Clinical trial NCT05683977: A French Real-life Study: EvaluatioN of durvALumab Utilization and Effectiveness for First Line Extensive Stage Small Cell Lung Cancer.
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
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Small Cell Lung Carcinoma
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Kappa Santé
First posted: 2023-01-13
Enrollment: 254
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: * Total population: all patients enrolled
* Safety analysis set: the safety population will be defined as all patients who receive at least one infusion of durvalumab.
* Full analysis set: the full analysis set will comprise all patients who receive at least one infusion of durvalumab and meet eligibility criteria.
* Follow up analysis set: it will comprise all patients of the full analysis set who have at least one follow up visit completed.

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: The time to first line treatment discontinuation (TTD).
timeFrame: 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 outcomes:
measure: Real-world Overall Survival (rwOS)
timeFrame: rwOS rate at 1, 2 and 3 years (rwOS1y, rwOS2y, rwOS3y)
measure: Real world Progression Free Survival (rwPFS)
timeFrame: rwPFS rate at 6, 12, 18, 24 and 36 months (rwPFS6m, rwPFS12m, rwPF18m, rwPFS24m, rwPFS36m) up to 36 months.
measure: Patient individual best response
timeFrame: From the start of treatment until disease progression (up to 36 months)..
measure: Overall response rate (ORR)
timeFrame: From the start of treatment until disease progression (up to 36 months).
measure: Disease control rate (DCR)
timeFrame: At the end of follow-up (up to 36 months)
measure: Time to second real-world progression (rwPFS2)
timeFrame: rwPFS2 (up to 36 months)
measure: Sociodemographics characteristics at durvalumab + platinum-etoposide initiation
timeFrame: At baseline
measure: Describe patient history prior to durvalumab initiation
timeFrame: Before durvalumab initiation
measure: Describe the safety profile of durvalumab + chemotherapy (PE) (treatment-related AE).
timeFrame: At the end of follow-up (up to 36 months).
measure: Sociodemographics characteristics at durvalumab + platinum-etoposide initiation
timeFrame: At baseline
measure: Sociodemographics characteristics at durvalumab + platinum-etoposide initiation
timeFrame: At baseline
measure: Sociodemographics characteristics at durvalumab + platinum-etoposide initiation
timeFrame: At baseline
measure: Clinical characteristics at durvalumab + platinum-etoposide initiation
timeFrame: At baseline
measure: Clinical characteristics at durvalumab + platinum-etoposide initiation
timeFrame: At baseline
measure: Clinical characteristics at durvalumab + platinum-etoposide initiation
timeFrame: At baseline
measure: Clinical characteristics at durvalumab + platinum-etoposide initiation
timeFrame: At baseline
measure: Clinical characteristics at durvalumab + platinum-etoposide initiation
timeFrame: At baseline
measure: Describe patient history prior to durvalumab initiation
timeFrame: Before durvalumab discontinuation
measure: Safety profile of durvalumab + chemotherapy (PE) (treatment-related AE).
timeFrame: At the end of follow-up (up to 36 months).
Other outcomes:
measure: Describe the nature and explore the impact of different sequential therapeutical strategies on patient outcomes.
timeFrame: At the end of follow-up (up to 36 months)
measure: Explore disease characteristics, that may influence the progression of cancer and/or response to durvalumab + platinum etoposide treatment
timeFrame: At the end of follow-up (up to 36 months).
measure: Time between chemotherapy and durvalumab initiation:
timeFrame: Between chemotherapy and durvalumab initiation (up to 1 year)
measure: Dosing regimen and scheme
timeFrame: At the end of follow-up (up to 36 months)
measure: Chemotherapy cycles description
timeFrame: At the end of follow-up (up to 36 months)
measure: Number of durvalumab cycles
timeFrame: At the end of follow-up -up to 36 months)
measure: Duration of treatment
timeFrame: At the end of follow-up (up to 36 months).
measure: Time to first subsequent therapy (TFST)
timeFrame: At the end of the follow-up (up to 36 months).
measure: Time to second subsequent therapy (TSST)
timeFrame: At the end of follow-up (up to 36 months).
measure: Local and supportive treatments
timeFrame: At the end of follow-up (up to 36 months).
measure: Describe the nature and explore the impact of different sequential therapeutical strategies on patient outcomes.
timeFrame: At the end of follow-up (up to 36 months)
measure: Describe the nature and explore the impact of different sequential therapeutical strategies on patient outcomes.
timeFrame: At the end of follow-up (up to 36 months)
measure: Dosing regimen and scheme
timeFrame: At the end of follow-up (up to 36 months)
measure: Number of chemotherapy cycles
timeFrame: At the end of follow-up (up to 36 months)
measure: Chemotherapy cycles delays
timeFrame: At the end of follow-up (up to 36 months)
measure: Durvalumab cycles delays
timeFrame: At the end of follow-up (up to 36 months)
measure: Description of durvalumab cycles
timeFrame: At the end of follow-up (up to 36 months)
measure: Local and supportive treatments timeline
timeFrame: At the end of follow-up (up to 36 months)
Locations:
city: Angers
country: France
facility: Research Site
city: Argenteuil
country: France
facility: Research Site
city: Avignon
country: France
facility: Research Site
city: Avignon
country: France
facility: Research Site
city: Bayonne
country: France
facility: Research Site
city: Bordeaux Cedex
country: France
facility: Research Site
city: Clermont-Ferrand
country: France
facility: Research Site
city: Créteil
country: France
facility: Research Site
city: Dijon
country: France
facility: Research Site
city: Epagny Metz-Tessy
country: France
facility: Research Site
city: Gleize
country: France
facility: Research Site
city: La Roche sur Yon
country: France
facility: Research Site
city: La Rochelle
country: France
facility: Research Site
city: Le Chesnay-Rocquencourt
country: France
facility: Research Site
city: Limoges
country: France
facility: Research Site
city: Marseille
country: France
facility: Research Site
city: Nancy
country: France
facility: Research Site
city: Nimes
country: France
facility: Research Site
city: Nîmes
country: France
facility: Research Site
city: Osny
country: France
facility: Research Site
city: Paris
country: France
facility: Research Site
city: Pau
country: France
facility: Research Site
city: Rennes
country: France
facility: Research Site
city: Rouen
country: France
facility: Research Site
city: Saint Gregoire
country: France
facility: Research Site
city: Saint-Etienne
country: France
facility: Research Site
city: Saint-Quentin
country: France
facility: Research Site
city: Toulon
country: France
facility: Research Site
city: Toulouse
country: France
facility: Research Site
city: Toulouse
country: France
facility: Research Site
city: Valenciennes
country: France
facility: Research Site
city: Vannes
country: France
facility: Research Site
city: Villeurbanne
country: France
facility: Research Site
city: Évreux
country: France
facility: Research Site
Study officials:
References:
citation: Avrillon V, Daniel C, Boisselier P, Le Pechoux C, Chouaid C. Nationwide Real-Life Safety and Treatment Exposure Data on Durvalumab After Concurrent Chemoradiotherapy in Unresectable Stage III, Locally Advanced, Non-small Cell Lung Cancer: Analysis of Patients Enrolled in the French Early Access Program. Lung. 2022 Feb;200(1):95-105. doi: 10.1007/s00408-022-00511-8. Epub 2022 Feb 9.
citation: Carter BW, Glisson BS, Truong MT, Erasmus JJ. Small cell lung carcinoma: staging, imaging, and treatment considerations. Radiographics. 2014 Oct;34(6):1707-21. doi: 10.1148/rg.346140178.
citation: Eberhardt WE, Mitchell A, Crowley J, Kondo H, Kim YT, Turrisi A 3rd, Goldstraw P, Rami-Porta R; International Association for Study of Lung Cancer Staging and Prognostic Factors Committee, Advisory Board Members, and Participating Institutions. The IASLC Lung Cancer Staging Project: Proposals for the Revision of the M Descriptors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer. J Thorac Oncol. 2015 Nov;10(11):1515-22. doi: 10.1097/JTO.0000000000000673.
citation: Evans WK, Shepherd FA, Feld R, Osoba D, Dang P, Deboer G. VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol. 1985 Nov;3(11):1471-7. doi: 10.1200/JCO.1985.3.11.1471.
citation: Goldstraw P, Chansky K, Crowley J, Rami-Porta R, Asamura H, Eberhardt WE, Nicholson AG, Groome P, Mitchell A, Bolejack V; International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee, Advisory Boards, and Participating Institutions; International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee Advisory Boards and Participating Institutions. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2016 Jan;11(1):39-51. doi: 10.1016/j.jtho.2015.09.009.
citation: Horn L, Mansfield AS, Szczesna A, Havel L, Krzakowski M, Hochmair MJ, Huemer F, Losonczy G, Johnson ML, Nishio M, Reck M, Mok T, Lam S, Shames DS, Liu J, Ding B, Lopez-Chavez A, Kabbinavar F, Lin W, Sandler A, Liu SV; IMpower133 Study Group. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med. 2018 Dec 6;379(23):2220-2229. doi: 10.1056/NEJMoa1809064. Epub 2018 Sep 25.
citation: Nicholson AG, Chansky K, Crowley J, Beyruti R, Kubota K, Turrisi A, Eberhardt WE, van Meerbeeck J, Rami-Porta R; Staging and Prognostic Factors Committee, Advisory Boards, and Participating Institutions; Staging and Prognostic Factors Committee Advisory Boards and Participating Institutions. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for the Revision of the Clinical and Pathologic Staging of Small Cell Lung Cancer in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2016 Mar;11(3):300-11. doi: 10.1016/j.jtho.2015.10.008. Epub 2015 Dec 24.
citation: Paz-Ares L, Chen Y, Reinmuth N, Hotta K, Trukhin D, Statsenko G, Hochmair MJ, Ozguroglu M, Ji JH, Garassino MC, Voitko O, Poltoratskiy A, Musso E, Havel L, Bondarenko I, Losonczy G, Conev N, Mann H, Dalvi TB, Jiang H, Goldman JW. Durvalumab, with or without tremelimumab, plus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer: 3-year overall survival update from CASPIAN. ESMO Open. 2022 Apr;7(2):100408. doi: 10.1016/j.esmoop.2022.100408. Epub 2022 Mar 10.
citation: Paz-Ares L, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, Statsenko G, Hochmair MJ, Ozguroglu M, Ji JH, Voitko O, Poltoratskiy A, Ponce S, Verderame F, Havel L, Bondarenko I, Kazarnowicz A, Losonczy G, Conev NV, Armstrong J, Byrne N, Shire N, Jiang H, Goldman JW; CASPIAN investigators. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019 Nov 23;394(10212):1929-1939. doi: 10.1016/S0140-6736(19)32222-6. Epub 2019 Oct 4.
citation: Travis WD, Asamura H, Bankier AA, Beasley MB, Detterbeck F, Flieder DB, Goo JM, MacMahon H, Naidich D, Nicholson AG, Powell CA, Prokop M, Rami-Porta R, Rusch V, van Schil P, Yatabe Y; International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee and Advisory Board Members. The IASLC Lung Cancer Staging Project: Proposals for Coding T Categories for Subsolid Nodules and Assessment of Tumor Size in Part-Solid Tumors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer. J Thorac Oncol. 2016 Aug;11(8):1204-1223. doi: 10.1016/j.jtho.2016.03.025. Epub 2016 Apr 21.
citation: Wang S, Zimmermann S, Parikh K, Mansfield AS, Adjei AA. Current Diagnosis and Management of Small-Cell Lung Cancer. Mayo Clin Proc. 2019 Aug;94(8):1599-1622. doi: 10.1016/j.mayocp.2019.01.034.
citation: Wang S, Tang J, Sun T, Zheng X, Li J, Sun H, Zhou X, Zhou C, Zhang H, Cheng Z, Ma H, Sun H. Survival changes in patients with small cell lung cancer and disparities between different sexes, socioeconomic statuses and ages. Sci Rep. 2017 May 2;7(1):1339. doi: 10.1038/s41598-017-01571-0.
citation: Falchero L, Tissot C, Duruisseaux M, Souquet P-J,Planchard D , et le comité de rédaction des référentiels Auvergne Rhône-Alpes en oncologie thoracique. Référentiel Cancer Bronchique à petites Cellules : actualisation 2022. ARISTOT 2022.
citation: APM News. L'activité de prise en charge des cancers dans les établissements Français en 2018 (Infographie). 21/11/2019.
citation: Brierley JD, Gospodarowicz MK, Wittekind C, et al, eds. TNM Classification of Malignant Tumours. 8th ed. Oxford, UK: Wiley Blackwell; 2017.
citation: Deffossez, G. Estimations nationales de l'incidence et de la mortalité par cancer en France métropolitaine entre 1990 et 2018. Volume 1 - Tumeurs solides. 2019.
citation: Navada S, Lai P, Schwartz AG, and Kalemkerian GP (2006). Temporal trends in small cell lung cancer: Analysis of the national Surveillance, Epidemiology, and End Results database (abstract 7082). J Clin Oncol 24(18_suppl), 7082-7082.
citation: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982 Dec;5(6):649-55. No abstract available.
citation: Oronsky B, Reid TR, Oronsky A, Carter CA. What's New in SCLC? A Review. Neoplasia. 2017 Oct;19(10):842-847. doi: 10.1016/j.neo.2017.07.007. Epub 2017 Sep 6.
citation: Armeni P, Borsoi L, Fornaro G, Jommi C, Grossi F, Costa F. Cost-effectiveness and Net Monetary Benefit of Durvalumab Consolidation Therapy Versus No Consolidation Therapy After Chemoradiotherapy in Stage III Non-small Cell Lung Cancer in the Italian National Health Service. Clin Ther. 2020 May;42(5):830-847. doi: 10.1016/j.clinthera.2020.03.012. Epub 2020 Apr 27.