Chemoradiotherapy + Immunotherapy for Non-Small Cell Lung Cancer

Overseen By Rene Bonilla

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Joel Neal

Must be taking: Durvalumab

Must not be taking: Immunosuppressants

Disqualifiers: Autoimmune disorders, Active infection, 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

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

Compensation: Varies

Number of Visits: 5

Duration: 12 weeks

48 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to test whether or not number of circulating cancer cells detected in the blood can be decreased the by combining the standard treatment (durvalumab) with Tremelimumab and additional chemotherapy

Do I need to stop taking my current medications to join the trial?

The trial does not specify if you need to stop taking your current medications. However, you cannot use immunosuppressive medications within 14 days before enrollment, except for certain corticosteroids. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment for non-small cell 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 found significant improvements in overall survival and progression-free survival with durvalumab after chemoradiotherapy. ^{1 2 3 4 5}

Is the combination of chemoradiotherapy and immunotherapy generally safe for humans?

Research shows that durvalumab, an immunotherapy drug used with chemoradiotherapy, can increase the risk of immune-related side effects, such as pneumonitis (lung inflammation), which can be serious. It's important to monitor these side effects in clinical practice to ensure patient safety. ^{2 4 6 7 8}

How is the drug Durvalumab used in treating non-small cell lung cancer different from other treatments?

Durvalumab is unique because it is an immunotherapy drug that blocks PD-L1, a protein that helps cancer cells evade the immune system, and is used after chemoradiotherapy to improve survival in patients with stage III non-small cell lung cancer. This combination of chemoradiotherapy followed by Durvalumab has become a standard of care, offering significant survival benefits compared to chemoradiotherapy alone. ^{1 4 9 10 11}

Research Team

Maximilian Diehn, MD

Principal Investigator

Stanford Universiy

Eligibility Criteria

Adults over 18 with stage III NSCLC who've had two doses of durvalumab after chemo and radiation without disease progression. They must have good blood counts, organ function, a life expectancy of at least 12 weeks, and an ECOG status of 0 or 1. Not eligible if pregnant/breastfeeding without effective birth control, on other clinical trials within the last month, have certain autoimmune diseases or prior severe reactions to trial drugs.

Inclusion Criteria

You are expected to live for at least 12 weeks.

My liver function tests are within the required range.

My lung cancer is at an advanced stage and cannot be removed by surgery.

Exclusion Criteria

Previous enrollment or randomization in the present study

Involvement in the planning and/or conduct of the study

I have nerve damage that affects my daily activities.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants in Cohort 1 MRD+ receive 4 cycles of platinum doublet chemotherapy, tremelimumab, and durvalumab. Cohort 2 MRD- receives standard of care durvalumab.

12 weeks

Every 3 weeks

Consolidation

Following ctDNA evaluation, participants continue with durvalumab to complete 1 year of treatment as standard of care.

1 year

Every 2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including adverse events and survival outcomes.

2 years

Treatment Details

Interventions

• Carboplatin
• Cisplatin
• Durvalumab
• Paclitaxel
• Pemetrexed

Trial Overview The study is testing if adding more chemotherapy to standard treatment (durvalumab) can reduce circulating cancer cells in the blood for those with stage III NSCLC. It involves using a ctDNA Surveillance Kit to monitor response and may include additional consolidation chemotherapy as part of the protocol.

Participant Groups

Group I: Cohort 2 minimal residual disease negative (MRD ) Experimental Treatment 2 Interventions

Subjects with undetectable ctDNA at study enrollment will receive standard of care durvalumab (10 mg/kg every 2 weeks, or equivalent, for 1 year). If subjects in Cohort 2 MRD progress prior to close of study, blood will be drawn for ctDNA testing.

Group II: Cohort 1 minimal residual disease positive (MRD+) Experimental Treatment 7 Interventions

Subjects with detectable ctDNA will receive 4 cycles of platinum doublet chemotherapy \[carboplatin/pemetrexed\], tremelimumab (75 mg IV every 21 days) and durvalumab (1500 mg IV every 21 days), except subjects with squamous cell carcinoma histology will receive carboplatin/paclitaxel. Subjects will be evaluated with PET/CT and/or computed tomography (CT) thorax every 12 weeks. Following ctDNA evaluation, in the absence of progression or toxicity, subject will continue with durvalumab to complete 1 year of treatment as standard of care.

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?

Joel Neal

Lead Sponsor

Trials

4

Recruited

110+

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Maximilian Diehn

Lead Sponsor

Trials

2

Recruited

80+

AstraZeneca

Industry 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 a study of 1006 patients with stage III non-small cell lung cancer (NSCLC), early discontinuation of adjuvant durvalumab therapy was common, primarily due to tumor progression and immune-related adverse events, highlighting the need for careful monitoring during treatment.

The analysis indicated that shorter durations of durvalumab (6 or 9 months) may provide similar progression-free survival compared to the full 12-month course, suggesting that optimizing treatment duration could balance efficacy and patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

De-escalating adjuvant durvalumab treatment duration in stage III non-small cell lung cancer. Bryant, AK., Sankar, K., Zhao, L., et al.[2023]

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 421 patients with stage III nonsmall-cell lung cancer (NSCLC) who completed chemoradiation, 76.5% initiated adjuvant durvalumab, indicating a strong uptake of this treatment in real-world settings.

The initiation of adjuvant durvalumab increased significantly over time, from 66% to 92%, suggesting that it has been rapidly integrated into clinical practice, particularly among patients with better performance status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Uptake of Adjuvant Durvalumab After Definitive Concurrent Chemoradiotherapy for Stage III Nonsmall-cell Lung Cancer. Bryant, AK., Yin, H., Schipper, MJ., 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]

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 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 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 323 patients with stage III unresectable non-small cell lung cancer (NSCLC) treated with durvalumab after chemo-radiotherapy, the overall survival was promising at a median of 47 months, but progression-free survival (PFS) varied significantly based on specific genomic alterations.

Patients with KRAS mutations showed better PFS (not reached) compared to those with EGFR or BRAF mutations, indicating that durvalumab may be less effective for certain driver genomic alterations, highlighting the need for further research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab consolidation in patients with unresectable stage III non-small cell lung cancer with driver genomic alterations. Riudavets, M., Auclin, E., Mosteiro, M., et al.[2022]

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 107 patients with stage III non-small cell lung cancer (NSCLC) treated with concurrent chemoradiotherapy (CCRT) and intensity-modulated radiotherapy (IMRT), the median progression-free survival (PFS) was 20.7 months, indicating effective treatment outcomes.

Factors associated with longer PFS included a favorable response to CCRT, a radiation dose of 62 Gy or more, and having stage IIIA NSCLC, while shorter durations of durvalumab treatment and lower radiation doses were linked to increased mortality risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy profiles of concurrent chemoradiotherapy with intensity-modulated radiotherapy followed by durvalumab in patients with unresectable stage III non-small cell lung cancer: A multicenter retrospective cohort study. Takeda, Y., Kusaba, Y., Tsukita, Y., 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]

References

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

De-escalating adjuvant durvalumab treatment duration in stage III non-small cell lung cancer. [2023]

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

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

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

Uptake of Adjuvant Durvalumab After Definitive Concurrent Chemoradiotherapy for Stage III Nonsmall-cell Lung Cancer. [2023]

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. 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]

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

Durvalumab consolidation in patients with unresectable stage III non-small cell lung cancer with driver genomic alterations. [2022]

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. Ireland pubmed.ncbi.nlm.nih.gov

The efficacy profiles of concurrent chemoradiotherapy with intensity-modulated radiotherapy followed by durvalumab in patients with unresectable stage III non-small cell lung cancer: A multicenter retrospective cohort study. [2022]

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

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