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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Small Cell Lung Carcinoma

Intervention / Treatment
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* Drug: durvalumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients (at least 18 years of age at time of treatment decision), Patients with histologically or cytologically proven SCLC and extensive disease according to the Veterans Administration Lung Study Group (VALSG) classification or TNM staging (Brierley et al, 2017) before durvalumab + platinum-etoposide treatment*, Patients newly treated in first line with durvalumab + platinum-etoposide**, Patients informed and not opposed to participating in the study. Exclusion Criteria: Patients with contraindications to receiving durvalumab + platinum-etoposide, Patients participating in another interventional clinical trial for first line ES-SCLC.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: durvalumab|Visits will be completed at W0 (durvalumab in combination with chemotherapy initiation) and at regular visits approximately every 6 weeks during the induction period (durvalumab + PE) (W6 and W12), then every two months during the maintenance period (durvalumab alone) for the first year and every three months up to the end of follow-up or the final visit at M36.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The time to first line treatment discontinuation (TTD). | For patients who start durvalumab at a later cycle than first cycle PE, the index date will be the first infusion of PE. If the treatment is stopped during the first phase of 4 to 6 cycles (induction) with a new re- start of durvalumab and PE, the treatment will be considered as temporary stop. If the treatment is stopped during the durvalumab maintenance with a re-start of durvalumab in monotherapy, the treatment will be also considered as temporary stop. Durvalumab will be considered definitely discontinued when the maintenance phase with durvalumab in monotherapy is stopped and results in a new administration of PE (+/-durvalumab) (subsequent treatment line). For patients still receiving durvalumab at the end of follow-up or when they are lost to follow-up, TTD will be right-censored at the last recorded day of ongoing durvalumab treatment. | TTD is defined as the time from the index date to the date of last durvalumab infusion (+3 weeks during induction period and +4 weeks during maintenance period) or date of death (up to 36 months)). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Real-world Overall Survival (rwOS) | rwOS is defined as the time from index date (date of first infusion of durvalumab and/ or platinum-etoposide) to date of death due to any cause. rwOS will be censored on the last date patient is known to be alive. rwOS rate at 1, 2 and 3 years (rwOS1y, rwOS2y, rwOS3y) and median real-world overall survival (mrwOS) will be assessed. | rwOS rate at 1, 2 and 3 years (rwOS1y, rwOS2y, rwOS3y) | 
| Real world Progression Free Survival (rwPFS) | rwPFS is defined as the time from index date (date of first infusion of durvalumab and/ or platinum-etoposide) to the date of disease progression as assessed by physicians or the date of death, whichever occurs first. rwPFS will be censored on the date of last follow-up. The rwPFS date will be based on the investigator's judgement. The real-world progression may be based on radiological evaluation or clinical judgement, or other measure to compensate absence of RECIST criteria. rwPFS rate at 6, 12, 18, 24 and 36 months (rwPFS6m, rwPFS12m, rwPF18m, rwPFS24m, rwPFS36m) and median rwPFS (mrwPFS) will be assessed. | rwPFS rate at 6, 12, 18, 24 and 36 months (rwPFS6m, rwPFS12m, rwPF18m, rwPFS24m, rwPFS36m) up to 36 months. | 
| Patient individual best response | The tumour response will be assessed by investigator as Complete response (CR), Partial response (PR), Stable disease (SD), Progressive disease (PD). The patient individual best response is defined as the best response recorded from the start of treatment until disease progression. The proportion of patients with a CR as best response, with a PR as best response, with SD as best response and with PD as best response will be assessed. | From the start of treatment until disease progression (up to 36 months).. | 
| Overall response rate (ORR) | ORR is defined as proportion of patients with at least one complete response (CR) or partial response (PR) at least one visit (Paz Ares et al, 2019). | From the start of treatment until disease progression (up to 36 months). | 
| Disease control rate (DCR) | DCR is defined as the proportion of patients with at least one complete response (CR), partial response (PR) or stable disease. | At the end of follow-up (up to 36 months) | 
| Time to second real-world progression (rwPFS2) | rwPFS2 is defined as the time from index date (date of first infusion of durvalumab and/ or platinum-etoposide) to the second record of disease progression determined by physicians' assessment, or death. rwPFS2 will be right-censored at the date of last follow-up. | rwPFS2 (up to 36 months) | 
| Sociodemographics characteristics at durvalumab + platinum-etoposide initiation | Age | At baseline | 
| Describe patient history prior to durvalumab initiation | Proportion of patients with previous history of cancer, Proportion of patients with history of paraneoplastic syndromes, Proportion of patients with history of auto-immune disease (including past, stabilized or active disease, disease duration), Proportion of patient treated with antibiotics, corticosteroids or other immunosuppressive therapy in the last 4 weeks before treatment initiation. Treatment history at durvalumab + platinum-etoposide initiation will be described in terms of: Proportion of patients with previous SCLC anti-cancer therapy (for limited and extensive stage), Proportion of patients with previous auto-immune disease associated treatment, Proportion of patients with previous non cancer therapies of interest (immunosuppressive therapy, nephrotoxic and anti-inflammatory drugs, antibiotherapy, corticosteroid therapy, supportive treatments). | Before durvalumab initiation | 
| Describe the safety profile of durvalumab + chemotherapy (PE) (treatment-related AE). | Safety profile of durvalumab + platinum-etoposide will be described in terms of: Incidence rate of grade ≥3 durvalumab -related according to Common Terminology Criteria for Adverse Events (CTCAE), Incidence rate of durvalumab -related immune-related AEs (imAE), Incidence rate of SAEs, AESIs, AEs resulting in treatment modification, Incidence rate of AEs resulting in treatment discontinuation, | At the end of follow-up (up to 36 months). | 
| Sociodemographics characteristics at durvalumab + platinum-etoposide initiation | Gender | At baseline | 
| Sociodemographics characteristics at durvalumab + platinum-etoposide initiation | BMI | At baseline | 
| Sociodemographics characteristics at durvalumab + platinum-etoposide initiation | Smoking status | At baseline | 
| Clinical characteristics at durvalumab + platinum-etoposide initiation | Duration between initial SCLC diagnosis and ES-SCLC for patients with first diagnosis at limited stage, Duration between initial ES-SCLC diagnosis and treatment initiation, | At baseline | 
| Clinical characteristics at durvalumab + platinum-etoposide initiation | - Disease stage at tumour diagnosis (limited or extensive stage; number of metastatic sites) and at baseline, | At baseline | 
| Clinical characteristics at durvalumab + platinum-etoposide initiation | - Actual number and localization of metastases at baseline including brain metastases (symptomatic or asymptomatic, treated or not), bone metastases (extension), and liver metastases, | At baseline | 
| Clinical characteristics at durvalumab + platinum-etoposide initiation | - Performance status at baseline (before durvalumab initiation), | At baseline | 
| Clinical characteristics at durvalumab + platinum-etoposide initiation | Comorbidities. | At baseline | 
| Describe patient history prior to durvalumab initiation | Time from discontinuation of the last treatment received for limited stage to start of first treatment for extensive stage | Before durvalumab discontinuation | 
| Safety profile of durvalumab + chemotherapy (PE) (treatment-related AE). | - Description of concomitant treatments including nephrotoxic and steroids-immunosuppressive drugs used to manage durvalumab related adverse events. | At the end of follow-up (up to 36 months). |