Multiple Therapies for Stage III Non-Small Cell Lung Cancer
Recruiting in Palo Alto (17 mi)
+211 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
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
Pivotal Trial (Near Approval)
Prior Safety Data
Breakthrough Therapy
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.
12345Is 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.
46789How 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.
510111213Eligibility 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.
+14 more
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.
+43 more
Trial 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
Participant Groups
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.
4Treatment groups
Experimental Treatment
Active Control
Group I: Cohort A2: ROS 1-positive (entrectinib arm)Experimental Treatment1 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 Treatment1 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 Control1 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 Control1 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Virginia Cancer Specialists (Fairfax) - USORFairfax, VA
The University of Texas MD Anderson Cancer CenterHouston, TX
Mount Sinai Medical Center; Comprehensive Cancer CenterMiami Beach, FL
University of South Alabama; Mitchell Cancer InstituteMobile, AL
More Trial Locations
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Who Is Running the Clinical Trial?
Hoffmann-La RocheLead Sponsor
References
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]The 5 year survival rate for patients with locally advanced non-small-cell lung cancer (NSCLC) not amenable for definitive resection with historical standard-of-care concurrent chemoradiotherapy (cCRT) ranges from 15% to 32%. cCRT primes anti-tumor immunity and also upregulates programmed death ligand-1 (PD-L1), providing a rationale for combining an immune checkpoint inhibitor with cCRT to improve outcomes. In the PACIFIC trial, consolidation therapy with the PD-L1 inhibitor durvalumab improved progression-free survival (PFS) and overall survival (OS) vs. placebo in patients with stage III NSCLC who did not have disease progression after cCRT. CheckMate73L (NCT04026412), a randomized phase 3 study, evaluates the efficacy of nivolumab plus cCRT followed by nivolumab with or without ipilimumab vs. cCRT followed by durvalumab for untreated, stage III NSCLC.
Durvalumab Promising for NSCLC. [2019]The PD-L1 inhibitor durvalumab increases progression-free survival and objective response rate in patients with inoperable and locally advanced stage III non-small cell lung cancer, according to interim results of a phase III trial. The benefit was great enough that the drug could become the standard of care in the United States for these patients.
Pembrolizumab plus chemotherapy for first-line treatment of metastatic nonsquamous non-small-cell lung cancer: a network meta-analysis. [2022]A systematic review and network meta-analysis were conducted to evaluate the efficacy of pembrolizumab + pemetrexed + platinum relative to other regimens in metastatic nonsquamous non-small-cell lung cancer (NSq-NSCLC).
Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study. [2022]Immune checkpoint inhibitors are a new standard of care for patients with advanced non-small-cell lung cancer (NSCLC) without EGFR tyrosine kinase or anaplastic lymphoma kinase (ALK) genetic aberrations (EGFR-/ALK-), but clinical benefit in patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) has not been shown. We assessed the effect of durvalumab (anti-PD-L1) treatment in three cohorts of patients with NSCLC defined by EGFR/ALK status and tumour expression of PD-L1.
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]The treatment paradigm of non-small-cell lung cancer (NSCLC) has rapidly changed in recent years following the introduction of immune-checkpoint inhibition (ICI). Pre-clinically, both chemotherapy and radiotherapy modulate the tumour microenvironment, providing the rationale for clinical trials evaluating their role in combination with immunotherapy. Standard-of-care treatment for patients with unresectable stage III disease is concurrent chemoradiotherapy (cCRT); however, only recently, the combination with ICI has been explored. The Phase 3 PACIFIC study randomised 713 patients with confirmed locally advanced, unresectable, stage III NSCLC, whose disease has not progressed following cCRT, to either the anti-programmed death-ligand 1 (PD-L1) agent durvalumab (Imfinzi®▼, AstraZeneca UK Limited) or placebo. Patients with a PD-L1 status ≥1% treated with durvalumab had a significantly longer median progression-free survival compared with placebo (17.2 vs. 5.6 months, respectively; HR: 0.51; 95% CI: 0.41-0.63), prolonged median overall survival (OS) (NR vs. 28.7 months, respectively; HR: 0.68; 99.73% CI: 0.47-0.997; P = 0.0025) and long-term clinical benefit (3-year OS HR: 0.69; 95% CI: 0.55-0.86). Grade 3 or 4 toxicity was marginally greater in the durvalumab cohort versus placebo (30.5% vs. 26.1%). Based on these results, durvalumab has been licensed in this setting, and further clinical trials are exploring the use of ICI in unresectable stage III NSCLC.
Mocetinostat in Combination With Durvalumab for Patients With Advanced NSCLC: Results From a Phase I/II Study. [2023]Histone deacetylase (HDAC) inhibitors have potential to augment the effectiveness of immune checkpoint inhibitors and overcome treatment resistance. This dose-escalation/expansion study (NCT02805660) investigated mocetinostat (class I/IV HDAC inhibitor) plus durvalumab in patients with advanced non-small cell lung cancer (NSCLC) across cohorts defined by tumor programmed death-ligand 1 (PD-L1) expression and prior experience with anti-programmed cell death protein-1 (anti-PD-1) or anti-PD-L1 regimens.
Real-World Incidence of Pneumonitis in Patients Receiving Durvalumab. [2022]Durvalumab is a programmed cell death ligand 1 (PD-L1) inhibitor indicated for stage III, unresectable non-small cell lung cancer (NSCLC) consolidation therapy following concurrent platinum-based chemoradiation based on results of the PACIFIC trial. Safety data of durvalumab demonstrates an increased risk of immune-related adverse effects (irAEs), most notably pneumonitis. Pneumonitis is a serious and potentially fatal complication of immunotherapy. It is important to investigate the incidence of pneumonitis in clinical practice to evaluate the generalizability of published data. The objective of this study is to assess and characterize real-world incidence of pneumonitis in patients with NSCLC receiving durvalumab.
Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. [2022]The prominent immune checkpoint molecule, programmed cell death ligand-1 (PD-L1), is the object of increasing attention. Here, we report a meta-analysis investigating the safety and efficacy of durvalumab (MEDI4736), an inhibitor of PD-L1, in various solid tumors.
DUART: durvalumab after radiotherapy in patients with unresectable, stage III NSCLC who are ineligible for chemotherapy. [2022]Consolidation durvalumab is standard of care in patients with unresectable, stage III non-small-cell lung cancer (NSCLC) without disease progression following chemoradiotherapy (the 'PACIFIC regimen'). However, many patients with poor performance status, older age or comorbidities may be ineligible for chemotherapy due to expected high toxicity. These patients typically receive radiotherapy alone, with poor survival outcomes. Based on the PACIFIC trial data, and the strong biological rationale for combining radiotherapy with anti-programmed cell death ligand-1 therapy, durvalumab following radiotherapy could provide additional survival benefit versus radiotherapy alone. Here, we describe the DUART trial, a Phase II, open-label, single-arm study assessing the safety and tolerability of durvalumab following radiotherapy in patients with unresectable, stage III NSCLC who are ineligible for chemotherapy (ClinicalTrials.gov Identifier: NCT04249362).
Open issues in the therapeutic management of unresectable stage III NSCLC in the immunotherapy era. [2022]Treatment of stage III non-small cell lung cancer (NSCLC) has traditionally been controversial and challenging: multidisciplinary approach is mandatory and defining resectability is a critical issue; furthermore, patients are often frail due to age or comorbidities. After PACIFIC trial publication, a new therapeutic path has been defined for patients with unresectable NSCLC, with a prominent prognostic advantage. A trimodality treatment, with chemo-radiotherapy followed by maintenance durvalumab is now the standard of care, recommended by international guidelines. However, despite an impressive activity, the use of consolidative immunotherapy after concurrent chemoradiotherapy is highly debated in some clinically-relevant situations, including patients harboring EGFR mutations, older and/or frail patients not suitable for combined treatment, PD-L1 tumor expression. Here we report an expert virtual Italian meeting summary, where six medical oncologists and six radiation oncologists discussed all these aspects trying to underline the critical aspects and to find the possible clinical solutions.
Role of immunotherapy in stage III nonsmall cell lung cancer. [2020]Despite aggressive treatment based on definitive chemoradiotherapy, 5-year overall survival in unresectable stage III nonsmall cell lung cancer remains poor (15-20%). The novel immunotherapy based on immune checkpoint inhibitors (ICIs) presents as the therapeutic 'Holly Grail' in lung cancer treatment.
The Evolving Role of Immunotherapy in Stage III Non-Small Cell Lung Cancer. [2022]The management of Stage III non-small cell lung cancer (NSCLC) is complex and requires multidisciplinary input. Since the publication of the PACIFIC trial (consolidative durvalumab post concurrent chemotherapy and radiation in Stage III disease) which showed improved survival for patients in the immunotherapy arm, there has been much interest in the use of immunotherapy in the Stage III setting. In this review, we explore the biologic and clinical rationale for the use of immunotherapy in Stage III NSCLC, present previously published and upcoming data in the neoadjuvant, adjuvant, and concurrent realms of Stage III management, and discuss unanswered questions and challenges moving forward.
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]For patients with resectable, early-stage non-small-cell lung cancer (NSCLC), surgery is the primary treatment; however, 5-year survival rates remain poor. Postoperative adjuvant platinum-doublet chemotherapy is associated with a statistically significant but modest improvement in survival of ∼5% at 5 years and is widely accepted as standard of care in patients with resectable, Stage II-III NSCLC. Neoadjuvant chemotherapy has been associated with similar improvements in overall survival to adjuvant therapy in this setting. Durvalumab, a high-affinity PD-L1 inhibitor, has become the standard of care for patients with unresectable, Stage III NSCLC following chemoradiotherapy based on improved progression-free and overall survival in the phase III PACIFIC trial. AEGEAN is a phase III, double-blind, placebo-controlled, international study that will assess pathological and clinical outcomes of durvalumab plus chemotherapy prior to surgery, followed by durvalumab monotherapy after surgery in adults with resectable, Stage II-III NSCLC. Approximately 800 patients will be randomized (1:1) to receive durvalumab or placebo every 3 weeks (q3w) alongside platinum-based chemotherapy (≤4 cycles) prior to surgery, followed by durvalumab or placebo monotherapy q4w, for an additional 12 cycles post surgery, stratified by disease stage (IASLC 8th Edition, Stage II vs. Stage III) and PD-L1 tumor cell expression levels (