Prospective validation of the modified metastatic colorectal cancer score (mCCS) in >600 patients with RAS-wild-type metastatic colorectal cancer treated with first-line panitumumab plus FOLFIRI/FOLFOX: Final results of the non-interventional study VALIDATE.

1
INTRODUCTION
The clinical management of patients with metastatic colorectal cancer (mCRC) remains a subject of debate, and there is a clear need for better stratification of patients by prognostic risk in order to improve clinical research, palliative treatment results, and the quality of care. In Germany and Austria, the standard treatment for RAS‐wild‐type (WT) mCRC includes chemotherapy regimens like FOLFIRI and FOLFOX, often combined with monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) or the vascular endothelial growth factor (VEGF), while for frail and elderly patients with RAS‐WT tumors, the standard of care is anti‐EGFR monotherapy or a combination therapy with single agent chemotherapy.
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Several prognostic scores have been developed based on data from randomized clinical trials (RCTs) with selected patient populations, with the aim of predicting survival in mCRC.
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,
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,
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,
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However, the majority of published prognostic scores concentrate on parameters that are evaluated at the start of first‐line (1L) treatment and are based on patient populations from clinical studies. In contrast, the mCRC prognostic score (mCCS) was developed using real‐world data from routine clinical practice within the German tumor registry (n = 1704; tumor registry colorectal cancer [TKK]) and is based on information which is routinely available before the start of 1L treatment.
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These baseline patient characteristics are: two or more metastatic sites at the start of first‐line treatment, tumor grading ≥G3 at primary diagnosis, residual tumor classification ≥R1/unknown, lymph node ratio (of primary tumor) ≥0.4, tumor stage ≥UICC stage III/unknown at primary diagnosis, and KRAS status mutated/unknown.
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As the mCCS was developed prior to extended RAS analyses and the restriction of therapeutic options for patients with RAS mutations, a modified mCCS was introduced, which excluded the (K)RAS status as a risk factor.
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A retrospective analysis of 1504 patients with KRAS/RAS‐WT mCRC showed that prognosis could be predicted by the modified mCCS. It still efficiently stratified (K)RAS‐WT patients into three distinct survival risk groups, namely into patients with low, intermediate, and high risk.
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The modified mCCS aims to predict overall survival (OS) of patients with (K)RAS‐WT mCRC at the start of 1L treatment. Efficiently stratifying patients and finding the optimal treatment recommendation for each risk group is a concept already adopted in many cancer types. Together with the current efforts in molecular stratification of patients with mCRC,
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the implementation of such a risk‐group adapted treatment for RAS‐WT tumors would represent a significant contribution toward personalized therapy in mCRC.
In order to facilitate the future development of risk‐based treatment approaches, the primary focus of the non‐interventional study (NIS) VALIDATE was to prospectively validate the modified mCCS in a large real‐world cohort of patients with RAS‐WT mCRC, aiming to stratify the tumors based on malignancy. Therefore, patients were prospectively assigned into three prognostic risk groups with different prognoses for OS from low to intermediate to high risk, defined by the number of risk factors according to the modified mCCS.
The patients in VALIDATE received panitumumab and FOLFIRI or FOLFOX as 1L antineoplastic treatment, which was chosen as a model treatment in the NIS. Additionally, data on real‐world treatment effectiveness, safety, and quality of life (QoL) were analyzed.

2
PATIENTS AND METHODS
2.1
Patients and risk groups
Eligible patients were ≥18 years of age with documented RAS‐WT mCRC who had not received prior systemic therapy in the palliative setting and received panitumumab in combination with FOLFIRI (folinic acid, fluorouracil, and irinotecan) or FOLFOX (folinic acid, fluorouracil, and oxaliplatin) as 1L treatment. Prescription of the medication was independent from the decision to include the patient in the study. Treatment was according to the Summary of Product Characteristics (SmPC). Evidence of RAS‐WT status (KRAS exon 2/3/4 and NRAS exon 2/3/4) was required before initiating treatment with panitumumab and participation in VALIDATE. The specific testing methods were determined by the participating sites based on their routine clinical workflows.
The handling of primary tumors was documented in detail, including whether the tumor had been surgically resected or not, the timing of the resection (relative to the start of panitumumab treatment), and the resection status (R0, R1, R2, or Rx).
For patients whose primary tumors were not resected, tumor characteristics such as grading, lymph node ratio, and tumor stage were assessed using biopsy specimens or radiological evaluations. This variability in data sources was accounted for in the analysis and is acknowledged as a potential source of heterogeneity in the dataset.
Patients were assigned to one risk group (low, intermediate or high risk) according to the modified mCCS.
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Therefore, the risk groups were determined by evaluating five risk factors: ≥2 metastatic sites at the start of 1L treatment, tumor grading ≥G3/unknown at primary diagnosis, residual tumor classification ≥R1/unknown, lymph node ratio (of primary tumor) ≥0.4, and tumor stage ≥UICC stage III/unknown at primary diagnosis. Low risk was defined by the presence of 0 to 1 risk factors, intermediate risk by 2 risk factors, and high risk by ≥3 risk factors. While tumor grading ≥G3 was used in this study, this aligns with the “high grade” category in the updated two‐tiered grading system recommended by the WHO.

2.2
Endpoints and assessments
The primary objective was to prospectively validate the modified mCCS by demonstrating different prognoses for overall survival (OS) based on the risk group. OS was defined as time from the start of 1L therapy to the date of death due to any cause. OS of patients alive at the end of the study were censored at the date of last contact according to the Kaplan–Meier method.
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Further objectives were the collection of data on real‐world effectiveness of panitumumab in combination with FOLFIRI or FOLFOX as 1L treatment and an exploratory analysis of safety. Progression‐free survival (PFS) was defined as the interval between the start of 1L treatment and the date of progression or death. Patients without an event prior to the start of subsequent treatment (if applicable) were censored at the start of subsequent therapy or the last available tumor assessment. Response to treatment was assessed according to local standards. Overall Response Rate (ORR) was defined as the proportion of patients with complete or partial response (CR/PR). Disease control rate (DCR) was defined as the proportion of patients with CR, PR, or stable disease (SD). Patients without response measurement were considered non‐responders. Duration of response (DoR) was defined as time from CR/PR to progression or death, whichever comes first.

2.3
Safety
Adverse events (AE) were recorded from the day of first administration of panitumumab until 30 days after the last dose of treatment. Only AEs related to panitumumab were reported. Treating physicians determined whether an AE was causally related to panitumumab. AEs were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.03) and coded using the Medical Dictionary for Regulatory Activities (MedDRA version 26.0).

2.4
Quality of Life
All enrolled patients who had received at least one dose of panitumumab and who were willing to participate in the patient reported outcomes (PRO) satellite project were part of the PRO analysis set. The questionnaires EORTC QLQ‐C30 (European Organization for Research and Treatment of Cancer General quality of life, version 3.0) and EORTC QLQ‐CR29 (colorectal module, health‐related quality of life, version 2.1) were distributed at baseline before the start of 1L treatment and thereafter three‐monthly until the end of 1L treatment for each individual patient. Scores were calculated according to the respective EORTC manuals.

2.5
Statistical Analysis
The primary analysis population (full analysis set [FAS]) comprised all patients who received at least one dose of panitumumab and who were treated according to SmPC. The FAS was used to assess patient and disease characteristics and to analyze effectiveness. The safety analysis set (SAF) contained all patients of the FAS for whom one further post‐baseline information was available. The SAF was used for evaluation of safety data. Analyses were conducted descriptively. The Kaplan–Meier method
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was used to estimate PFS and OS. For OS, modified mCCS risk groups were compared using a two‐sided log‐rank test. In a hierarchical manner, the first test compared the high‐risk with the low‐risk group at a significance level of 5%. If significant, the comparison of the intermediate risk with the low‐risk group would be performed at a significance level of 10%. If significant, the comparison of the intermediate with the high‐risk group would be performed at a significance level of 10%. Estimates for hazard ratios with confidence intervals for potentially prognostic covariates (including the modified five‐factor mCCS) were obtained with a multivariate Cox proportional hazard regression model. All statistical analyses were performed using SAS Version 9.4.

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RESULTS
3.1
Patient and disease characteristics
Between January 2017 and November 2020, a total of 646 patients were enrolled in 113 sites across Germany and Austria and assigned to risk groups according to their mCCS risk score. Treatment regimens were panitumumab + FOLFOX (n = 194) and panitumumab + FOLFIRI (n = 427). At database lock on January 17, 2024, the estimated median follow‐up for all patients was 50.2 months (95% CI 47.1, 55.5). In total, 611 patients were included in the FAS, 617 patients were included in the SAF, and 309 patients were part of the PRO analysis set (Figure 1).
Detailed demographic and clinical characteristics are shown in Table 1. Median age at inclusion was 66.1 years, and 68.9% of patients were male. Most patients presented with an ECOG Performance Status of 0/1 (83.5%). An ECOG ≥2 was assessed in 3.0% and 4.0% of patients in the low and intermediate risk groups and in 10.0% of patients in the high risk group, respectively. Tumors were mostly left‐sided (84.5%) and 15.0% of patients in the low risk, 11.9% in the intermediate risk, and 17.1% of patients in the high risk group had right‐sided tumors. The proportion of colon tumors was lower in the low risk group compared to the intermediate and high risk groups (n = 109, 54.5% vs. n = 126, 62.7% and n = 127, 60.5%, respectively). At primary diagnosis, 66.9% of patients (n = 409) had stage IV disease, and more than one metastatic site was detected in 39.1% of patients (n = 239). Among all patients included, 75.1% underwent resection of the primary tumor prior to study enrollment, with 43.4% undergoing resection less than 1 year before the start of panitumumab treatment and 30.9% undergoing resection more than 1 year prior. A small proportion (0.3%) underwent resection after the start of panitumumab treatment. Resection status was categorized as R0 (63.3%), R1 (5.6%), R2 (4.1%), or Rx (27.0%).
MSI and BRAF mutation status were not routinely assessed at the time of study design and were therefore not incorporated into the mCCS. However, MSI and BRAF data were collected for a subset of patients in the study. MSI‐high status was observed in 1.8% of patients, while BRAF mutations were identified in 4.7% of patients (data not shown). Despite their relevance, a significant proportion of patients had unknown MSI (66.1%) and BRAF (14.6%) status, which limits the ability to fully evaluate their prognostic impact within the current dataset.

3.2
Effectiveness
OS was significantly longer in patients in the low risk group compared to those in the high risk group (Figure 2) with a median OS [95% CI] of 29.1 months [25.9, 32.1] in the low risk group vs. 20.1 months [15.0, 23.9] in the high risk group. There was no significant difference in median OS between the low risk and intermediate risk groups. Due to hierarchical testing, the comparison between the high risk and intermediate risk groups was not conducted. The median OS in the total population was 27.0 months [24.8, 29.2] (Table 2). There was no difference in median OS between the two chemotherapy backbones (Figure S1).
A multivariable Cox regression analysis to identify factors with a potential impact on OS among a set of pre‐defined covariates was performed. In this analysis, it was found that tumor location (right‐sided vs. left‐sided; HR = 1.58 [1.19, 2.09]; p = .002), risk based on the 3‐factor Chibaudel score (high vs. low risk: HR = 2.37 [1.47, 3.83]; p < .001; intermediate vs. low risk: HR = 1.59 [1.17, 2.18]; p = .003), and the five‐factor mCCS risk group (high vs. low risk: HR = 1.75 [1.30, 2.37]; p = .001) significantly impacted OS when combined with other covariates. Note that the result cannot be generalized, for example, for pairwise comparisons of single covariates with OS (Figure 3).
The median PFS [95% CI] in the total population was 10.1 months [9.5, 10.8] (Table 2). In the mCCS subgroups, the median PFS [95% CI] was 10.5 months [9.6, 11.7] in the low risk group, 10.9 months [9.4, 12.2] in the intermediate risk group, and 9.0 months [8.1, 10.4] in the high risk group (Table 2). In summary, a clear separation between the three risk groups in terms of PFS was not evident (Figure S2).
Of the total population, 7.4% (n = 45) patients were documented with a CR, 58.6% (n = 358) patients with a PR, and 15.4% (n = 94) with SD, resulting in an ORR of 66.0% and a DCR of 81.3% (Table 2). In the mCCS subgroups, the ORR was 64.5% in the low risk group, 68.2% in the intermediate risk group, and 65.2% in the high risk group, respectively (Table 2). The KM‐estimated median DoR [95% CI] in the total population was 12.9 months [11.3, 14.5] (Table 2). In the mCCS subgroups, the median DoR [95% CI] was 15.8 months [11.6, 24.4] in the low risk group, 14.1 months [11.9, 16.7] in the intermediate risk group, and 9.4 months [6.9, 11.4] in the high risk group, respectively.
In the total population, 19.6% (n = 120) of patients underwent a secondary resection for metastases after the start of 1L therapy with panitumumab in combination with FOLFIRI or FOLFOX. The rate of secondary resections was higher for patients with low risk (n = 46, 23.0%) and intermediate risk (n = 49, 24.4%) and lower among patients with high risk (n = 25, 11.9%) (Table S1). For patients with disease limited to liver (n = 246) or lung (n = 51), surgical resection of liver or lung metastases was performed in 29.3% (n = 72) and 7.8% (n = 4) of patients, respectively.

3.3
Safety
In total, 70% (n = 432) of all patients were reported with at least one AE related to panitumumab; of these, 27.6% (n = 170) experienced AEs of CTCAE grade 3/4 and 8.6% (n = 53) were documented with a serious AE (Table S2). One patient experienced a fatal AE. AEs leading to discontinuation of study treatment were reported in 16.2% (n = 100) patients. The most common AEs with CTCAE grade 3/4 were skin and subcutaneous tissue disorders, such as acneiform dermatitis (6% [n = 37]) and rash (3.1% [n = 19]). The second most common grade 3/4 AEs were gastrointestinal disorders, such as diarrhea (3.2% [n = 20]) and stomatitis (1.6% [n = 10]).

3.4
Quality of Life
Throughout the treatment, the global health status, as assessed by the EORTC QLQ‐C30, remained largely unchanged compared to baseline. Additionally, the quality of life did not exhibit a clinically significant decline in most functional and symptom scales, or in the single item scores of the QLQ‐C30 and QLQ‐CR29. Questionnaire time points and return rates are summarized in Table S3.

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DISCUSSION
Personalized treatment approaches, guided by biomarkers and prognostic scores, are essential in optimizing outcomes and improving survival rates in patients with mCRC. The non‐interventional VALIDATE study prospectively validated the prognostic value of the mCCS by demonstrating a significantly longer OS of patients in the low risk group compared to those in the high risk group. Findings of VALIDATE furthermore support the effectiveness and safety of 1L therapy with panitumumab in combination with FOLFOX/FOLFIRI and highlight the clinical value of this therapy in the real‐world setting.
In the total study population, effectiveness outcomes were comparable to previously published data. The median OS of VALIDATE (27.0 months [24.8, 29.2]) compares well with the OS of patients in the FOLFOX + panitumumab arm of the registrational PRIME study (23.9 months [20.3, 27.7]).
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Other RCTs such as the PEAK and PARADIGM trial have shown longer median OS in their FOLFOX + panitumumab arms (36.9 months [no CI reported] and 37.9 months [34.1, 42.6], respectively).
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However, PARADIGM only included patients with left‐sided tumors, which have a better prognosis.
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The same prognostic effect was seen for patients in VALIDATE, as the left‐sided location of the tumor was found to have a positive impact on OS in a multivariable Cox regression analysis, while the section of the colon (colon or rectum) did not. In addition, patients in VALIDATE were slightly older compared to patients enrolled in PEAK and PRIME,
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which may further explain the differences in median OS.
The ORR of 66% observed in patients in VALIDATE aligns with the ORR reported in the PEAK trial (65%)
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and the VALENTINO trial (67%),
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yet remarkably surpasses the ORR documented in PRIME (57%)
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as well as published real‐world data from multiple European countries.
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Of note, the CR rate in VALIDATE was remarkably high with 7.4%, as compared to less than 1% in PRIME.
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In a real‐world study, the patient population may be more diverse and reflective of routine clinical practice, encompassing individuals with varying comorbidities, treatment histories, and adherence levels. This diversity can influence treatment outcomes, potentially leading to higher CR and ORR due to a broader representation of patients. However, it is important to note that tumor assessment in VALIDATE was not standardized according to RECIST criteria. This lack of standardization could introduce a potential bias in assessing PFS and treatment response.
Secondary surgery following 1L mCRC treatment represents a pivotal opportunity for achieving a potential cure.
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Within the entire study cohort of VALIDATE, a striking 19.6% of patients underwent a secondary resection of one or multiple metastases, and R0 as best resection status was achieved in 12.6% of these cases. These findings compare favorably with published data.
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High‐risk patients exhibited the lowest rate of secondary resections among all subgroups, with only 11.9% undergoing any metastasis resection, probably due to a higher number of metastases at baseline and a wider metastatic spread. This is in stark contrast to a notable 23.0% and 24.4% in the low and intermediate‐risk groups, respectively. Additionally, their percentage of R0 as best resection status was lower, suggesting significant challenges in achieving successful secondary resections in the high‐risk group. Exploring whether the notable rates of secondary resection in VALIDATE correspond to an improved mOS, as seen in liver‐limited disease within the LICC, CELIM, and FIRE‐3 studies,
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would be an intriguing field of investigation.
In VALIDATE, the patient‐reported QoL was preserved with no clinically relevant worsening of health‐related QoL during 1L panitumumab + FOLFIRI/FOLFOX treatment, which is a fundamental aspect of treatment for patients with advanced‐stage cancer.
Based on the known safety profile of panitumumab, the documented frequencies of AEs related to panitumumab were lower than expected. The remarkably low incidence of skin toxicity may indicate the successful implementation of current guidelines for the prevention and management of dermatological adverse effects into standard clinical practice.
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No new safety signals emerged during the study period.
The modified mCCS was developed as a practical tool for stratifying patients based on readily available clinical and pathological features. While the mCCS demonstrated strong prognostic value in the VALIDATE study, it is important to contextualize its performance in relation to other prognostic scores, such as the Chibaudel score. The Chibaudel score incorporates factors such as tumor burden, primary tumor location, and additional clinical parameters, and has been shown to provide robust prognostic insights. In comparison, the modified mCCS was specifically designed for use in routine clinical practice, with a focus on simplicity and accessibility, unlike the Chibaudel score, which may require more detailed and sometimes less readily available data. However, the Chibaudel score's inclusion of additional prognostic factors, such as tumor burden and detailed metastatic patterns, may enhance its prognostic accuracy. While the Chibaudel score may offer superior prognostic precision in some scenarios, the mCCS remains a practical and accessible tool, particularly in settings where simplicity and ease of use are prioritized.
However, the modified mCCS is capable of clearly defining a high risk group based on information about tumor characteristics easily available at the start of 1L therapy. However, the low and intermediate risk groups of patients showed a comparable OS, PFS, and DoR, suggesting that these two patient groups do not differ as much as the low and high risk groups. Taking the baseline characteristics of patients into account, as expected, patients from the intermediate risk group exhibited worse TNM staging, more metastases, and tumor‐related symptoms, while fewer patients presented with liver‐limited disease than patients from the low risk group. On the other hand, they also had a slightly better Charlson Comorbidity Index and more left‐sided and rectal tumors associated with a better prognosis.
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This combination of risk factors, along with the baseline characteristics, might have shifted the balance of prognostic factors within the intermediate risk group toward a more favorable outcome.
Belonging to the high risk group in the modified mCCS classification was correlated not only with a significantly reduced OS and a lower 24‐month OS rate than the other groups, but also with a shorter median PFS and a decreased 12‐month PFS rate, although these differences were not statistically significant. Hence, PFS should not be viewed as a surrogate for OS in VALIDATE. Similar findings have been observed in the FIRE‐3 and PARADIGM studies.
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Patients in the low and intermediate risk groups exhibited similar median PFS and 12‐month PFS rates. However, fewer high risk patients had a CR, but due to a higher number of patients with a PR in this group, the ORR between the modified mCCS subgroups was comparable. Nevertheless, the DoR was clearly reduced in the high risk group.
To summarize, the study highlights the importance of utilizing risk stratification tools like the modified mCCS to identify high‐risk patients early, allowing for tailored treatment strategies that could enhance outcomes in this challenging population. Selecting the optimal 1L regimen for patients with mCRC should maintain the balance between efficacy, toxicity, quality of life, and patient preferences. The ERMES trial,
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underscores the value of treatment de‐escalation based on patient preference or tolerability, while ongoing translational analysis seeks to identify patients who benefit the most from treatment de‐escalation. Thus, the modified mCCS may further improve the selection of these patients.

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LIMITATIONS
As in all real‐world studies, direct comparisons between effectiveness outcomes to data reported in RCTs are limited due to the different study settings and heterogeneity of the study populations. Caution should be exercised when interpreting differences in subgroups, given the absence of randomization and the small group sizes. Nevertheless, the findings of VALIDATE can serve as a valuable addition to the evidence obtained from RCTs by offering insights into real‐world treatment effectiveness and providing comprehensive data on treatment in routine clinical practice. The VALIDATE study included a majority of male patients (68.9%), reflecting the higher incidence of mCRC in men also observed in epidemiological studies and therefore not diminishing the generalizability of the findings.
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The mCCS was originally developed based on clinical parameters from patients with mCRC who began first‐line treatment between 2006 and 2017. Prognostic markers like BRAF, MSI‐H, and tumor sidedness, which were initially not considered clinically relevant, were not included then. However, MSI and BRAF data were in fact collected for a subset of patients in the study, but a significant proportion of patients had unknown MSI and BRAF status, which limits the ability to fully evaluate their prognostic impact within the current dataset. The absence of MSI and BRAF data for a large portion of the cohort reflects the real‐world clinical workflows at the time of study design. MSI‐high tumors are known to have distinct biological behavior, often associated with better prognoses, while BRAF mutations are associated with poorer outcomes and more aggressive disease. The inability to comprehensively account for these molecular markers in the mCCS limits its applicability in contemporary clinical practice, where MSI and BRAF testing are now routinely performed and play a critical role in treatment decisions. Despite these limitations, the mCCS remains a practical tool for stratifying patients based on widely available clinical and pathological features. This is particularly relevant in settings where molecular testing may not be readily available. However, our findings underscore the need for future validation efforts to incorporate MSI and BRAF status into the mCCS to enhance its prognostic accuracy and relevance in modern clinical workflows.

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CONCLUSION
Data from VALIDATE supports the effectiveness and safety of 1L therapy with panitumumab in patients with WT mCRC and highlights the clinical value of this therapy in the real‐world setting. The prognostic value of the modified mCCS was prospectively validated by demonstrating a significantly longer OS of patients in the low risk group as compared to the high risk group. It would be interesting to see a clinical trial stratifying the patients according to the modified mCCS and finding the optimal treatment recommendation for each risk group. While other prognostic scores, such as the Chibaudel score, may offer enhanced precision by incorporating additional factors, the mCCS was specifically designed for simplicity and accessibility, making it particularly valuable in real‐world settings. However, the limited availability of MSI and BRAF data in the VALIDATE cohort reflects the clinical workflows at the time of study design and represents a limitation of this analysis. In current clinical practice, MSI and BRAF testing are routinely performed and are critical for guiding treatment decisions and prognosis in mCRC. Despite these limitations, we believe the mCCS remains a practical tool for stratifying patients based on widely available clinical and pathological features. This is particularly relevant in settings where molecular testing may not be readily available. Therefore, the modified mCCS could provide a practical tool for oncologists in routine clinical practice to aid in treatment decision‐making and effectively communicating prognosis to patients.

AUTHOR CONTRIBUTIONS

Norbert Marschner: Conceptualization; writing – review and editing; funding acquisition. Jens Uhlig: Writing – review and editing; investigation; resources. Lutz Jacobasch: Writing – review and editing; investigation; resources. Lothar Müller: Writing – review and editing. Marcel Reiser: Writing – review and editing. Rebecca de Buhr: Writing – review and editing. Silke Polata: Writing – review and editing; investigation; resources. Armin Gerger: Writing – review and editing; investigation; resources. Viktor Zehrer: Writing – review and editing. Arno Amann: Writing – review and editing. Thomas Göhler: Writing – review and editing; investigation; resources. Laura Serrer: Writing – review and editing; project administration. Jan Schröder: Writing – review and editing. Dieter Semsek: Writing – review and editing; investigation; resources. Andreas Köhler: Writing – review and editing; investigation; resources. Patrick Stübs: Writing – review and editing; investigation; resources. Gerald Prager: Writing – review and editing; investigation; resources. Hans Ulrich Siebenbach: Writing – review and editing; formal analysis. Anita Schuch: Writing – review and editing; project administration. Norbert Marschner: Conceptualization; writing – review and editing; funding acquisition. Karin Potthoff: Writing – review and editing; writing – original draft; conceptualization; methodology; validation; funding acquisition.

FUNDING INFORMATION
The VALIDATE study is managed and analyzed by iOMEDICO and was partly funded by AMGEN GmbH. AMGEN GmbH had no role in study design, data collection and analysis, interpretation of results, decision to publish, or preparation of the manuscript.

CONFLICT OF INTEREST STATEMENT
AA, MR, LM, TG, DS, RdB, SP, PS, LS, HUS, AS, and KP declare no conflicts of interest. JU participated in advisory boards and workshops for Roche, Amgen, Servier, MSD, Bristol‐Myers Squibb, Sanofi, Merck, Celgene, Novartis, Janssen‐Cilag, Boehringer‐Ingelheim, Bayer, and Beigene. LJ received support for attending meetings from Boehringer Ingelheim, Daiichi Sankyo, Sanofi, Ipsen, and Abbvie and participated in advisory boards for Beigene, BMS, Abbvie, and Incyte. AG received honoraria for lectures from Amgen and participated in advisory boards for Amgen. VZ received support for attending meetings from Amgen, Sevier, Roche, and Novartis. JS received honoraria from Celgene, Medixline GmbH, Roche, Eisai, BMS, HE Research GmbH, Clovis Oncology GmbH, Octapharma, GSK, AbbVie, Boehringer Ingelheim, NIO, Amgen, I + E Research, Novartis, IPSEN, MSD, BeiGene, AOP, Miltenyi, Searchlight, Seagen, Pharma Partner, and Aurikamed and participated in advisory boards for the same companies. AK participated in advisory boards for Abbvie, Agendia, Amgen, Astra Zeneca, Daiichi Sankyo, Menarini, Stemline, MSD, Novartis, Pfizer, and Roche. GP received consulting fees from Arcus, Bayer, Merck, Astellas, Servier, Roche, Sanofi, and Beigene and honoraria for lectures from Arcus, Bayer, Servier, Roche, Lilly, Sanofi, Incyte, MSD, BMS, Pierre Fabre, Astra Zeneca, and Merck. NM received honoraria, consulting fees, and travel support from Amgen. He is Chief Scientific Officer and shareholder of iOMEDICO AG.

ETHICS STATEMENT
The study was approved by the responsible ethics committees (Ethics Committee at the General Medical Council of the State of Baden‐Wuerttemberg, Germany, approval number F‐2016‐109; Ethics Committee of the Medical University of Vienna, Austria, approval number ECS 2008/2018) and is registered at ClinicalTrials.gov (NCT03043950). Written informed consent was obtained from all patients. All procedures performed comply with the current laws in Germany and Austria, as well as with the ethical standards of the national research committee and the 1964 Helsinki declaration and its later amendments.

Supporting information

Figure S1. Overall survival in patients with RAS‐WT stratified by chemotherapy.

Figure S2. Progression‐Free Survival in patients with RAS‐WT stratified by mCCS risk group.

Table S1. Resections by mCCS risk group.

Table S2. Frequency of adverse events related to panitumumab.

Table S3. Questionnaire overview.