A French Real-life Study: EvaluatioN of durvALumab Utilization and Effectiveness for First Line Extensive Stage Small Cell Lung Cancer. — ARSENAL  

Small Cell Lung Carcinoma Clinical Trial

Official title: EvaluatioN of durvALumab Utilization and Effectiveness for First Line Extensive Stage Small Cell Lung Cancer. Prospective Cohort of Extensive Stage Small Cell Lung Cancer Patients Treated With Durvalumab Associated With Platinum-etoposide Chemotherapy

Status Recruiting

Clinical Trial Summary

Small cell lung cancer (SCLC), characterized by rapid proliferation, high growth fraction and early development of metastases, is the most aggressive form of lung cancer. In 2021, an estimated 2.3 million people around the world are diagnosed with lung cancer. In France, in 2018, with 46 363 new cases and 33 117 deaths, lung cancer represented the second most common cancer and the first cause of death from cancer. Among those, SCLC represented 10,8% of all new lung diagnosis, and about two thirds presented at the extensive stage (ES-SCLC).

Since last three decades, standard treatment in ES-SCLC is based on combination chemotherapy with a platinum agent and etoposide in first-line with or without concurrent radiation therapy. Then, the second-line of treatment is topotecan, with few results in terms of response rates and survival rate. However, the emergence of immune checkpoint inhibitors targeting the programmed cell death receptor-1 (PD-1)/PD-ligand 1 (PD-L1) pathway, having an important role in immune regulation became an alternative method in the management and care of disease. Indeed, recent studies have shown an overall survival (OS) benefit for patients with ES-SCLC treated in first line with a combination of platinum-etoposide and immune checkpoint inhibitors. Atezolizumab (Tecentriq®, Roche) and durvalumab (Imfinzi®, AstraZeneca), two anti-Programmed death-ligand 1 (PD-L1) antibodies, delivered positive phase III results, respectively through the Impower-133 and CASPIAN studies, and were granted European market authorisations.

Durvalumab is approved for use in combination with etoposide and either carboplatin or cisplatin for the first-line treatment of patients with ES-SCLC. On March 10, 2020 French health authorities allowed durvalumab utilization in this setting through a national "early access program" (Autorisation Temporaire d'Utilisation "de cohorte" - ATUc), thus preceding the European market authorization (August 28, 2020). Since 2020 October 1st, durvalumab is used as a post ATU treatment. Since 2020, French AURA treatment guidelines for SCLC have referenced durvalumab in combination with chemotherapy as a first-line treatment option for patients with ES-SCLC.

Whereas the safety and efficacy of the durvalumab have been evaluated in a clinical trial, data are required to further evaluate the use of durvalumab in real-life condition and in less selected population than in clinical trials.

Clinical Trial Description

Small cell lung cancer (SCLC), characterized by rapid proliferation, high growth fraction and early development of metastases, is the most aggressive form of lung cancer. SCLC is a relatively rare but really aggressive tumour accounting for 10-15% of all newly diagnosed lung cancer. In 2021, an estimated 2.3 million people around the world are diagnosed with lung cancer . In France, in 2018, with 46 363 new cases and 33 117 deaths, lung cancer represented the second most common cancer and the first cause of death from cancer. Among those, SCLC represented 10,8% of all new lung diagnosis, and about two thirds presented at the extensive stage (ES-SCLC).

Between 2010 and 2018, the incidence rate increased of 0,3 % per year in men. In contrast, from 1990 to 2018, the incidence increased more dramatically among women, with an increase of 5% in average per year. The 5-year survival rate for all people with all types of lung cancer is 21%. The 5-year survival rate is 17% and 24% for men and women, respectively. For SCLC, due to the rapid proliferation and high growth fraction associated to early development of metastases in the disease course (most commonly to the brain, liver, or bone), the 5-year survival rate is low at 10%. Therefore, SCLC is the most lethal lung cancer subtype. Most cases of SCLC develop in patients aged 60-80 years and the estimated overall death rate is 25,000-30,000 per year in United States. More than 90% of patients with SCLC are elderly and have heavy smoking histories.

SCLC is defined histologically as "a malignant epithelial tumour consisting of small cells with scant cytoplasm, ill-defined cell borders, finely granular nuclear chromatin, and absent or inconspicuous nucleoli", assessed by imaging techniques such as computerized tomography (CT), positron emission tomography (PET) and magnetic resonance imaging (MRI).

The Veterans' Administration Lung Study Group (VALG) staging system is usually used in the clinic routine to stage SCLC. Two categories represent SCLC, limited stage (LS) and extensive stage (ES). Limited-stage small-cell lung cancer (LS-SCLC) is defined as tumour confined to one hemithorax, with or without regional lymph-node involvement, which can be safely encompassed in a tolerable radiation field, corresponding at stage I to III of TNM system. ES-SCLC is defined as disease that cannot be safely encompassed in a tolerable radiation field, corresponding to stage IV of TNM system.

The management of SCLC is complicated by aggressiveness and substantial comorbidities, and impaired performance status. According to ESMO guidelines (2021), as well as in the French guidelines from Auvergne Rhone Alpes region, the standard management design of SCLC is described and outlined in Figure 1.

Since last three decades, standard treatment in ES-SCLC is based on combination chemotherapy with a platinum agent and etoposide in first-line with or without concurrent radiation therapy. Then, the second-line of treatment is topotecan, with few results in term of response rates and survival rate.

However, the emergence of immune checkpoint inhibitors targeting the programmed cell death receptor-1 (PD-1)/PD-ligand 1 (PD-L1) pathway, having an important role in immune regulation became an alternative method in the management and care of disease. Indeed, recent studies have shown an overall survival (OS) benefit for patients with ES-SCLC treated in first line with a combination of platinum-etoposide and immune checkpoint inhibitors. Atezolizumab (Tecentriq®, Roche) and durvalumab (Imfinzi®, AstraZeneca), two anti-Programmed death-ligand 1 (PD-L1) antibodies, delivered positive phase III results, respectively through the Impower-133 and CASPIAN studies, and were granted European market authorisations.

Durvalumab (Imfinzi®, AstraZeneca), a fully human monoclonal antibody against programmed cell death-ligand 1 (PD-L1), is approved for use in combination with etoposide and either carboplatin or cisplatin for the first-line treatment of patients with ES-SCLC. On March 10, 2020 French health authorities allowed durvalumab utilization in this setting through a national "early access program" (Autorisation Temporaire d'Utilisation "de cohorte" - ATUc), thus preceding the European market authorization (August 28, 2020). Since 2020 October 1st, durvalumab is used as a post ATU treatment.

Since 2020, French AURA treatment guidelines for SCLC have referenced durvalumab in combination with chemotherapy as one of the first-line treatment options for patients with ES-SCLC based on evidence from the CASPIAN phase III international randomized clinical trial, which demonstrated that adding durvalumab to chemotherapy significantly improved the median overall survival (mOS; hazard ratio: 0.73, 95% confidence interval (CI): 0.59-0.91) over chemotherapy alone.

Results from this CASPIAN study was recently updated with an assessment of 3-year overall survival. As of 2021 March, with a median follow-up 39.4 months, durvalumab plus chemotherapy continued to demonstrate a significant improvement OS versus chemotherapy alone (P = 0.0003). Authors concluded three times more patients were estimated to be alive at 3 years when treated with durvalumab plus chemotherapy versus chemotherapy, with the majority still receiving durvalumab at data cut-off, further establishing durvalumab plus chemotherapy as first-line standard of care for ES-SCLC.

To date, durvalumab has thus been available to first-line ES-SCLC patients and clinicians have the choice between atezolizumab + carboplatin-etoposide, durvalumab + carbo- or cisplatin-etoposide, and carbo- or cisplatin-etoposide alone.

Whereas the safety and efficacy of the durvalumab have been evaluated in clinical trial, data are required to further evaluate the use of durvalumab in real-life condition and in less selected population than in clinical trials, while it received EMA approval in 2020. Some studies with durvalumab were performed in real-life, but only for non-SCLC.

This observational uncontrolled prospective cohort study is conducted to complement evidence from the CASPIAN clinical trial and generate real-world evidence. There is indeed a need to describe durvalumab use in the clinical practice for the treatment of first-line ES-SCLC patients and broaden the CASPIAN results to real-life setting in France.

Therefore, the aim of this study is to describe of platinum-etoposide and durvalumab real-life utilization and effectiveness for first line ES-SCLC. ;

Related Conditions & MeSH terms

• Small Cell Lung Carcinoma

• NCT number: NCT05683977
• Study type: Observational
• Source: AstraZeneca
• Contact: AstraZeneca Clinical Study Information Center
• Phone: 1-877-240-9479
• Email: information.center@astrazeneca.com
• Status: Recruiting
• Start date: November 14, 2022
• Completion date: April 16, 2027