Primary and Acquired Resistance to Targeted Treatment in BRAF V600E-mutated Metastatic Colorectal Cancer (PARTACER)

Primary and Acquired Resistance to Targeted Treatment in BRAF V600E-mutated Metastatic Colorectal Cancer (PARTACER-Suisse)

This study prospectively investigates the molecular mechanisms of primary and acquired resistance to standard-of-care BRAF V600E-directed therapy in patients with metastatic colorectal cancer and aims to pre-clinically develop novel strategies to reverse therapy resistance. Clinically approved combination treatment with cetuximab, encorafenib and chemotherapy improves patient outcomes, yet patients eventually experience disease progression. In this prospective multicenter study, tumor tissue, blood, and stool samples will be collected before treatment and at progression, to identify genetic and non-genetic mechanisms of resistance. Additionally, tumor tissue-based in vitro models (patient-derived organoids, PDOs) will be generated and exploited for functional in vitro testing, including genomic and pharmacologic perturbation studies. The overarching goal is to generate knowledge that can help develop new and more effective treatment strategies for future patients.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Colorectal Cancer; BRAF V600E Mutation
• Intervention / Treatment: Other: Longitudinal translational sampling

Detailed Description

BRAF V600E-mutated metastatic colorectal cancer accounts for about 8-10% of cases and is an aggressive disease with poor prognosis and limited treatment options. The current standard treatment for patients is the combination of the BRAF inhibitor encorafenib and the anti-EGFR antibody cetuximab, together with FOLFOX or FOLFIRI chemotherapy in 1st line systemic treatment, which improves survival and response rates compared to chemotherapy alone. However, nearly all patients eventually develop resistance to this treatment, and there are no well-established therapies after progression. Resistance develops through complex and often multiple mechanisms, including genetic changes in signaling pathways such as MAPK and receptor tyrosine kinases, as well as non-genomic factors such as changes in gene expression, the tumor microenvironment, and potentially the microbiome. These mechanisms are not yet fully understood, especially in combination and over time during treatment.

This study, PARTACER-Suisse, is a prospective multicenter investigator-initiated study in patients with BRAF V600E-mutated metastatic colorectal cancer receiving standard treatment with encorafenib and cetuximab, with or without concomitant chemotherapy. The study is conducted across a federated network of Swiss oncology centers organized under the Swiss Cancer Center/Swiss Group for Clinical Cancer Research (SCI/SAKK), with a central translational research backbone at the University Hospital Zurich. The aim is to better understand how resistance develops by analyzing tumor samples, blood samples, and stool samples collected before treatment and at disease progression. Blood samples will be used to study circulating tumor DNA over time, and stool samples will allow analysis of the microbiome. Tumor tissue will undergo detailed molecular analyses to identify genetic and non-genetic changes associated with resistance. In addition, tumor samples will be used to generate patient-derived organoids, which are laboratory models that allow functional testing of tumor behavior and response to treatment. By combining molecular analyses with functional experiments, the study aims to identify key resistance mechanisms and explore new treatment strategies that could prevent or overcome resistance.

Overall, this study is expected to provide a more complete understanding of resistance to combined BRAF and EGFR inhibition in this patient population and to support the development of improved and more personalized treatment approaches for the future.

• Study Type: Observational
• Enrollment (Estimated): 30

Contacts and Locations

• Study Contact: Name: Krista Zackel; Phone Number: +41313899191; Email: trials@swisscancerinstitute.ch

Study Locations

• Switzerland
  • Aarau, Switzerland, CH-5000
    • Recruiting
    • Kantonsspital Aarau
    • Contact: Peter Moosmann, MD et phil.; Phone Number: +41 62 838 60 53; Email: peter.moosmann@ksa.ch
    • Principal Investigator: Peter Moosmann, MD et phil.
  • Baden, Switzerland, 5404
    • Recruiting
    • Kantonsspital Baden
    • Contact: Stefanie Pederiva, MD; Phone Number: +41 56 486 34 11; Email: stefanie.pederiva@ksb.ch
    • Principal Investigator: Stefanie Pederiva, MD
  • Basel, Switzerland, 4058
    • Recruiting
    • St. Claraspital
    • Contact: Melanie Löffler-Baumann, MD; Phone Number: +41 61 685 85 85; Email: melanie.loeffler-baumann@claraspital.ch
    • Principal Investigator: Melanie Löffler-Baumann, MD
  • Basel, Switzerland, CH-4031
    • Recruiting
    • Universitaetsspital Basel
    • Contact: Viviane Hess, MD; Phone Number: +41 61 265 50 59; Email: viviane.hess@usb.ch
    • Principal Investigator: Viviane Prof Hess
  • Bern, Switzerland, 3010
    • Recruiting
    • Inselspital Bern
    • Contact: Martin D. Berger, Prof; Phone Number: +41 31 632 41 14; Email: martin.berger@insel.ch
    • Principal Investigator: Martin Berger, Prof
  • Chur, Switzerland, 7000
    • Recruiting
    • Kantonsspital Graubunden
    • Principal Investigator: Sara Bastian, MD
    • Contact: Sara Bastian, MD; Phone Number: +41 81 256 66 46; Email: sara.bastian@ksgr.ch
  • Lucerne, Switzerland, 6004
    • Recruiting
    • Luzerner Kantonsspital
    • Principal Investigator: Simon Häfliger, MD
    • Contact: Simon Häfliger, MD; Phone Number: +41 41 926 58 98; Email: simon.haefliger.1@luks.ch
  • Sankt Gallen, Switzerland, 9007
    • Recruiting
    • HOCH Health Ostschweiz - Kantonsspital St. Gallen
    • Contact: Barbara Denecke, MD; Phone Number: +41 71 494 11 11; Email: barbara.denecke@h-och.ch
    • Principal Investigator: Barbara Denecke, MD
  • Solothurn, Switzerland, 4500
    • Recruiting
    • Bürgerspital Solothurn
    • Contact: Julian Schardt, MD et phil.; Phone Number: +41 32 627 47 26; Email: julian.schardt@spital.so.ch
    • Principal Investigator: Julian Schardt, MD et phil.
  • Villars-sur-Glâne, Switzerland, 1752
    • Recruiting
    • HFR Freiburg - Kantonsspital
    • Contact: Rahel Odermatt, MD; Phone Number: +41 26 306 22 60; Email: rahel.odermatt@h-fr.ch
    • Principal Investigator: Rahel Odermatt, MD
  • Winterthur, Switzerland, 8004
    • Recruiting
    • Kantonsspital Winterthur
    • Contact: Guacimara Ortega Sanchez, MD; Phone Number: +41 52 266 25 43; Email: guacimara.ortegasanchez@ksw.ch
    • Principal Investigator: Guacimara Ortega Sanchez, MD
  • Zurich, Switzerland, 8091
    • Recruiting
    • Universitätsspital Zürich USZ
    • Principal Investigator: Ralph Fritsch, MD
    • Contact: Ralph Fritsch, MD; Phone Number: +41 44 255 48 74; Email: ralph.fritsch@usz.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Participants will be recruited from oncology centers across Switzerland participating in the Swiss Group for Clinical Cancer Research (SAKK). The study population consists of adult patients with metastatic colorectal cancer treated in routine clinical practice at tertiary care and regional cancer centers. Eligible patients are identified by their treating oncologists at participating sites and enrolled prior to initiation of standard-of-care systemic therapy. Recruitment is limited to centers with access to molecular diagnostics and the capability to perform tumor biopsies and longitudinal sample collection.

Description

Inclusion Criteria:

• Diagnosis of unresectable or metastatic BRAF V600E-mutated colorectal cancer
• Planned initiation of treatment with combined anti-EGFR antibody and BRAF inhibitor
• Patients receiving treatment in any line, with or without chemotherapy
• At least one tumor lesion accessible for biopsy
• ECOG performance status 0-2
• Life expectancy of at least 3 months
• Age ≥18 years
• Ability to provide written informed consent

Exclusion Criteria:

• Medical or surgical contraindication for tumor biopsy
• Active second malignancy (except non-melanoma skin cancer)
• Inability to comply with study procedures (e.g., due to language barriers or cognitive impairment)
• Pregnancy or breastfeeding
• Previous treatment with a BRAF inhibitor

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Patients with BRAF V600E-mutated metastatic colorectal cancer; Patients with unresectable or metastatic BRAF V600E-mutated colorectal cancer receiving standard-of-care treatment with combined BRAF and EGFR inhibition (e.g., encorafenib and cetuximab), with or without concomitant chemotherapy. Participants are enrolled prior to treatment initiation and followed longitudinally with collection of tumor tissue, blood, and stool samples to study mechanisms of treatment resistance.

Other: Longitudinal translational sampling; Longitudinal translational sampling (tumor tissue, plasma ctDNA, stool, PBMCs).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Detection rate of molecular alterations associated with acquired resistance	Proportion of patients with detectable molecular alterations associated with acquired resistance to combined BRAF and EGFR inhibition, identified in tumor tissue collected before treatment and at disease progression using molecular profiling.	from baseline (pre-treatment) to disease progression (approximately 12 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Detection rate of targetable resistance alterations	Proportion of patients with acquired resistance alterations that are potentially targetable by available or investigational therapies, identified through molecular profiling of tissue and liquid biopsy samples.	Baseline to disease progression (approximately 12 months)
Detection rate of non-genomic resistance mechanisms	Proportion of patients with non-genomic mechanisms of resistance, including transcriptomic changes and tumor microenvironment alterations, identified through molecular analyses.	Baseline to disease progression (approximately 12 months)
Comparison of resistance alterations in tissue versus liquid biopsies	Concordance and detection rates of resistance-associated molecular alterations in matched tumor tissue and circulating tumor DNA samples.	Baseline to disease progression (approximately 12 months)
Establishment rate of patient-derived organoids (PDOs)	Proportion of collected tumor biopsies (baseline and progression) from which patient-derived organoid cultures are successfully established for downstream functional analyses.	From baseline biopsy collection through PDO establishment (approximately 3 to 6 months per sample)
Longitudinal dynamics of circulating tumor DNA (ctDNA)	Quantitative changes in plasma ctDNA tumor fraction and variant allele frequencies of mutations from baseline through on-treatment time points to progression, and their association with radiological response and resistance evolution.	Baseline, every 8 to 12 weeks during treatment, and at disease progression (up to approximately 24 months)
Compositional characterization of the gut microbiome	Compositional and functional features of the gut microbiome at baseline and at disease progression, and their association with treatment response and resistance.	Baseline and at disease progression (approximately 12 months)

Collaborators and Investigators

• Sponsor: Swiss Cancer Institute
• Investigators: Study Chair: Ralph Fritsch, MD, University of Zurich

Study record dates

Study Major Dates

• Study Start (Actual): May 25, 2025
• Primary Completion (Estimated): September 1, 2030
• Study Completion (Estimated): September 1, 2030

Study Registration Dates

• First Submitted: May 22, 2026
• First Submitted That Met QC Criteria: May 22, 2026
• First Posted (Actual): June 1, 2026

Study Record Updates

• Last Update Posted (Actual): June 1, 2026
• Last Update Submitted That Met QC Criteria: May 22, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Microbiome; Cetuximab; Liquid biopsy; ctDNA; Precision oncology; Metastatic Colorectal Cancer; Circulating tumor DNA; BRAF V600E; Encorafenib; mCRC; Comprehensive genomic profiling; EGFR inhibition; Patient-derived organoids; Targeted therapy resistance; BRAF inhibition; SCI/SAKK
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms
• Other Study ID Numbers: SAKK 41/23

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: This is a non-interventional observational study with translational research components. Individual participant data sharing is not planned. Aggregate study results, including de-identified molecular and clinical data summaries, will be disseminated through peer-reviewed publications and scientific meetings. De-identified data may be shared with collaborators on a case-by-case basis upon reasonable request to the Study Chair and subject to applicable Swiss data protection regulations, institutional review, and a data-transfer agreement.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No