Multiple Therapies for Stage III Non-Small Cell Lung Cancer

(HORIZON 1 Trial)

Recruiting at 166 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

71 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests several treatments to evaluate their effectiveness and safety for individuals with a type of lung cancer that cannot be surgically removed. The study examines different medicines, such as alectinib (a targeted therapy), durvalumab (an immunotherapy), and entrectinib (a targeted therapy), for advanced-stage non-small cell lung cancer that has not spread to other parts of the body. Suitable candidates for this trial have lung cancer and have previously undergone specific chemotherapy combined with radiation, without cancer progression during that treatment. Individuals diagnosed with ALK-positive or ROS1-positive lung cancer who have not progressed to Stage IV may be eligible. As a Phase 3 trial, this study represents the final step before FDA approval, providing access to potentially groundbreaking treatments.

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.

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

Research has shown that alectinib is generally safe for patients with advanced ALK-positive non-small cell lung cancer (NSCLC). Patients tolerate it well, even those who have previously used crizotinib. Entrectinib is also considered safe, particularly for patients with ROS1-positive NSCLC. Studies indicate it works effectively and is tolerable, even for Japanese patients with advanced stages of the disease. Various studies have tested both alectinib and entrectinib, and patients usually handle them well, with most side effects being manageable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for Stage III Non-Small Cell Lung Cancer because they offer targeted approaches that differ from traditional chemotherapy. Alectinib and entrectinib are oral medications that specifically target genetic mutations, ALK and ROS1 respectively, which are not addressed by standard chemotherapy. Meanwhile, durvalumab is an immune checkpoint inhibitor that helps the immune system recognize and attack cancer cells, offering a different angle compared to traditional treatments. These innovations promise more personalized and potentially effective strategies for managing lung cancer.

What evidence suggests that this trial's treatments could be effective for Stage III NSCLC?

Research has shown that alectinib, which participants in this trial may receive in the ALK-positive cohort, works effectively for people with ALK-positive non-small cell lung cancer (NSCLC). In studies, it significantly improved survival rates and reduced the chance of cancer recurrence by 76%. Entrectinib, another treatment option in this trial for the ROS1-positive cohort, has proven effective for those with ROS1-positive NSCLC, with patients experiencing positive outcomes and tolerating the treatment well. Both treatments have succeeded in managing specific genetic types of lung cancer, offering hope for better disease management. ^{6 7 8 9 10}

Who Is on the Research Team?

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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 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]

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 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 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 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]

Citations

1. onclive.com onclive.com/view/adjuvant-alectinib-impresses-in-updated-alina-results-for-alk-nsclc

Adjuvant Alectinib Impresses in Updated ALINA Results ... Alectinib achieved a 4-year overall survival rate of 98.4% in resected, ALK-positive, early-stage NSCLC, surpassing chemotherapy outcomes. The ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12167269/

Cost-Effectiveness of Adjuvant Alectinib Versus ... In the phase III ALINA trial (NCT03456076), adjuvant alectinib significantly improved disease-free survival (DFS) compared with chemotherapy in ...

3. roche.com roche.com/media/releases/med-cor-2023-10-18

Roche's Alecensa reduces the risk of disease recurrence ... Roche's Alecensa reduces the risk of disease recurrence or death by an unprecedented 76% in people with ALK-positive early-stage non-small cell ...

4. annalsofoncology.org annalsofoncology.org/article/S0923-7534(25)04788-X/fulltext

final overall survival analysis of the phase III ALEX study Overall, 149 patients died: 76/152 (50.0%) in the alectinib arm and 73/151 (48.3%) in the crizotinib arm. Median OS was 81.1 months [95% CI 62.3 ...

5. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-approves-alectinib-adjuvant-treatment-alk-positive-non-small-cell-lung-cancer

FDA approves alectinib as adjuvant treatment for ALK- ... The major efficacy outcome measures were disease-free survival (DFS) in the subgroup of patients with stage II-IIIA NSCLC and DFS in the overall ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31706099/

Pooled overall survival and safety data from the pivotal ... alectinib has robust clinical activity and a manageable safety profile in patients with advanced, ALK+ NSCLC pretreated with crizotinib.

7. sciencedirect.com sciencedirect.com/science/article/pii/S1556086419302102

Updated Efficacy and Safety Data and Impact of the EML4 ... Alectinib continues to demonstrate superior investigator-assessed PFS versus crizotinib in untreated ALK-positive NSCLC, irrespective of EML4-ALK variant.

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2019.37.15_suppl.9092

Final PFS analysis and safety data from the phase III J- ... In the final PFS analysis, ALC continued to demonstrate the superiority in IRF-PFS in ALK-inhibitor naïve ALK+ NSCLC regardless of baseline CNS metastases.

9. nejm.org nejm.org/doi/abs/10.1056/NEJMoa2310532

Alectinib in Resected ALK-Positive Non–Small-Cell Lung ... Data on the efficacy and safety of adjuvant alectinib as compared with chemotherapy in patients with resected ALK-positive NSCLC are lacking.

10. clinicaltrials.gov clinicaltrials.gov/study/NCT05015010

Alectinib in Neo-adjuvant Treatment of Stage III NSCLC ... In this trial we want to test in ALK positive stage III locally advanced NSCLC patients, the efficacy of Alectinib to induce tumor shrinkage when administered ...