Contrasting the evidence from pivotal trials with the real world evidence (RWE)

Project team ALL: Andrea Titieni-Schuhmann, Anja Panhuber
Project team DLCBL & PMBCL: Anja Panhuber, Gregor Götz
Duration: April 2022 – November 2022
Language: English with German summary

Publication: HTA Project Report No. 146: https://eprints.aihta.at/1415/

Background: Various malignant diseases of the hematopoietic system arise from malignant B cells. Depending on the site of origin of the degenerated B cells, a differentiation is made between the various types of blood cancer. Acute lymphoblastic leukemia (ALL) is a disease of the lymphoid cells from the bone marrow, approximately 75% of ALL is caused by degenerate B cells (B cell ALL) [1]. Diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBCL) belong to the non-Hodgkin's lymphomas (NHL) and are malignancies that usually arise in the lymph nodes [2, 3]. Through the blood or lymphatic system, the malignant B cells can eventually spread throughout the body and affect other organs.

The mentioned blood cancers are considered to be particularly aggressive and lead to death within months if left untreated. ALL occurs mainly in children under five years of age, with an incidence of 5.3 per 100,000 children per year (Germany) [4]. While DLBCL frequently affects older people over 70 years of age, PMBCL occurs more frequently in young women between 30 and 40 years of age. DLBCL is one of the most common NHLs, with an incidence of 5-7 per 100,000 population [5, 6], while PMBCL is a rare disease, accounting for 2-4 percent of all NHLs [7]. However, the actual incidence of PMBCL is controversial, the prevalence is 1-9 cases per 100,000 people [8].

Chemotherapy is the standard treatment in the first and second line, often in combination with stem cell transplantation [4, 6]. However, not all patients are suitable for or respond to stem cell therapy. For this reason, intensive research is conducted to find new therapeutic approaches for these patients. These include, among others, genetic engineering methods, like the so-called CAR-T cell therapies (Chimeric Antigen Receptor). [9]. In 2018, the European Medicines Agency (EMA) approved two of these CAR-T cell therapies, axicabtagen ciloleucel (Yescarta®, Kite Pharma) and tisagenlecleucel (Kymriah®, Novartis), as orphan drugs for relapsed or refractory B-cell ALL, DLBCL, or PMBCL after two or more lines of therapy [10, 11].

For treatment with CAR T cells, the patient's own T cells are removed and genetically altered in order to express a new receptor (CAR) on their cell surface. This receptor can bind to antigens on the cell surface of tumor cells. The modified CAR-T cells can thus recognize and specifically eliminate cancer cells in the body. The extracted T cells are multiplied in the laboratory and returned to the patient's body [12]. According to the European Society for Blood and Marrow Transplantation (EBMT) Annual Report (2021), 2,750 patients have been treated with CAR-T cell therapies to date [13].

Due to the small number of patients and the resulting small cohorts in the pivotal studies, an analysis of the patient-relevant benefit and safety by comparing the results of post-approval studies as well as registry studies is needed. Initial systematic studies of the beneficial effects of CAR-T cell therapies in DLBCL have already been conducted in 2020 and are updated in this report [14].

Table 1: Therapy (line) recommendations according to guidelines

Project aims and research questions: The primary aim of this project is to systematically synthesize the evidence from health care studies (RWE: observational and registry studies) on the use of CAR-T cell therapies since their approval in 2018, and to compare the results from pivotal studies and health care studies regarding patient characteristics, efficacy/safety endpoints. Instead of a separate HTA, a summary of the results of HTAs - based on the pivotal studies - is given.

The following research questions result from the defined objectives:

1. RQ1: What are the results of HTAs regarding the available evidence (clinical trials) and their critical evaluation of approved CAR-T cell therapies:
   1. Kymriah® in r/r B cell acute lymphoblastic leukemia (B ALL), children, adolescents and young adults up to and including 25 years of age.
   2. Yescarta® or Kymriah® in adult patients with r/r diffuse large B cell lymphoma (DLBCL) with at least two prior systemic therapies.
   3. Yescarta® in adult patients r/r with primary mediastinal large B-cell lymphoma (PMBCL) with at least two prior systemic therapies.
2. RQ2: What are the differences in patient characteristics, efficacy, and safety in the results of pivotal studies and in health care studies (observational and registry studies) regarding therapy with
   1. Kymriah® in r/r B cell acute lymphoblastic leukemia (B ALL), children, adolescents and young adults up to and including 25 years of age.
   2. Yescarta® or Kymriah® in adult patients with r/r diffuse large B cell lymphoma (DLBCL) with at least two prior systemic therapies.
   3. Yescarta® in adult patients r/r with primary mediastinal large B-cell lymphoma (PMBCL) with at least two prior systemic therapies.

Methods: Derived from the research questions presented, this project consists of three parts.

Part 1: Health Technology Assessments (HTAs) on the approved CAR-T cell therapies Yescarta® and Kymriah® (Anja Panhuber)

Method RQ1: Hand search and systematic summary of assessments from (selected) national HTA institutions for health policy decision making regarding reimbursement of CAR-T cell therapies, highlighting patient populations (with greatest benefit), prior therapies and co-medication, etc.:

Table 2: HTA reports from selected HTA institutions.

Part 2: Approved CAR-T cell therapies in children, adolescents and young adults up to 25 years of age with r/r B-cell acute lymphoblastic leukemia (ALL) (Andrea Titieni-Schuhmann, Anja Panhuber)

Method RQ2: For the systematic review, a systematic literature search and an extended hand search (registry studies) are conducted. After selection of the literature, the data will be extracted and then summarized to answer research questions 1 and 2. All steps (literature selection, data extraction, quality assessment) will be performed by two authors (ATS & AP) using the 4-eyes principle.

Criteria for systematic search/inclusion criteria ALL:

Part 3: Approved CAR-T cell therapies in adult patients with r/r diffuse large B cell lymphoma (DLBCL) and with r/r primary mediastinal large B cell lymphoma (PMBCL) (Anja Panhuber, Gregor Götz)

Method: For the systematic review, a systematic literature search and an extended hand search (registry studies) are conducted. After selection of the literature, the data will be extracted and then summarized to answer research questions 1 and 2. All steps (literature selection, data extraction, quality assessment) will be performed by two authors (AP & GG) using the four-eyes principle.

Criteria for systematic search/inclusion criteria DLBCL/PMBCL:

Schedule and milestones:

References:

[1]     Huang F.-L., Liao E.-C., Li C.-L., Yen C.-Y. and Yu S.-J. Pathogenesis of pediatric B-cell acute lymphoblastic leukemia: Molecular pathways and disease treatments. Oncology letters. 2020;20(1):448-454. Epub 2020/05/04. DOI: 10.3892/ol.2020.11583.

[2]     Li S., Young K. H. and Medeiros L. J. Diffuse large B-cell lymphoma. Pathology. 2018;50(1):74-87. Epub 2017/11/24. DOI: 10.1016/j.pathol.2017.09.006.

[3]     Martelli M., Ferreri A., Di Rocco A., Ansuinelli M. and Johnson P. W. M. Primary mediastinal large B-cell lymphoma. Critical Reviews in Oncology/Hematology. 2017;113:318-327. DOI: https://doi.org/10.1016/j.critrevonc.2017.01.009.

[4]     Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V. (AWMF). Akute lymphoblastische Leukämie - ALL - im Kindesalter. 2021  [cited 19.04.2022]. Available from: https://www.awmf.org/uploads/tx_szleitlinien/025-014l_S1_Akute-lymphoblastische-Leukaemie-ALL-im-Kindesalter_2021-07.pdf.

[5]     National Cancer Institute. Cancer Stat Facts: NHL — Diffuse Large B-Cell Lymphoma (DLBCL). 2019 [cited 19.04.2022]. Available from: https://seer.cancer.gov/statfacts/html/dlbcl.html.

[6]     Lenz G., Chapuy B., Glaß B., Keil F., Klapper W., Nickelsen M., et al. Diffuses großzelliges B-Zell-Lymphom. 2021  [cited 19.04.2022]. Available from: https://www.onkopedia.com/de/onkopedia/guidelines/diffuses-grosszelliges-b-zell-lymphom/@@guideline/html/index.html#ID0ETHAE.

[7]     Lees C., Keane C., Gandhi M. K. and Gunawardana J. Biology and therapy of primary mediastinal B-cell lymphoma: current status and future directions. British Journal of Haematology. 2019;185(1):25-41. DOI: https://doi.org/10.1111/bjh.15778.

[8]     Orphanet. Primary mediastinal large B-cell lymphoma. [updated 20.04.2022; cited 20.04.2022]. Available from: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=98838.

[9]     Sehic O. and Wild C. CAR-T Zell-Therapien in Entwicklung - Update 2022. Vienna: AIHTA, 2022  [cited 21.04.2022]. Available from: https://eprints.aihta.at/1368/1/Policy%20Brief_006a_1st%20Update.pdf.

[10]   European Medicines Agency. Orphan Maintenance Assessment Report - Yescarta. London: Committee for Orphan Medicinal Products, 2018  [cited 19.04.2022]. Available from: https://www.ema.europa.eu/en/documents/orphan-maintenance-report/yescarta-orphan-maintenance-assessment-report-initial-authorisation_en.pdf.

[11]   European Medicines Agency. Orphan Maintenance Assessment Report - Kymriah. London: European Medicines Agency, 2018  [cited 19.04.2022]. Available from: https://www.ema.europa.eu/en/documents/orphan-maintenance-report/kymriah-orphan-maintenance-assessment-report-initial-authorisation_en.pdf.

[12]   National Cancer Institute. CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers. [updated 10.03.2022; cited 19.04.2022]. Available from: https://www.cancer.gov/about-cancer/treatment/research/car-t-cells.

[13]   European Society for Blood and Marrow Transplantation. EBMT Annual Report 2021. [cited 21.04.2022]. Available from: https://www.ebmt.org/annual-report-2021.

[14]   Ernst M., Oeser A., Besiroglu B., Caro-Valenzuela J., Abd El Aziz M., Monsef I., et al. Chimeric antigen receptor (CAR) T?cell therapy for people with relapsed or refractory diffuse large B?cell lymphoma. Cochrane Database of Systematic Reviews. 2021(9). DOI: 10.1002/14651858.CD013365.pub2.