Maintenance Therapy With 5-FU/FA Plus Panitumumab vs. 5-FU/FA Alone After Prior Induction and Re-induction After Progress for 1st-line Treatment of Metastatic Colorectal Cancer

This is a phase II, randomized, multi-center, open-label, parallel-group study to evaluate the progression-free survival during maintenance therapy. Eligible patients will be treated within a 12-week induction therapy. Those patients achieving CR/PR or SD at 12 weeks and qualifying for maintenance treatment and re-induction treatment with all potential drug components, will be randomized in a ratio of 1:1 to receive chemotherapy plus panitumumab or chemotherapy alone during maintenance. In case of progression, re-induction treatment will be started.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

* Signed written informed consent
* Male or female ≥ 18 years of age
* Histologically proven metastatic colorectal cancer
* Molecular testing showing RAS wild-type in colorectal carcinoma cells
* Life expectancy \> 12 weeks
* At least one measurable lesion according to RECIST 1.1
* Adequate bone marrow, liver, kidney, organ and metabolic function
* Bone marrow function:

  * leukocyte count ≥ 3.0 × 109/L
  * ANC ≥ 1.5 × 109/L
  * platelet count ≥ 100 × 109/L
  * hemoglobin ≥ 9 g/dL or 5.59 mmol/L (may be transfused or treated with erythropoietin to maintain/ exceed this level)
* Hepatic function:

  * Total bilirubin ≤ 1.5 × UNL
  * ALT and AST ≤ 2.5 × UNL (or ≤ 5 × UNL in presence of liver metastases)
  * AP ≤ 5 × UNL
* Renal function:

  * Creatinine clearance ≥ 50 mL/min according to Cockcroft-Gault formula or serum creatinine ≤ 1.5 × UNL
* Metabolic function:

  * Magnesium ≥ lower limit of normal
  * Calcium ≥ lower limit of normal
* ECOG performance status 0 - 1
* Women of child-bearing potential must have a negative pregnancy test

Exclusion Criteria:

* Previous treatment for colorectal cancer in the metastatic setting
* Previous EGFR-targeting therapy \< 6 months after end of adjuvant therapy
* Known brain metastases unless adequately treated (surgery or radiotherapy) with no evidence of progression and neurologically stable off anticonvulsants and steroids
* Chronic inflammatory bowel disease
* Peripheral neuropathy ≥ NCI-CTCAE V 4.03 grade 2
* Other previous malignancies with the exception of a history of previous curatively treated basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix or other curatively treated malignant disease without recurrence after at least 5 years of follow-up
* Significant disease that, in the investigator's opinion, would exclude the patient from the study
* History of cardiac disease; defined as:

  * Congestive heart failure \> New York Heart Association (NYHA) class 2
  * Active coronary artery disease (myocardial infarction more than 6 months prior to start of study treatment is allowed)
  * Cardiac arrhythmias requiring anti-arrhythmic therapy (beta-blockers or digoxin are permitted)
  * Uncontrolled hypertension (defined as blood pressure ≥ 160 mmHg systolic and/or ≥ 90 mmHg diastolic on medication)
* Patients with interstitial lung disease, e.g., pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on baseline chest CT scan
* Known HIV, hepatitis B or C infection
* Known hypersensitivity reaction to any of the study components
* Radiotherapy, major surgery or any investigational drug 30 days before registration
* Pregnancy or lactation or planning to be pregnant during treatment and within 6 months after the end of treatment
* Subject (male or female) is not willing to use highly effective methods of contraception (per institutional standard) during treatment and for at least an additional 6 months after the end of treatment
* Known alcohol or drug abuse
* Any condition that is unstable or could jeopardize the safety of the patient and his compliance in the study

• DERIVEDStahler A, Modest DP, Stintzing S, Borelli B, Keller T, Held S, Fischer von Weikersthal L, Muller L, Graeven U, Decker T, Heintges T, Kahl C, Hoppe B, Kiani A, Kaiser F, Schwaner I, Fruehauf S, Karthaus M, Trarbach T, Klauschen F, Horst D, Cremolini C, Heinemann V. Individual Patient Data Meta-Analysis of Consensus Molecular Subtypes as Biomarkers of First-Line Treatment in RAS Wild-Type Metastatic Colorectal Cancer. J Clin Oncol. 2026 Jan;44(1):31-41. doi: 10.1200/JCO-25-00596. Epub 2025 Nov 18. PMID 41252656
• DERIVEDBallhausen A, Swoboda S, Horst D, Fruehauf S, Graeven U, Muller L, Trarbach T, Fischer von Weikersthal L, Goekkurt E, Heinemann V, Kasper S, Kurreck A, Alig AHS, Reinacher-Schick AC, Bullinger L, Stahler A, Stintzing S, Jarosch A, Modest DP. Spatial Tumor Immune Microenvironment as a Prognostic and Predictive Biomarker in Anti-EGFR-Based Maintenance for RAS wt Metastatic CRC-The PanaMa (AIO KRK0212) Trial. Clin Cancer Res. 2025 Oct 1;31(19):4049-4058. doi: 10.1158/1078-0432.CCR-25-0879. PMID 40736443
• DERIVEDStahler A, Karthaus M, Fruehauf S, Graeven U, Muller L, Fischer von Weikersthal L, Caca K, Goekkurt E, Ballhausen A, Sommerhauser G, Alig AHS, Held S, Jarosch A, Horst D, Reinacher-Schick A, Kasper S, Heinemann V, Stintzing S, Trarbach T, Modest DP. Panitumumab plus 5-fluorouracil and folinic acid or 5-fluorouracil and folinic acid alone as maintenance therapy in RAS wild-type metastatic colorectal cancer (PanaMa, AIO KRK 0212): final efficacy analysis of a randomised, open-label, phase 2 trial. EClinicalMedicine. 2024 Dec 16;79:103004. doi: 10.1016/j.eclinm.2024.103004. eCollection 2025 Jan. PMID 39802302
• DERIVEDStahler A, Kind AJ, Sers C, Mamlouk S, Muller L, Karthaus M, Fruehauf S, Graeven U, Fischer von Weikersthal L, Sommerhauser G, Kasper S, Hoppe B, Kurreck A, Held S, Heinemann V, Horst D, Jarosch A, Stintzing S, Trarbach T, Modest DP. Negative Hyperselection of Resistance Mutations for Panitumumab Maintenance in RAS Wild-Type Metastatic Colorectal Cancer (PanaMa Phase II Trial, AIO KRK 0212). Clin Cancer Res. 2024 Apr 1;30(7):1256-1263. doi: 10.1158/1078-0432.CCR-23-3023. PMID 38289994
• Ballhausen A, Karthaus M, Fruehauf S, Graeven U, Muller L, Konig AO, von Weikersthal LF, Sommerhauser G, Alig AHS, Goekkurt E, Meyer-Knees JW, Kurreck A, Stahler A, Held S, Kasper S, Heinrich K, Heinemann V, Stintzing S, Trarbach T, Modest DP. Health-related quality of life in patients with RAS wild-type metastatic colorectal cancer treated with fluorouracil and folinic acid with or without panitumumab as maintenance therapy: a prespecified secondary analysis of the PanaMa (AIO KRK 0212) trial. Eur J Cancer. 2023 Sep;190:112955. doi: 10.1016/j.ejca.2023.112955. Epub 2023 Jun 28.