cell Lung Cancer Treated With Chemoradiation and Durvalumab. [2023]

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. Switzerland pubmed.ncbi.nlm.nih.gov

Consolidation Immunotherapy After Platinum-Based Chemoradiotherapy in Patients With Unresectable Stage III Non-Small Cell Lung Cancer-Cross-Sectional Study of Eligibility and Administration Rates. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Durvalumab for the treatment of non-small cell lung cancer. [2019]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Durvalumab after definitive chemoradiotherapy in locally advanced NSCLC: Data of the German EAP. [2020]

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

Nationwide Real-Life Safety and Treatment Exposure Data on Durvalumab After Concurrent Chemoradiotherapy in Unresectable Stage III, Locally Advanced, Non-small Cell Lung Cancer: Analysis of Patients Enrolled in the French Early Access Program. [2022]

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

Association of Driver Oncogene Variations With Outcomes in Patients With Locally Advanced Non-Small Cell Lung Cancer Treated With Chemoradiation and Consolidative Durvalumab. [2023]

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

Pneumonitis During Durvalumab Consolidation Therapy Affects Survival in Stage III NSCLC. [2023]