Multiple Therapies for Stage III Non-Small Cell Lung Cancer

Recruiting at 217 trial locations

Overseen By Reference Study ID Number: BO42777 https://forpatients.roche.com/

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Hoffmann-La Roche

Must not be taking: Antibiotics, ALK inhibitors, ROS1 inhibitors, others

Disqualifiers: Stage IV disease, Liver disease, HIV, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 1-3 years

121 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing different treatments to see how well they work and how safe they are. It focuses on patients with advanced lung cancer that cannot be removed by surgery and have specific biological markers. The goal is to find out if these treatments can stop the cancer from growing or spreading and improve patients' health.

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, it does exclude participants who are on certain treatments like systemic immunosuppressive medications or concurrent cancer therapies, so it's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Durvalumab (Imfinzi) for treating stage III non-small cell lung cancer?

Research shows that Durvalumab, when used after chemoradiotherapy, significantly improves progression-free survival and overall survival in patients with stage III non-small cell lung cancer compared to a placebo. This suggests that Durvalumab can be an effective treatment option for this condition. ^{1 2 3 4 5}

Is the treatment generally safe for humans?

Durvalumab, one of the treatments being considered, has been shown to increase the risk of immune-related side effects, particularly pneumonitis (inflammation of the lungs), which can be serious and potentially life-threatening. Safety data from various studies indicate that while durvalumab is used in treating certain cancers, it is important to monitor for these side effects. ^{4 6 7 8 9}

How is the drug combination of Alectinib, Durvalumab, Entrectinib, and Pralsetinib unique for treating Stage III non-small cell lung cancer?

This drug combination is unique because it includes multiple targeted therapies and immunotherapy agents, such as Durvalumab, which has shown improved survival in patients with unresectable Stage III non-small cell lung cancer when used after chemoradiotherapy. The combination of these drugs may offer a novel approach by targeting different pathways involved in cancer growth and immune evasion. ^{5 10 11 12 13}

Research Team

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Eligibility Criteria

This trial is for adults with Stage III Non-Small Cell Lung Cancer (NSCLC) who can swallow pills, have had prior chemo and radiotherapy without disease progression, and are expected to live at least 12 weeks. They must not be pregnant or planning pregnancy, agree to use contraception, and have no history of certain bone disorders or severe allergies.

Inclusion Criteria

My cancer has a confirmed ALK fusion from an approved test.

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

My cancer did not worsen during or after platinum-based chemo.

Exclusion Criteria

I have moderate to severe numbness, tingling, or pain in my hands or feet.

I have severe side effects from previous treatments that haven't improved.

I have a family or personal history of bone disorders.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive entrectinib 600 mg orally once daily or durvalumab 1500 mg IV every 4 weeks, depending on cohort, until completion of treatment period or other specified conditions

1-3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Alectinib
• Durvalumab
• Entrectinib
• Pralsetinib

Trial Overview The study tests the effectiveness and safety of Entrectinib, Durvalumab, Alectinib in NSCLC patients with specific biomarkers. It requires a PET/CT scan for staging and uses electronic patient-reported outcomes for monitoring.

Participant Groups

Group I: Cohort A2: ROS 1-positive (entrectinib arm) Experimental Treatment 1 Intervention

Participants will receive entrectinib 600 mg orally once daily until completion of treatment period (3 years), or until disease progression, unacceptable toxicity, patient or physician decision to discontinue, or death, whichever occurs first. Cohort A2 has been closed to enrollment.

Group II: Cohort A1: ALK-Positive (alectinib arm) Experimental Treatment 1 Intervention

Participants will receive alectinib 600 mg orally twice daily until completion of treatment period (3 years), or until disease progression, unacceptable toxicity, patient or physician decision to discontinue, or death, whichever occurs first

Group III: Cohort A2: ROS 1-positive (durvalumab arm) Active Control 1 Intervention

Participants will receive 1500 mg of IV durvalumab every 4 weeks until completion of treatment period (1 year) or until disease progression, unacceptable toxicity, patient or physician decision to discontinue, or death, whichever occurs first Cohort A2 has been closed to enrollment.

Group IV: Cohort A1: ALK-positive (durvalumab arm) Active Control 1 Intervention

Participants will receive 1500 mg of intravenous (IV) durvalumab every 4 weeks until completion of treatment period (1 year) or until disease progression, unacceptable toxicity, patient or physician decision to discontinue, or death, whichever occurs first

Alectinib is already approved in United States, European Union for the following indications:

Approved in United States as Alecensa for:

• Metastatic ALK-positive non-small cell lung cancer (NSCLC)
• Adjuvant treatment following tumor resection in patients with ALK-positive NSCLC

Approved in European Union as Alecensa for:

• Metastatic ALK-positive non-small cell lung cancer (NSCLC)
• Adjuvant treatment following tumor resection in patients with ALK-positive NSCLC

Who Is Running the Clinical Trial?

Hoffmann-La Roche

Lead Sponsor

Trials

2,482

Recruited

1,107,000+

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Avastin, Herceptin, Rituxan, Accu-Chek

Dr. Levi Garraway

Hoffmann-La Roche

Chief Medical Officer since 2019

MD from the University of Basel

Dr. Thomas Schinecker

Hoffmann-La Roche

Chief Executive Officer since 2023

PhD in Molecular Biology from New York University

Findings from Research

The CheckMate73L trial is investigating the effectiveness of combining nivolumab with concurrent chemoradiotherapy (cCRT) followed by additional nivolumab with or without ipilimumab, compared to the standard treatment of cCRT followed by durvalumab, in patients with untreated stage III non-small-cell lung cancer (NSCLC).

The primary goals of the study are to evaluate progression-free survival (PFS) and overall survival (OS), with results expected to provide insights into whether the combination therapy offers better outcomes than the current standard of care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CheckMate 73L: A Phase 3 Study Comparing Nivolumab Plus Concurrent Chemoradiotherapy Followed by Nivolumab With or Without Ipilimumab Versus Concurrent Chemoradiotherapy Followed by Durvalumab for Previously Untreated, Locally Advanced Stage III Non-Small-Cell Lung Cancer. De Ruysscher, D., Ramalingam, S., Urbanic, J., et al.[2022]

Durvalumab, a PD-L1 inhibitor, has shown promising results in increasing progression-free survival and objective response rates in patients with inoperable and locally advanced stage III non-small cell lung cancer, based on interim results from a phase III trial.

The significant benefits observed suggest that durvalumab could potentially become the standard treatment for these patients in the United States.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab Promising for NSCLC. [2019]

In a systematic review and network meta-analysis of first-line treatments for metastatic nonsquamous non-small-cell lung cancer (NSq-NSCLC), the combination of pembrolizumab, pemetrexed, and platinum showed a statistically significant improvement in overall survival compared to various other regimens, with hazard ratios ranging from 0.42 to 0.62.

This combination therapy had a 95.6% probability of being the most effective treatment option for overall survival in patients without known targetable mutations, indicating its strong potential as a first-line treatment for this type of lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus chemotherapy for first-line treatment of metastatic nonsquamous non-small-cell lung cancer: a network meta-analysis. Frederickson, AM., Arndorfer, S., Zhang, I., et al.[2022]

In a phase 2 trial involving 444 patients with advanced non-small-cell lung cancer (NSCLC), durvalumab (an anti-PD-L1 treatment) showed a response rate of 30.9% in patients with ≥90% PD-L1 expression, indicating its potential efficacy in heavily pretreated cases.

The safety profile of durvalumab was consistent with other similar treatments, with 9% of patients experiencing grade 3 or 4 treatment-related adverse events, suggesting it is manageable and generally safe for use in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study. Garassino, MC., Cho, BC., Kim, JH., et al.[2022]

In the Phase 3 PACIFIC study involving 713 patients with unresectable stage III non-small-cell lung cancer (NSCLC), the anti-PD-L1 agent durvalumab significantly improved median progression-free survival (17.2 months vs. 5.6 months for placebo) and overall survival (not reached vs. 28.7 months for placebo).

While durvalumab showed a slight increase in grade 3 or 4 toxicity (30.5% vs. 26.1% for placebo), its efficacy in prolonging survival justifies its use, leading to its licensing for this treatment setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beyond chemoradiotherapy: improving treatment outcomes for patients with stage III unresectable non-small-cell lung cancer through immuno-oncology and durvalumab (Imfinzi®▼, AstraZeneca UK Limited). Patel, P., Alrifai, D., McDonald, F., et al.[2023]

The combination of mocetinostat (70 mg TIW) and durvalumab was generally well tolerated in patients with advanced non-small cell lung cancer (NSCLC), with an objective response rate (ORR) of 11.5% across all phase II cohorts, indicating some effectiveness in this challenging population.

Notably, the treatment showed a higher ORR of 23.1% in patients whose disease was refractory to prior checkpoint inhibitor therapies, suggesting that mocetinostat may help overcome resistance to existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mocetinostat in Combination With Durvalumab for Patients With Advanced NSCLC: Results From a Phase I/II Study. Johnson, ML., Strauss, J., Patel, MR., et al.[2023]

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]

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]

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]

The PACIFIC trial has established a new standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC), recommending a trimodality treatment of chemo-radiotherapy followed by maintenance with durvalumab, which shows a significant prognostic advantage.

Despite the effectiveness of consolidative immunotherapy, its use remains controversial for certain patient groups, such as those with EGFR mutations, older or frail patients, and those with varying levels of PD-L1 tumor expression, highlighting the need for tailored treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open issues in the therapeutic management of unresectable stage III NSCLC in the immunotherapy era. Catania, C., Piperno, G., Russo, A., et al.[2022]

Immunotherapy using immune checkpoint inhibitors (ICIs) shows promise in improving survival rates for patients with unresectable stage III nonsmall cell lung cancer (NSCLC), which currently has a low 5-year survival rate of 15-20%.

The phase III PACIFIC trial demonstrated that the anti-PDL-1 antibody durvalumab significantly improves survival in patients with locally advanced NSCLC who have responded to concurrent chemoradiotherapy, suggesting it may become a standard treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of immunotherapy in stage III nonsmall cell lung cancer. Wrona, A.[2020]

The PACIFIC trial demonstrated that consolidative durvalumab, an immunotherapy, significantly improves survival rates in patients with Stage III non-small cell lung cancer (NSCLC) after concurrent chemotherapy and radiation.

This review highlights the growing interest and rationale for incorporating immunotherapy into various treatment phases (neoadjuvant, adjuvant, and concurrent) for Stage III NSCLC, while also addressing ongoing challenges and unanswered questions in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Evolving Role of Immunotherapy in Stage III Non-Small Cell Lung Cancer. Perdrizet, K., Cheema, PK.[2022]

The AEGEAN trial is a phase III study involving approximately 800 patients with resectable, early-stage non-small-cell lung cancer (NSCLC) that aims to evaluate the effectiveness of durvalumab combined with chemotherapy before surgery and as a monotherapy after surgery.

This study will assess key outcomes such as pathological complete response and event-free survival, potentially improving treatment strategies for patients with Stage II-III NSCLC, where current survival rates remain low despite standard postoperative chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design and Rationale for a Phase III, Double-Blind, Placebo-Controlled Study of Neoadjuvant Durvalumab + Chemotherapy Followed by Adjuvant Durvalumab for the Treatment of Patients With Resectable Stages II and III non-small-cell Lung Cancer: The AEGEAN Trial. Heymach, JV., Mitsudomi, T., Harpole, D., et al.[2022]

References

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

CheckMate 73L: A Phase 3 Study Comparing Nivolumab Plus Concurrent Chemoradiotherapy Followed by Nivolumab With or Without Ipilimumab Versus Concurrent Chemoradiotherapy Followed by Durvalumab for Previously Untreated, Locally Advanced Stage III Non-Small-Cell Lung Cancer. [2022]

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

Durvalumab Promising for NSCLC. [2019]

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

Pembrolizumab plus chemotherapy for first-line treatment of metastatic nonsquamous non-small-cell lung cancer: a network meta-analysis. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study. [2022]

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

Beyond chemoradiotherapy: improving treatment outcomes for patients with stage III unresectable non-small-cell lung cancer through immuno-oncology and durvalumab (Imfinzi®▼, AstraZeneca UK Limited). [2023]

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

Mocetinostat in Combination With Durvalumab for Patients With Advanced NSCLC: Results From a Phase I/II Study. [2023]

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

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

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

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

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

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

10. Netherlands pubmed.ncbi.nlm.nih.gov

Open issues in the therapeutic management of unresectable stage III NSCLC in the immunotherapy era. [2022]

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

Role of immunotherapy in stage III nonsmall cell lung cancer. [2020]

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

The Evolving Role of Immunotherapy in Stage III Non-Small Cell Lung Cancer. [2022]

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

Design and Rationale for a Phase III, Double-Blind, Placebo-Controlled Study of Neoadjuvant Durvalumab + Chemotherapy Followed by Adjuvant Durvalumab for the Treatment of Patients With Resectable Stages II and III non-small-cell Lung Cancer: The AEGEAN Trial. [2022]