Natural History, Treatment Patterns, and Real-World Clinical Outcomes in Patients with Unresectable Advanced or Metastatic Colorectal Cancer in Europe

Objectif(s) de la recherche et intérêt pour la santé publique

Finalité de l'étude

Objectifs poursuivis

Domaines médicaux investigués

Bénéfices attendus

Public health interest:

Patients with unresectable advanced or metastatic CRC who progress after 1L face significant unmet need: efficacy beyond 1L is low, prognosis is poor, and quality of life (QoL) is compromised. In biomarker agnostic populations, trials have shown modest improvements in survival with minimal response rates, and although biomarker directed therapies can yield higher response rates, as many as 50% of the late-line unresectable advanced or metastatic CRC population are ineligible. Approved 3L options deliver very low objective response rates with limited improvements in PFS and OS, highlighting the need for more efficacious 3L therapies that provide durable benefit, overcome resistance to immuno‑oncology and targeted agents, and extend long‑term survival and QoL.

Given the promising results from ARTEMIS-001 and the upcoming Phase 1b/2 223675 trials, real-world evidence from unresectable advanced or metastatic CRC patients treated in the routine care setting can provide important insights and opportunities for contextualizing results from clinical trials. IQVIA’s OEN in the EU and UK offers the opportunity to conduct a natural history of disease study in unresectable advanced or metastatic CRC to better understand clinical outcomes, patient demographics, and treatment patterns. This EU and UK natural history study will help contextualize findings from both the Phase 1b/2 Pan-gastrointestinal 2L/3L study investigating dose optimization in CRC, as well as the Phase 1b/2 2L/3L combination study evaluating GSK’227 in combination with standard of care, in preparation for a 3L Phase 3 trial in 2027.

Objectives of the study:

The aim of this study is to describe real-world clinical outcomes, patient characteristics, and treatment patterns for patients with unresectable advanced or metastatic CRC in the European Union (EU) and United Kingdom (UK). To achieve the following objectives, patients will be delineated into the following cohorts:

1. Diagnosed cohort, i.e., patients diagnosed with either unresectable advanced or metastatic CRC (both synchronous and metachronous).

2. 1L-treated cohort, i.e., patients diagnosed with unresectable advanced or metastatic CRC who initiated 1L treatment.

3. 2L-treated cohort, i.e., patients diagnosed with unresectable advanced or metastatic CRC who initiated 2L treatment.

4. 3L-treated cohort, i.e., patients diagnosed with unresectable advanced or metastatic CRC who initiated 3L treatment.

5. Fourth-line (4L)-treated cohort, i.e., patients diagnosed with unresectable advanced or metastatic CRC who initiated 4L treatment. 

6. Trial-like cohort, i.e., patients diagnosed with unresectable advanced or metastatic CRC who received one or two prior lines of therapy and fulfill other key eligibility criteria of the GSK223675 Phase 1b/2 trial (cohort A) that can be assessed in real-world settings.

Primary objective

1. Describe real-world overall survival (rwOS) in the diagnosed cohort.

Secondary objectives 

1. Describe the following real-world clinical outcomes in the 1L-treated, 2L-treated, 3L-treated, and trial-like cohorts: rwOS, real-world objective response rate (rwORR), real-world time-to-treatment discontinuation (rwTTD), real-world time-to-next-treatment or death (rwTTNT), real-world progression-free survival (rwPFS), real-world disease control rate (rwDCR), and real-world duration of response (rwDoR).

2. Describe baseline characteristics, including demographic and clinical characteristics, in the diagnosed, 1L-treated, 2L-treated, 3L-treated, and trial-like cohorts.

3. Describe treatment patterns to characterize real-world standard of care for unresectable advanced or metastatic CRC in the diagnosed, 1L-treated, 2L-treated, 3L-treated, and trial-like cohorts.

Exploratory objectives

1. Describe the relationship between rwOS and rwORR, rwPFS and rwOS, rwPFS and rwORR, rwPFS and rwDCR, and rwOS and rwDCR in the 2L-treated, 3L-treated, and trial-like cohorts.

2. Describe, where sample size allows (n≥25), real-world clinical outcomes (limited to rwOS, rwORR, and rwPFS), baseline characteristics, and treatment patterns among the following subgroups in the diagnosed, 1L-treated, 2L-treated, 3L-treated, and trial-like cohorts, as appropriate:

- Pan-RAS mutation (KRAS, NRAS, or HRAS) status prior to index date: any Pan-RAS mutation; wildtype
- BRAF V600E mutation status prior to index date: positive v negative
- Microsatellite instability (MSI)/mismatch repair (MMR) status at index date: MSI-high (-H)/deficient (d)MMR v microsatellite stable (MSS)/proficient (p)MMR
- Tumor sidedness at initial diagnosis: left side; right side; rectum
- Presence of liver-only metastasis at diagnosis: liver-only metastasis; non-liver metastasis; liver + non-liver metastasis
- Presence of liver-only metastasis at index date: liver-only metastasis; non-liver metastasis; liver + non-liver metastases
- Presence of lung-only metastasis at diagnosis: lung-only metastasis; non-lung metastasis; lung + non-lung metastasis
- Presence of lung-only metastasis at index date: lung-only metastasis; non-lung metastasis; lung + non-lung metastasis
- Stage at initial diagnosis: Stage I-III resectable; Stage III unresectable advanced; Stage IV metastatic
- Stage at eligibility for the diagnosed cohort: unresectable advanced; metastatic
- Topoisomerase 1 inhibitor exposure prior to index date: topoisomerase 1 inhibitor pre-treated v topoisomerase 1 inhibitor naïve  

3. Describe, where sample size allows (n≥25), real-world clinical outcomes, baseline characteristics, and treatment patterns (objectives 1, 2 [limited to rwOS, rwORR, and rwPFS], 3, and 4) stratified by European country in the diagnosed, 1L-treated, 2L-treated, and 3L-treated cohorts. 

4. Describe, where sample size allows (n≥25), real-world clinical outcomes, baseline characteristics, and treatment patterns (objective 1, 2 [limited to rwOS, rwORR , and rwPFS], 3, and 4) stratified by index year in the trial-like cohort. 

5. Describe, where sample size allows (n≥25), real-world clinical outcomes and baseline characteristics (objective 1, 2 [limited to rwOS, rwORR, and rwPFS], 3, and 6 [limited to rwOS, rwORR, and rwPFS and baseline characteristics in the ‘topoisomerase 1 inhibitor exposure prior to index date’ subgroup]) in the 4L-treated cohort.

6. Describe the size of the trial-like cohort that emulates GSK’s Phase 1b/2 223675 (cohort A) target population and assess the availability and completeness of variables to describe clinical characteristics, treatment patterns, and outcomes. 

Research Method:

This is a non-interventional, multi-center, multi-national, longitudinal, retrospective cohort study of patients diagnosed with unresectable advanced or metastatic CRC. This study will use real-world secondary care data from across approximately 5 sites in the EU and UK.
Patients in the study will be analyzed in 6 cohorts: diagnosed, 1L-treated, 2L-treated, 3L-treated, 4L-treated, and trial-like cohorts and will be indexed at unresectable advanced or metastatic CRC diagnosis, initiation of 1L, initiation of 2L, initiation of 3L, initiation of 4L, and initiation of 2L/3L, respectively.

Study Population:

Patients who are aged ≥18 years across approximately 5 OEN sites with a diagnosis of unresectable advanced or metastatic CRC from 01 January 2020 will be assessed for eligibility into each cohort.

Broad eligibility for each cohort is defined as follows: adult patients diagnosed with unresectable advanced or metastatic CRC will be eligible for inclusion in the diagnosed cohort, and all those in the diagnosed cohort who initiate treatment for unresectable advanced or metastatic CRC will be eligible for at least the 1L-treated cohort, as well as the 2L-treated, 3L-treated, and 4L-treated cohorts if subsequent lines of therapy (LoTs) are initiated. Those who were treated with 1L or 2L treatment for unresectable advanced or metastatic CRC and fulfil other key eligibility criteria of Phase 1b/2 223675, will be included in the trial-like cohort. Patients will be excluded from the trial-like cohort if they have participated in any interventional clinical trial prior to and including index date or meet other selected exclusion criteria of the 223675 trial.