Characteristics, Treatment Patterns and Outcomes of patients with Refractory Metastatic Colorectal Cancer

Takeda Development Centre Americas, Inc. (hereafter referred to as "Takeda") requires Evidera Ltd to have access to NHS England data for the purpose of the following research project:

Characteristics, Treatment Patterns and Outcomes of patients with Refractory Metastatic Colorectal Cancer.

This study aims to examine the demographic and clinical characteristics, treatment patterns, and outcomes among patients with metastatic colorectal cancer (mCRC) who have been treated with at least 3 lines of therapy.

Analyses will be conducted in separate groups of patients receiving third-line (3L) and fourth-line (4L) treatment for mCRC regardless of prior treatments received and in groups of patients receiving 3L and 4L treatment who were previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and an anti-VEGF biological therapy.

The study objectives are:

1. Describe demographic and clinical characteristics of groups of patients with mCRC treated with 3L and 4L, regardless of prior therapy received (overall cohort) as well as 3L and 4L groups of patients with the specified prior treatments of interest (described above).

2. Describe the prior treatment patterns and treatment sequences of patients with mCRC included in the 3L and 4L groups.

3. Quantify time to next treatment in patients with mCRC included in the 3L and 4L groups.

4. Quantify overall survival in patients with mCRC included in the 3L and 4L groups.

The following NHS England Data will be accessed:

• NDRS Hospital Episode Statistics-

o Linked Admitted Patient Care – necessary to understand other cancer care received by the patients (e.g., surgery and radiation) as well as capture data on comorbidities prior to the study index date and on or after the mCRC diagnosis.

o Linked Accident & Emergency – necessary to more accurately capture other cancer care received by the patients as well as capture additional data on comorbidities treated in settings other than hospital.

o Linked Outpatients – necessary to more accurately capture other cancer care received by the patients as well as capture additional data on comorbidities treated in settings other than hospital.

• NDRS Cancer Registry Dataset- Required to identify relevant patients and obtain information on cancer diagnosis history/at baseline, including cancers other than CRC.

• NDRS Systemic Anti-Cancer Therapy Dataset- Required to assess the type of cancer treatment that the patients have received on or prior to the index date and also during the follow-up.

• NDRS Somatic Molecular Testing Dataset- Required to assess oncogenic drivers (e.g., RAS mutation, BRAF mutation, HER2 status) which are important clinical factors for treatment selection.

• NDRS National Radiotherapy Dataset (RTDS)- Required to describe the history of radiotherapy during the treatment of mCRC and is required to assess complete data on radiotherapy including start date, dose, anatomical treatment site, etc.

The datasets are required to adequately define a cohort mCRC patients who have received at least 3L of therapy with SOC systemic regimens and to assess relevant demographic and clinical characteristics and outcomes.

The level of the Data will be Pseudonymised.

The Data will be minimised as follows:

• Limited to data from 01 January 2013 to the latest available.

• This study is restricted to patients aged 18 or older who have been diagnosed with metastatic colorectal cancer (mCRC) and have received at least three lines of standard-of-care (SOC) systemic therapy, as recorded in the SACT dataset. The date they begin third line (3L) treatment is considered the index date for the overall cohort.

• Limited to conditions relevant to the study identified by specific ICD-10 codes.

Takeda is the research sponsor and the controller as the organisation responsible for ensuring that the Data will only be processed for the purpose described above.

The lawful basis for processing personal data under the UK GDPR is:

Article 6(1)(f) - processing is necessary for the purposes of the legitimate interests pursued by the controller or by a third party.

Takeda Development Centre Americas, Inc. has determined the processing is necessary for its legitimate interests in being able to conduct scientific research that will inform healthcare organisations and policy makers about the effectiveness of current mCRC treatment strategies and potential areas for improvement.

The lawful basis for processing special category data under the UK GDPR is:

Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject.

This research is considered to be in the public interest as it addresses a significant gap in the understanding of treatment patterns for metastatic colorectal cancer (mCRC) in the UK. By evaluating how closely current practices align with established guidelines from the European Society of Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN), the findings will offer valuable insights for policymakers, helping to improve adherence to best practices. Furthermore, the study sheds light on real-world patient outcomes, which is crucial for informing future advancements in treatment, including emerging therapies like fruquintinib. Ultimately, this research has the potential to improve patient care, guide treatment decisions, and shape healthcare policy, benefiting both individuals affected by mCRC and the broader public.

The funding is provided by Takeda. The funding is specifically for the project described. Takeda will not suppress or otherwise limit the publication of findings.

Evidera Ltd is a processor acting under the instructions of Takeda. Evidera Ltd's role is limited to designing the study, performing the data analysis and writing up the study report.

Takeda’s commercial interest is centred on generating real-world evidence to support the positioning of Fruquintinib, its VEGF receptor inhibitor, as a later-line treatment for metastatic colorectal cancer (mCRC). The research will analyse treatment patterns and outcomes for patients in third-line and beyond settings in the UK, helping Takeda:

- Understand how treatment decisions are made and identify unmet clinical needs.

- Strengthen the case for reimbursement by NICE and other European payers.

- Estimate the potential patient population who may benefit from Fruquintinib.

- Inform strategic positioning and clinical recommendations for the drug.

Evidera Ltd, part of Thermo Fisher Scientific, has been contracted and funded by Takeda. Evidera’s commercial benefit lies in fulfilling this contract as part of its role as a global research organisation.

Where individuals have opted out of disease registration by the National Disease Registration Service (NDRS), their data has been permanently removed from the registry and therefore will not be disseminated under this Data Sharing Agreement (DSA). https://digital.nhs.uk/ndrs/patients/opting-out.

No data will flow to NHS England for the purposes of this Data Sharing Agreement (DSA).

NHS England will provide the relevant records from the requested datasets to Evidera Ltd. The Data will contain no direct identifying data items. The Data will be pseudonymised and individuals cannot be reidentified through linkage with other data in the possession of the recipient.

The Data will not be transferred to any other location.

The Data will be stored on servers at Evidera Ltd offices in England.

The Data will be backed up on a separate Evidera Ltd server in England.

The Data will be accessed by authorised personnel via remote access.

Takeda must confirm and provide evidence upon audit by NHS England that access via any remote device complies with the data security obligations within this DSA and the Data Sharing Framework Contract.

For remote access:

- Remote access will only be from secure locations situated within the territory of use (as further restricted elsewhere within the DSA if so done) stated within this DSA;

- Access controls granting users the minimum level of access required are in place;

- Remote access is only via secure connections (e.g., VPNs or secure protocols) to protect data;

- Multifactor authentication (MFA) is required for remote access;

- Device security, including up-to-date software and operating systems, antivirus software, and enabled firewalls are utilised for the remote access;

- All remote access is undertaken within the scope of the organisation’s DSPT (or other security arrangements as per this DSA) and complies with the organisation’s remote access policy.

The above applies in addition to any condition set out elsewhere within the DSA (e.g. who may carry out processing, and for what purpose).

The Data will not leave England/Wales at any time.

Access is restricted to employees of Evidera Ltd.

Employees of Takeda are only permitted to access or receive aggregated anonymised data including information derived from NHS England Data. Such datasets will adhere to the relevant small number suppression rules to minimise the risk of individuals being identified.

All personnel accessing the Data have been appropriately trained in data protection and confidentiality.

The Data will not be linked with any other data.

Data sources from Spain and Italy will also be used to assess treatment options and outcomes. In Spain, Evidera Ltd are collaborating with the company Atrys to access the BIG-PAC database, which consolidates medical records from seven Autonomous Communities across the country. In Italy, Evidera Ltd. are partnering with CliCon, who is granting them access to data sourced from various Local Health Units (LHUs). This data will not be linked to NHSE data.

There will be no requirement and no attempt to reidentify individuals when using the Data.

Researchers from Evidera Ltd will process the Data for the purposes described above.

The expected outputs of the processing will be:

• A report of findings to Takeda after completion of the data analysis.

• Submissions to Health Technology Assessment (HTA)- Findings on existing treatment options and outcomes in the UK and other European countries may be used in economic models, or used to inform economic models, which indirectly support relevant HTA submissions, including those to NICE.

• Engagement with Key Opinion Leaders in the UK- Results will be communicated with clinicians to help interpret the findings and facilitate their application in clinical practice. The information can be used by Medical Science Liaisons to share information regarding treatment patterns of colorectal cancer with HCPs in the UK.

• Engagement with Patients and Patient groups- the information can be used by Medical Science Liaisons to share information regarding treatment patterns of colorectal cancer with advocacy groups.

• Open Access Publications- Where possible, results will be published via the open access route to ensure that all stakeholders, including clinicians, policymakers, patients and the public, can access the findings freely.

• Transparency and Reproducibility- The planned outputs will be designed to include sufficient information on methods to ensure research transparency and reproducibility. All types of results, including those deemed unfavorable, will be published. Additionally, administrative coding lists used for identifying mCRC patients and creating study variables will be shared.

• A lay summary of key findings will be disseminated via the Takeda or other publicly available websites.

The outputs will not contain NHS England Data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived.

The outputs will be communicated to relevant recipients through the following dissemination channels:

• High Impact Journals

• Presentations

• Posters displayed at conferences such as the European Society for Medical Oncology (ESMO) or the American Society of Clinical Oncology (ASCO)

• Public reports outlining key findings will be made available on Takeda’s website.

Evidera Ltd estimates that the analysis will be completed by the end of Q4 2025 with a study report in Q1 2026. Once the study report has been drafted, manuscripts will be prepared for submission to peer-reviewed journals and abstracts for conference presentation in Q3 2026.

The expected benefits to health and social care include the following:

1. Public Health Benefits: This study aims to provide valuable insights into the treatment patterns and outcomes of patients with mCRC who have received at least three lines of therapy. Colorectal cancer is the second most common cause of cancer death in the UK, affecting a large number of people of all ages. By examining the demographic and clinical characteristics, as well as the treatment sequences of these patients, the study can contribute to a better understanding of the disease and its management.

2. Informing Healthcare Providers and Policymakers: It is anticipated that this study will inform healthcare providers and policymakers about the effectiveness of current treatment strategies, potential areas for improvement, and the need for new therapeutic interventions. Findings from this study may also help guide clinicians in selecting optimal treatments that maximise outcomes. Additionally, findings from the study will help determine whether there is significant variation from the treatment guidelines in the types of regimens that patients receive in actual clinical practice.

3. Contributions to Future Research: The study's outcomes can contribute to the broader body of knowledge on mCRC treatment in the 3L and above settings, benefiting future research and ultimately, public health. These insights can guide the development of new therapeutic approaches and clinical trials, aiming to improve outcomes of later lines of therapy.

4. Cost and Efficiency Savings: By understanding the real-world effectiveness and identifying the most beneficial treatment sequences, the study can potentially help to optimize treatment protocols, potentially leading to cost savings and the more efficient use of healthcare resources.

The specific benefits to patients include:

Empowering Patients and Informed Decision-Making: The study's findings can help inform patients about what they can expect from different treatment approaches. This can empower them to make more informed decisions about their care and potentially improve their quality of life.

The expected benefits can be measured by:

1. The number of scientific publications

2. Number of submissions to regulatory/payers/HTA incorporating relevant research findings

3. Citations of study publications by other researchers

4. Number of NICE evidence reviews that have cited findings from this study

5. Number of consultations and workshops held with clinicians, policy makers and patient groups

6. Number of conference presentations

7. Number of other dissemination materials published on the Takeda or other websites.

It is envisioned that results will be presented in medical journals and, where possible, results will be published via the open access route to ensure that all stakeholders, including clinicians, policymakers, and patients, can access the findings freely. There will also be communication of results with Key Opinion Leaders in the UK to help interpret the findings and facilitate their application in clinical practice. Finally, a lay summary of the key findings from this study will be published on the Takeda or other publicly accessible website.

Yielded Benefits is not a requirement for new applications.