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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether combining standard lung cancer treatment with additional drugs can reduce the number of cancer cells in the blood for those with non-small cell lung cancer. Participants will receive a mix of treatments, including chemotherapy and immunotherapy drugs like durvalumab and tremelimumab, to determine if this combination is more effective. It suits individuals who have completed initial chemotherapy and radiation for locally advanced or returning lung cancer and are currently receiving durvalumab. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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.

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

Research has shown that the treatments tested in this clinical trial have proven safe in earlier studies.

Durvalumab, an immunotherapy drug, has a strong safety record. Studies have found it well-tolerated by patients with non-small cell lung cancer (NSCLC), with most side effects, such as tiredness and cough, being common and manageable.

Carboplatin combined with pemetrexed is also considered safe for treating NSCLC. Research indicates these drugs are generally well-tolerated, though some patients may experience low blood cell counts or fatigue.

For those with squamous cell carcinoma, carboplatin combined with paclitaxel is used. This combination is a standard treatment for NSCLC and has shown to be safe. Common side effects can include hair loss and numbness in fingers or toes, but these are often manageable.

Overall, the treatments in this trial have been extensively studied, and their safety is well-understood. They are approved for use in other settings, which may provide reassurance about their safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for non-small cell lung cancer because they combine chemoradiotherapy with immunotherapy, using drugs like durvalumab and tremelimumab. Unlike traditional treatments that usually focus on chemotherapy alone, this approach harnesses the immune system to better target and destroy cancer cells. Durvalumab, in particular, acts as a checkpoint inhibitor, which helps the immune system recognize and attack cancer more effectively. Additionally, the study includes innovative monitoring techniques, using ctDNA to tailor treatment plans based on the presence or absence of minimal residual disease (MRD). This personalized approach aims to improve outcomes by adapting treatment strategies to each patient’s unique cancer profile.

What evidence suggests that this trial's treatments could be effective for non-small cell lung cancer?

Research has shown that durvalumab, which participants in this trial may receive, effectively treats non-small cell lung cancer (NSCLC). One study found that patients with locally advanced NSCLC who received durvalumab after their initial treatment lived 11 months longer without their cancer worsening, indicating a clear benefit in delaying disease progression. Additionally, the combination of carboplatin and pemetrexed (or paclitaxel for some patients), part of the treatment regimen for certain participants in this trial, has effectively treated NSCLC. For instance, one study reported a 35.8% response rate with carboplatin and pemetrexed together. Tremelimumab, another treatment option in this trial, is thought to help the immune system fight cancer, although specific data on its effectiveness in this combination is limited. Overall, these treatments have shown promise in managing NSCLC. ^{1 4 6 7 8}

Who Is on the Research Team?

Maximilian Diehn, MD

Principal Investigator

Stanford Universiy

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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 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]

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 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 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]

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]

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 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 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 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 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/11396237/

Multi-center study of two dose levels of paclitaxel with ... In this multicenter study, the combination of paclitaxel and carboplatin produced a moderate RR of 23.8% in stages IIIA/B & IV NSCLC.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT01413750

Carboplatin and Paclitaxel With or Without Vorinostat in ... It is not yet known whether giving carboplatin and paclitaxel together is more effective with or without vorinostat in treating non-small cell lung cancer.

3. cancernetwork.com cancernetwork.com/view/study-confirms-value-paclitaxel-plus-paraplatin-nsclc

Study Confirms Value of Paclitaxel Plus Paraplatin in NSCLC In the SWOG 9509 study, paclitaxel plus carboplatin produced a 1-year survival rate of 38%, and vinorelbine plus cisplatin yielded a 1-year survival rate of 36% ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0169500299000483

Phase I/II dose finding study of paclitaxel and carboplatin in ... Results: The MTD for the combination has been reached at 235 mg/m2 of paclitaxel and at 375 mg/m2 of carboplatin. The combination shows a good safety profile ...

5. cgtlive.com cgtlive.com/view/emerging-role-paclitaxel-plus-carboplatin-nonsmall-cell-lung-cancer

The Emerging Role of Paclitaxel Plus Carboplatin in Non– ... Paclitaxel plus carboplatin is currently the most widely used combination for advanced non–small-cell lung cancer in the United States. The efficacy results ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5865694/

The efficacy and safety of paclitaxel and carboplatin with ... Compared with PC alone, the combination of PC with Bev could prolong PFS, OS and RR for patients with advanced non-squamous NSCLC.

7. tlcr.amegroups.org tlcr.amegroups.org/article/view/73990/html

Safety and feasibility of carboplatin and paclitaxel in ... Safety and feasibility of carboplatin and paclitaxel in combination with nintedanib for non-small cell lung cancer patients with idiopathic pulmonary fibrosis: ...

8. jto.org jto.org/article/S1556-0864(15)31590-2/fulltext

Weekly Paclitaxel Combined with Monthly Carboplatin in ... We designed this phase II trial to evaluate the efficacy and safety of weekly paclitaxel in combination with monthly carboplatin as first-line treatment in ...