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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of treatments for individuals with stage III non-small cell lung cancer. After initial treatments such as chemoradiation and anti-PD-L1 therapy, participants receive local consolidative therapy, which involves surgery or radiation to target remaining cancer cells. They also receive an immunotherapy drug called durvalumab (Imfinzi), designed to enhance the immune system's ability to fight cancer. The trial aims to determine if this approach can better control the disease. It suits those with lung cancer who have a few (oligoprogressive) or many (polyprogressive) lesions that have progressed after initial treatments. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that durvalumab is generally safe for individuals with various solid tumors, including lung cancer. Studies found it well-tolerated when used alone or with other treatments. Patients with stage III non-small cell lung cancer experienced no unexpected side effects when receiving durvalumab immediately after chemotherapy and radiation.

Local consolidative therapy (LCT), which includes treatments like surgery and radiation, is also considered safe. Research indicates that LCT can extend patients' lives without causing severe side effects. For those with a limited spread of non-small cell lung cancer, LCT has been associated with longer survival rates.

In summary, both durvalumab and local consolidative therapy are safe, with studies showing that patients generally tolerate these treatments well without major issues. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of local consolidative therapy (LCT) and durvalumab for lung cancer because it offers a potentially more effective approach compared to current treatments. Unlike standard options that often involve just chemotherapy or radiation, this treatment combines targeted radiation or surgery with durvalumab, an immunotherapy that boosts the body's immune response to fight cancer. Furthermore, adding durvalumab to the regimen aims to enhance the immune system's ability to recognize and destroy cancer cells, potentially leading to better outcomes for patients with both oligoprogressive and polyprogressive lung cancer.

What evidence suggests that local consolidative therapy and durvalumab might be effective for lung cancer?

Research has shown that durvalumab yields promising results for treating certain lung cancers. For patients with stage III non-small cell lung cancer (NSCLC) that cannot be surgically removed, those who received durvalumab after initial treatments lived 11 months longer without cancer progression. In this trial, participants in Cohort A (oligoprogressive) and Cohort B (polyprogressive) will receive durvalumab following local consolidative therapy (LCT), which includes focused treatments like surgery and radiation. Studies have found that patients receiving LCT lived longer than those who did not, with some studies showing nearly 30% of patients surviving for 5 years. Together, these treatments aim to control the disease more effectively by boosting the immune system and using precise local treatments. ^{1 6 7 8 9}

Who Is on the Research Team?

Joe Y Chang, MD,MS,PHD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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, 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, 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 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]

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 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]

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 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]

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]

Citations

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2. ascopubs.org ascopubs.org/doi/10.1200/JCO-25-00036

The Phase III PACIFIC-2 Study | Journal of Clinical Oncology In PACIFIC, durvalumab significantly improved progression-free survival (PFS; stratified hazard ratio [HR], 0.52 [95% CI, 0.42 to 0.65]; P < .

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8412232/

Outcomes with durvalumab by tumour PD-L1 expression in ... Durvalumab significantly improved progression-free and overall survival (PFS/OS) versus placebo, with manageable safety, in unresectable, stage III non-small- ...

4. imfinzihcp.com imfinzihcp.com/nsclc/stage-3/efficacy.html

IMFINZI® Efficacy for unresectable Stage III NSCLC Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. J Clin Oncol. 2022;40(12): ...

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Safety and efficacy of durvalumab (MEDI4736) in various ... Durvalumab is safe in patients with many solid cancers and, in combination with tremelimumab, it has a tolerable safety profile and is associated with improved ...

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215TiP A phase II study of durvalumab (MEDI 4736) ... DURVALUNG study aims to evaluate the efficacy of durvalumab maintenance specifically in frail LD-SCLC pts who have not progressed following concomitant or ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT02087423?term=AREA%5BBasicSearch%5D(AREA%5BInterventionSearch%5D(DURVALUMAB%20OR%20MEDI4736%20OR%20MEDI-4736%20OR%20Imfinzi))&rank=10

A Global Study to Assess the Effects of MEDI4736 ... This study is designed to investigate the efficacy, safety, tolerability of a new drug, MEDI4736 (Durvalumab), in patients with Locally Advanced or ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.8536

A phase II study of durvalumab (MEDI4736) immediately ... Durvalumab can be safely administered immediately after completion of CCRT for patients with unresectable stage III NSCLC, no additional or unexpected toxicity ...

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