First-line Treatment Of mCRC Research Articles

First-line serplulimab plus HLX04 and XELOX versus placebo plus bevacizumab and XELOX in metastatic colorectal cancer: A phase 2/3 study.

3569 Background: This is a randomized, double-blind, multicenter phase 2/3 study comparing the efficacy and safety of serplulimab (a novel anti-PD-1 antibody) plus HLX04 (an approved bevacizumab biosimilar) and XELOX chemotherapy vs. placebo plus bevacizumab and XELOX as first-line treatment for metastatic colorectal cancer (mCRC). Interim analysis presented at the 2024 ASCO Gastrointestinal Cancers Symposium showed improvement in progression-free survival (PFS), and duration of response (DOR) for the serplulimab arm. Here we present the updated results with an extended follow-up duration of 24.2 months and the subgroup analysis results. Methods: In the phase 2 part, 114 patients with mCRC and no prior systemic therapy were randomized 1:1 (serplulimab arm, n = 57; placebo arm, n = 57) to receive intravenous (IV) serplulimab (300 mg) plus HLX04 (7.5 mg/kg) and XELOX (IV oxaliplatin [130 mg/m2] and oral capecitabine [1000 mg/m2]) (group A) or placebo plus bevacizumab and XELOX (group B) once every 3 weeks. Stratification factors were PD-L1 expression level, ECOG PS score, and primary tumor site. The primary endpoint was independent radiological review committee (IRRC)-assessed PFS per RECIST 1.1. Secondary endpoints included other efficacy endpoints, safety, pharmacokinetics, biomarker explorations, and quality-of-life assessments. Results: By the data cutoff of December 15, 2023, continuing improvements in PFS (16.8 vs. 10.7 months; stratified HR 0.62, 95% CI 0.33–1.12) and DOR (19.4 vs. 12.6 months; stratified HR 0.33, 95% CI 0.13–0.85) were observed for group A compared to group B. 55/112 (49.1%) patients in the efficacy evaluable set has died; 24/55 (43.6%) patients in group A and 31/57 (54.4%) in group B. Median overall survival (OS) was not reached (NR) in group A, and 21.2 months in group B (stratified HR 0.75, 95% CI 0.43–1.30). Subgroup analysis showed similar trends towards an improved median OS for key subgroups including microsatellite stable (MSS) (NR vs. 21.2 months; stratified HR 0.73, 95% CI 0.39–1.37), KRAS-mutant (21.9 vs. 18.2 months; unstratified HR 0.72, 95% CI 0.37–1.39), and liver metastasis (NR vs. 20.2 months; unstratified HR 0.75, 95% CI 0.40–1.41) patients. The estimated OS rate at 2 years was 53.7% (95% CI 39.1–66.2), and 43.1% (95% CI 29.5–55.9) in group A, and group B, respectively. 38 (69.1%) patients in group A and 34 (59.6%) in group B had grade ≥3 treatment-related adverse events. Serplulimab/placebo-related deaths occurred in 2 (3.6%) patients in group A and 1 (1.8%) patient in group B. Conclusions: With an extended follow-up duration, improved survival benefits demonstrated with the addition of serplulimab were maintained in the first-line treatment of mCRC, alongside a manageable safety profile. These results support serplulimab plus HLX04 and XELOX as a promising first-line treatment option for mCRC that warrants further investigation. Clinical trial information: NCT04547166 .

Preliminary efficacy and safety of fruquintinib as maintenance therapy after first-line treatment in metastatic colorectal cancer (mCRC): A multicenter, randomized, open-label clinical trial (the FRONT study).

126 Background: Maintenance therapy and discontinuation of treatment are options to mCRC patients who response to first-line treatment. We conducted this study to evaluate the efficacy and safety of fruquintinib as maintenance therapy after first-line treatment for mCRC. Methods: This is an ongoing, multicenter, open-label, randomized clinical trial. Patients (pts) with unresectable right-sided mCRC or RAS-mutant left-sided mCRC, who hadn’t suffer disease progression after first-line standard treatment (chemotherapy with or without bevacizumab) for four to six months, were eligible. According to the protocol, 110 patients would be randomly assigned (2:1) to fruquintinib (FR) group (4mg once daily for 21 days, followed by 7 days off in 28 day cycles) or observation (OB) group via interactive web response system. The primary endpoint was progression-free survival (PFS). Results: Up to Aug 22, 2023, 28 and 14 patients had been enrolled in FR group and OB group, of whom the median age was 61 (44 to 73) vs. 66.5 (36 to 81), including 20 (71%) vs. 10 (71%) males, respectively. 26 (93%) vs. 11 (79%) patients were RAS-mutant. In the full analysis set (FAS), the median PFS were 5.26 (95% CI: 3.71-19.12) months and 2.99 (95% CI: 1.91-4.63) months (HR=0.36; p=0.0158). 25 and 13 pts from two groups received at least one response evaluation after baseline, respectively. The disease control rate (DCR) was 88.00% (22/25) vs. 53.85% (7/13) (OR=6.29, 95% CI: 1.31-36.7; p=0.0267). As to the per-protocol set (PPS), since 6 pts in FR group initiated with a lower dose (3mg), the number of patients was 22 vs. 14. The median PFS were 6.51 (95% CI: 3.88-19.12) months and 2.99 (95% CI: 1.91-4.63) months (HR=0.25; p=0.0061). The DCR was 89.47% (17/19) vs. 53.85% (7/13) (OR=7.29, 95% CI: 1.32-58.9; p=0.0331). The common AEs in FR group were hypertension, hand-foot syndrome, fatigue, rash, oral mucositis, and proteinuria, while AEs of grades≥3 were hand-foot syndrome, hypertension, oral mucositis, and proteinuria. Conclusions: Fruquintinib at a moderate dose level indicated better outcomes of PFS as a maintenance therapy after first-line therapy with acceptable toxicity for patients with mCRC. Clinical trial information: NCT04296019 .

Analysis of immune-related genes (IRGs) and their potential role in sexual dimorphism in patients (pts) with metastatic colorectal cancer (mCRC).

182 Background: Sex-based disparities have been reported for mCRC both in incidence, males having higher incidence than females, and in outcome, younger females having better outcome than males of same age or older females. Tumor immune microenvironment is hypothesized to have role in this sexual dimorphic pattern. Herein, we explored the role of gene expression (exp) and genetic variation of IRGs on progression-free (PFS) and overall survival (OS) in mCRC pts. Methods: 21 IRGs with potential roles in CRC were identified from literature review. The association of tumor gene exp with PFS and OS was evaluated in pts with mCRC (433 pts, RNA seq) from CALGB/SWOG 80405. Subgroup analyses were based on treatment (bevacizumab [bev] (N = 226) / cetuximab [cet] (N = 207)) and sex (male (N = 271) / female (N = 162)). Further, the impact on outcome of 5 selected germline single nucleotide polymorphisms (SNPs) in 3 significant IRGs, SCG2 (rs600257, rs9283537), CRIP2 rs66717274, and AXIN2 (rs7591, rs2240308), was evaluated in genotyped (OncoArray, Illumina) samples of 451 pts from 2 clinical trials: FIRE-3 (FOLFIRI-bev, N = 107; FOLFIRI-cet, N = 129) and TRIBE (FOLFIRI-bev, N = 215). Unadjusted associations were evaluated using log-rank (lr) tests; covariate-adjusted analyses were performed using Cox models for hazard ratio (HR) estimation and likelihood ratio testing. Results: Of 21 analyzed IRGs, SCG2, CRIP2 and AXIN2 significantly associated with PFS and OS in mCRC pts in CALGB/SWOG 80405 divided into tertiles of high, medium and low exp. Among pts receiving cet treatment, SCG2high (PFS: median 9.0 vs 13.0 months (mo), lrP = 0.015; OS: 20.4 vs 37.4 mo, lrP = 2.9e-05) and CRIP2high (PFS: 9.2 vs 14.2 mo, lrP = 0.00076; OS: 20.9 vs 36.3 mo, lrP = 8.3e-05) were significantly associated with shorter PFS and OS, whereas AXIN2high (PFS: 14.1 vs 7.3 mo, lrP = 2.4e-06; OS: 37.1 vs 15.6 mo, lrP = 4.9e-05) correlated with longer PFS and OS. Sex-based differences were observed, SCG2high exp associated with shorter PFS (10.0 vs 13.1 mo, lrP = 0.0054) and OS (22.3 vs 36.0 mo, lrP = 7.7e-05), and similarly CRIP2high associated with shorter PFS (9.8 vs 14.2 mo, lrP = 0.012) and OS (23.6 vs 35.8 mo, lrP = 4e-04), in males but not in females. In univariate SNP analysis, SCG2 rs9283537 any A allele showed shorter PFS (HR = 0.62, 95% Confidence interval [CI] = 0.40-0.98, P = 0.039) in females but longer PFS (HR = 2.37, 95% CI = 1.07-5.22, P = 0.028) in males compared to G/G carriers in the FIRE-3 cet cohort and interaction analysis showed significant p-values for PFS and OS (P<0.005). Conclusions: Our results highlight important role for SCG2, CRIP2, and AXIN2 as prognostic and predictive biomarkers for first-line treatment in mCRC, with potential targeted agent- and pt’s sex-based differences. These biomarkers with further validation may contribute to personalized treatment strategies for mCRC pts.

First-line serplulimab plus HLX04 and XELOX versus placebo plus bevacizumab and XELOX in metastatic colorectal cancer: A phase 2/3 study.

124 Background: Immunotherapy significantly improved survival in patients with dMMR/MSI-H metastatic colorectal cancer (mCRC). However, whether the addition of immunotherapy to the current standard-of-care treatments can improve efficacy in pMMR/MSS mCRC, the predominant type of mCRC, is unclear. This study aimed to compare the efficacy of serplulimab, a novel PD-1 inhibitor, plus HLX04, a bevacizumab biosimilar, and XELOX versus placebo plus bevacizumab and XELOX as first-line treatment for mCRC. Methods: This was a randomized, double-blind, multicenter phase 2/3 study; current report will focus on the phase 2 part. Patients with unresectable metastatic/recurrent colorectal adenocarcinoma and no prior systemic therapy were randomized 1:1 to receive serplulimab (300 mg, Q3W IV) plus HLX04 (7.5 mg/kg, Q3W IV) and XELOX (group A) or placebo plus bevacizumab and XELOX (group B). Randomization was stratified by PD-L1 expression level (CPS <1 vs. 1≤ CPS <50 vs. CPS ≥50), ECOG PS score (0 vs. 1), and primary tumor site (left- vs. right-sided). The primary endpoint was IRRC-assessed PFS per RECIST 1.1. Secondary endpoints included other efficacy endpoints, safety, pharmacokinetics, biomarker explorations, and quality-of-life assessments. Results: Between July 16, 2021 and January 20, 2022, 114 patients were enrolled and randomly assigned to group A (n=57) and group B (n=57). 83 (72.8%) patients were male. All patients had stage IV CRC, and 90 out of the 94 (95.7%) with available MSI status were MSS. Current report will focus on efficacy and safety findings in the modified intention-to-treat population, which included only patients who received study treatment (group A, n=55; group B, n=57). As of June 1, 2023 (data cutoff), median follow-up duration was 17.7 months. IRRC-assessed median PFS was longer in group A than in group B (17.2 vs. 10.7 months; stratified HR 0.60, 95% CI 0.31–1.14). Median OS was not reached in either group (stratified HR 0.77, 95% CI 0.41–1.45). 36 (65.5%) patients in group A and 32 (56.1%) in group B had grade ≥3 treatment-related adverse events (AEs), most commonly neutrophil count decreased (21.8% vs. 10.5%) and platelet count decreased (16.4% vs. 10.5%). Grade ≥3 immune-related AEs were reported for 5 (9.1%) patients in group A and 1 (1.8%) in group B. Treatment-related deaths occurred in 4 (7.3%) patients in group A and 3 (5.3%) in group B. Conclusions: Serplulimab plus HLX04 and XELOX prolonged PFS compared to placebo plus bevacizumab and XELOX. Improvements in other efficacy endpoints were also observed with a manageable safety profile in patients with mCRC. Serplulimab plus HLX04 and XELOX is a promising first-line treatment option for mCRC patients that warrants further investigation. Clinical trial information: NCT04547166 .

Efficacy and quality of life for FOLFOX/bevacizumab +/− irinotecan in first-line metastatic colorectal cancer—final results of the AIO CHARTA trial

BackgroundFOLFOXIRI plus bevacizumab has demonstrated benefits for metastatic colorectal cancer (mCRC) patients. However, challenges arise in its clinical implementation due to expected side effects and a lack of stratification criteria.MethodsThe AIO “CHARTA” trial randomised mCRC patients into clinical Group 1 (potentially resectable), 2 (unresectable/risk of rapid progression), or 3 (asymptomatic). They received FOLFOX/bevacizumab +/− irinotecan. The primary endpoint was the 9-month progression-free survival rate (PFSR@9). Secondary endpoints included efficacy in stratified groups, QoL, PFS, OS, ORR, secondary resection rate, and toxicity.ResultsThe addition of irinotecan to FOLFOX/bevacizumab increased PFSR@9 from 56 to 67%, meeting the primary endpoint. The objective response rate was 61% vs. 69% (P = 0.21) and median PFS was 10.3 vs. 12 months (HR 0.83; P = 0.17). The PFS was (11.4 vs. 12.9 months; HR 0.83; P = 0.46) in potentially resectable patients, with a secondary resection rate of 37% vs. 51%. Moreover, Group 3 (asymptomatic) patients had a PFS of 11.1 vs. 16.1 months (HR 0.6; P = 0.14). The addition of irinotecan did not diminish QoL.ConclusionThe CHARTA trial, along with other studies, confirms the efficacy and tolerability of FOLFOXIRI/bevacizumab as a first-line treatment for mCRC. Importantly, clinical stratification may lead to its implementation.Trial registrationThe trial was registered as NCT01321957.

The prognostic impact of NKA dynamics in first-line treatment of metastatic colorectal cancer.

e15514 Background: Metastatic colorectal cancer (mCRC) remains a therapeutic challenge and new markers hold high priority. Natural Killer (NK) cells are immune cells with potent antitumor properties. The association between neoplastic development and level of effector functions of this cell type is well known. Moreover, it is recognized that NK cells are subject to tumor-mediated immune suppression. The present study aimed at elucidating a potential relationship between NK cell activity (NKA) and response to folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI) in mCRC. Methods: NKA was analyzed in patients enrolled in a randomized trial of mCRC receiving FOLFOXIRI and either tocotrienol or placebo as first-line treatment. Blood (1 mL) was sampled into NK Vue tubes at baseline and before treatment cycles 2-3, placed at 37°C for 24 hours, and after incubation, the level of interferon-γ (IFNγ) in the plasma was a surrogate measure for NKA. A cutoff of 250 pg/mL IFNγ distinguished normal and low NKA. The endpoints were response rate (RR), progression-free survival (PFS), and overall survival (OS). Results: A total of 70 patients were enrolled in the randomized clinical trial. The results showed that tocotrienol had no effect on either RR (p = 0.62), PFS (p = 0.52), or OS (p = 0.80). Patients were classified into two groups according to the dynamics of NKA measured at the available time points. Patients that dropped from a normal to a low level of NKA in samples taken between baseline and before cycle 3 and patients with continuous low NKA (IFNγ < 250 pg/mL) were categorized as NKA-low. The NKA-high group included patients that increased from an abnormal to a normal level of NKA and patients that remained within the normal range (IFNγ > 250pg/mL) in all available samples. The RR in the two groups were 38% (8/21) and 69% (24/35), respectively (p = 0.0496). The median PFS was 186 days (95% confidence interval (CI) 136-225 days, n = 23) for the NKA-low group and 252 days (95% CI 223-305 days, n = 37) for NKA-high (p = 0.0005). The hazard ratio (HR) was 2.65 (95% CI 1.28-5.50). After adjusting for age, performance status (PS), and tumor location, NKA remained an independent prognostic factor for PFS (HR = 3.32, 95% CI 1.67-6.61, p = 0.001). Median OS was 408 days (95% CI 219-679 days, n = 23) and 1051 days (95% CI 645-1225 days, n = 37), respectively (p = 0.0034). For OS, the NKA-low group also showed a poor prognosis, HR 2.23 (95% CI 1.17-4.25). NKA dynamics remained an independent prognostic marker for OS after adjusting for age, PS, and tumor location (HR = 2.74, 95% CI 1.50-5.03, p = 0.001). Conclusions: The results suggest that NKA dynamics within the first two cycles of treatment may hold relevant prognostic information in first-line treatment of mCRC. The possible causative relationship between NKA and treatment effect needs further elucidation, but calls for experimental trials combining chemotherapy with NK cell therapy in mCRC.

Single nucleotide polymorphisms (SNPs) in MHC class I and II genes to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from FIRE-3, MAVERICC, and TRIBE trials.

3578 Background: The immune system is alerted for virally infected cells in the body by the antigen presentation pathway, which is in turn mediated by the major histocompatibility complex (MHC) class I and II molecules. Cancer cells overcome immune evasion as a major hallmark by downregulation of antigen presentation pathway molecules. Therefore, the present study aimed to explore the effect of genetic variants in MHC class I and II pathways on first-line treatment outcome in mCRC pts. Methods: Genomic DNA from blood samples of 775 pts enrolled in three independent, randomized, first-line trials: TRIBE (FOLFIRI-bevacizumab [bev], N = 215), FIRE-3 (FOLFIRI-bev, N = 107; FOLFIRI-cetuximab [cet], N = 129) and MAVERICC (FOLFIRI-bev, N = 163; FOLFOX-bev, N = 161) was genotyped through OncoArray, a custom array manufactured by Illumina including approximately 530K SNP markers. The impact on outcome of 40 selected SNPs in 22 genes of MHC class I and II pathways ( ERAP1, ERAP2, TAP1, TAP2, TAPBP, B2M, HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, HLA-G, CIITA, HLA-DMA, HLA-DMB, HLA-DOA, HLA-DOB, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1 and HLA-DRA) was analyzed. Results: We identified several SNPs in multiple genes associated with targeted treatment benefit across different treatment arms in our study population ( P < .05). Germline variants in ERAP1 rs2287987 were associated with worse PFS in pts receiving FOLFIRI-bev in TRIBE (10.4 vs 8.8 months, HR 1.48, 95%CI 1.04-2.12, P = .035) and FIRE-3 trials (11.1 vs 9.9 months, HR 3.46, 95%CI 1.18-10.12, P = .049), while rs26653 SNP in the same gene was associated with better PFS in MAVERICC (10.1 vs 14.5 months, HR 0.54, 95%CI 0.35-0.84, P = .0062). TAP1 rs1135216, TAP2 rs1800454 and rs1044043, HLA-B rs2770, HLA-G rs1610696, CIITA rs4774, HLA-DRA rs7192 were associated with longer OS and/or PFS in cet-treated pts in FIRE-3; whereas TAP2 rs241447, TAPBP rs3106191, HLA-DMB rs10751, HLA-DOB rs11244, HLA-DPB1 rs3097671 showed worse PFS and/or OS. SNPs in TAP2 (rs1800454), HLA-C (rs1049281), HLA-G (rs1063320), CIITA (rs1139564), HLA-DMB (rs1042337), HLA-DOA (rs375256, rs3129303), HLA-DPA1 (rs1042190) and HLA-DRA (rs7192) were specifically associated with clinical outcomes in the FOLFOX-bev arm of MAVERICC but not in control cohorts of pts treated with FOLFIRI-bev. Treatment-SNP interaction analyses with targeted agents (bev vs cet) and chemotherapy backbone (FOLFIRI vs FOLFOX) confirmed a significant treatment interaction for HLA-G, TAP2, CIITA, and HLA-DMB SNPs ( P < .05). Conclusions: Our results highlight an important role for MHC SNPs as prognostic and predictive biomarkers for first-line treatment in mCRC, with differential effects based on biologic agent and chemotherapy backbone. These biomarkers, when further validated, may contribute to personalized treatment strategies for mCRC patients.

Systemic treatment for metastatic colorectal cancer.

Significant progress has been achieved in the treatment of metastatic colorectal cancer (mCRC) patients during the last 20 years. There are currently numerous treatments available for the first-line treatment of mCRC. Sophisticated molecular technologies have been developed to reveal novel prognostic and predictive biomarkers for CRC. The development of next-generation sequencing and whole-exome sequencing, which are strong new tools for the discovery of predictive molecular biomarkers to facilitate the delivery of customized treatment, has resulted in tremendous breakthroughs in DNA sequencing technology in recent years. The appropriate adjuvant treatments for mCRC patients are determined by the tumor stage, presence of high-risk pathologic characteristics, microsatellite instability status, patient age, and performance status. Chemotherapy, targeted therapy, and immunotherapy are the main systemic treatments for patients with mCRC. Despite the fact that these novel treatment choices have increased overall survival for mCRC, survival remains optimal for individuals with non-metastatic disease. The molecular technologies currently being used to support our ability to practice personalized medicine; the practical aspects of applying molecular biomarkers to regular clinical practice; and the evolution of chemotherapy, targeted therapy, and immunotherapy strategies for the treatment of mCRC in the front-line setting are all reviewed here.

Updated results of ALTER-C002: Anlotinib combined with CAPEOX as first-line treatment in RAS/BRAF wild-type unresectable metastatic colorectal cancer.

138 Background: Anlotinib is an oral multi-target tyrosine kinase inhibitor, mainly targeting VEGFR1-3, FGFR 1-4, PDGFR a/b and c-kit. Previous trial had demonstrated that anlotinib monotherapy was effective and safe in advanced colorectal cancer. ALTER-C002 trial is an open-label, single-arm, phase II study, aimed to evaluate the efficacy and safety of anlotinib plus CAPEOX as first-line therapy in patients with RAS/ BRAF wild-type unresectable metastatic colorectal cancer (mCRC). Preliminary results demonstrated significant antitumor activity and manageable toxicity. Here we reported the updated results at the data cutoff of August 19, 2022. Methods: RAS/BRAF wild-type unresectable mCRC patients with no prior systemic treatment received anlotinib (12 mg p.o. qd, d1-d14, q3w), capecitabine (850 mg/m2 p.o., bid, d1-d14, q3w) and oxaliplatin (130 mg/m2 i.v., d1, q3w) for 6 cycles followed by anlotinib and capecitabine as maintenance therapy until disease progression. Tumor response was assessed every 6 weeks according to RECIST v1.1 by investigator. The primary endpoint was ORR, and secondary endpoints included safety, DCR, DOR and PFS. Results: From Nov 2019 to February 2021, 30 eligible patients were enrolled, of whom, median age was 60y (range, 32-72y), 26 (86.7%) had left colon or rectal cancer, and 25 (83.3%) had liver metastases. The ORR was 76.7% (95% CI, 57.7-90.1%) with 2 patient achieved a complete response (CR); DCR was 93.3% (95% CI, 77.9-99.2%). At the data cutoff date, the median DOR was 7.9 months (95% CI, 4.3–11.4) and the median DOT was 8.38 months (95%CI, 5.9-10.9). The median OS has not reached yet, the 24-month OS rate was 72.8% (95%CI, 50.7-86.3%) and the 30-month OS rate was 58.3% (95%CI:25.5-80.8%). Grade 3-4 treatment-emergent adverse events (TEAEs) occurred in 25 (83.3%) patients; the most common grade 3 or 4 TEAEs ( > 10%) were hypertension (50%, 15/30 pts), neutropenia (26.7%, 8/30 pts) and diarrhea (13.3%, 4/30 pts). No grade 5 treatment-related events occurred. Conclusions: Anlotinib combined with CAPEOX exhibited promising ORR in the first-line treatment of mCRC compared to those of previous treatment. A longer follow-up is needed for a more complete assessment, and we launched a phase III, multicenter, open-label trial to assess the efficacy of this regimen comprehensively. Clinical trial information: NCT04080843 .

Costs of adverse event management associated with first-line cetuximab or panitumumab in patients with metastatic colorectal cancer in Spain.

83 Background: Patients with RAS wild-type metastatic colorectal cancer (mCRC) in Spain may be treated with an epidermal growth factor receptor inhibitor: cetuximab (cet) or panitumumab (pan), in combination with chemotherapy (CT). Several factors may influence the choice of treatment regimen, including adverse event (AE) management, as cet- and pan-based therapies have distinct individual safety profiles. Patients may experience multiple adverse events during treatment. This study aimed to estimate the associated financial impact on Spain’s National Health System (SNHS). Methods: An economic model was developed to project the mean number of AEs per patient (p-p) and to estimate p-p and population-level costs of AE management (cAEm) associated with first-line cet+CT and pan+CT treatment regimens. Data on common and very common AEs and their severity were sourced from the summaries of product characteristics and a meta-analysis by Petrelli, et al. Categorical values were converted into numerical values using the mean values of the frequencies for each AE. Applicable resource costs were obtained from a Spanish database with health unit costs from official records, and from literature on oncology treatment-related costs. The eligible patient population was determined from published and grey literature, and market research. AEs of grade 1-2 were assumed to be treated in an outpatient setting, and those of grade 3-4 treated in an inpatient setting. The model inputs were validated by clinical oncologists in Spain. Results: An estimated 3,794 (cet+CT) and 2,325 (pan+CT) eligible patients received first-line treatment for mCRC. For patients receiving cet+CT or pan+CT, the average frequency of AEs p-p was estimated to be 7.2 (cet+CT) and 17.2 (pan+CT), with estimated p-p cAEms of €5,655 and €13,571, respectively. Conclusions: The lower rates of AEs for cet+CT may result in a reduced AE burden for eligible patients with mCRC, with estimated savings of €7,917 p-p on average. Although overall costs and clinical outcomes should be considered, treatment with cet+CT could yield annual cAEm savings for the SNHS of 35%. Future studies should consider the impact of AE management in a real-world setting.

389P Randomized phase II study of FOLFIRI plus ramucirumab versus FOLFOXIRI plus ramucirumab as first-line treatment for metastatic colorectal cancer: WJOG9216G (RECAST)

FOLFIRI plus bevacizumab (BEV) is widely used as first-line treatment for metastatic colorectal cancer (mCRC), and FOLFOXIRI plus BEV is an option. Clinical outcomes of ramucirumab (RAM) combined with FOLFIRI and FOLFOXIRI in first-line treatment are not well known. We conducted a randomized phase II study to assess the superiority of FOLFOXIRI plus RAM over FOLFIRI plus RAM as first-line treatment for mCRC. Main eligibility criteria were unresectable colorectal adenocarcinoma, age 20-75 years, ECOG PS <1, no previous chemotherapy, measurable lesions, and wild-type or heterozygous UGT1A1 *28/*6. In arm A, patients received FOLFIRI (irinotecan [IRI] 180 mg/m2, l-leucovorin [l-LV] 200 mg/m2, bolus 5-fluorouracil [5-FU] 400 mg/m2, continuous 5-FU 2400 mg/m2) plus RAM (8 mg/kg) biweekly until disease progression. In arm B, patients received 8 cycles of FOLFOXIRI (oxaliplatin 85 mg/m2, IRI 165 mg/m2, l-LV 200 mg/m2, continuous 5-FU 3200 mg/m2) plus RAM biweekly followed by 5-FU/l-LV plus RAM. The primary endpoint was confirmed objective response rate (ORR). The sample size was 120, assuming ORRs of 50/70% in arm A/B with 80% power at a 10% α-level (one-sided). A total of 122 patients were randomized (59/63 in arm A/B) from Jun 2017 to Sep 2020. The baseline characteristics in arm A/B were as follows: median age 64/65, male 66/70%, right colon 29/30%, RAS mutant 61/67%, BRAF mutant 9/3%, liver-limited disease 32/19%. 50/51 (84.7/81.0%) patients in arm A/B completed 8 cycles. The ORRs in arm A/B were 57.6/60.3% (odds ratio 1.11, p=0.76). With median follow-up of 27.4/25.3 months in arm A/B, median progression free survival (PFS) was 11.7/10.5 months (hazard ratio 1.13, p=0.57). R0 resection was performed in 10/6 (16.9/9.5%) patients in arm A/B. Major grade >3 adverse events (incidence in arm A/B) were neutropenia (44.1/72.6%), hypertension (15.3/19.4%), proteinuria (13.6/12.9%), anorexia (3.4/14.5%), febrile neutropenia (3.4/11.3%), and diarrhea (1.7/8.1%). FOLFOXIRI plus RAM did not show significant superiority in terms of ORRs and PFS compared with FOLFIRI plus RAM as first-line treatment for mCRC.

P-182 Anti-EGFR antibodies may get benefit as first-line treatment in metastatic right-sided colon cancer

Location of the primary tumor can be prognostic and predictive of response to EGFR inhibitors as first-line treatment in mCRC suggesting that cetuximab and panitumumab confer little benefit for right side mCRC. HER2 has signaling kinase receptor as EGFR and has been successfully targeted in breast cancer and now showing activity in colon cancer.

P-257 In vitro drug screening of patient-derived 3D tumoroids replicates resistance to FOLFOX, FOLFIRI, and FOLFOXIRI in clinically resistant patients with metastatic colorectal cancer

International guidelines present three different chemotherapy regimens for first- and subsequent-line treatment of unresectable metastatic colorectal cancer (mCRC). The main doublet therapies used in first-line treatment is FOLFIRI (5-FU + irinotecan) and FOLFOX (5-FU + oxaliplatin). The two combination treatments offer a similar response rate of 34-55%. The treatments are therefore used indistinctly in the clinic. Evidence is however starting to appear showing that there are differences between the individual patients as to which of the combination treatments that are superior. One approach to increase effectiveness of chemotherapy treatment is to use a patient-derived 3D tumoroid test (such as IndiTreat ® ) to identify the most efficacious treatment and also the ones to which the patient is resistant. The tumoroids closely recapitulate a patient’s tumor. The objective of the present study was to evaluate if IndiTreat ® could distinguish between patients that are clinically drug resistant (CDR) from patients that are chemonaive to the regimens FOLFOX and FOLFIRI plus the triple combination FOLFOXIRI (5-FU + oxaliplatin + irinotecan). We included 8 chemonaive patients and 19 patients from the ongoing clinical trial, (ClinicalTrials.gov, NCT03251612). The latter were tested and treated in accordance with IndiTreat ® test results. To be enrolled in the trial, patients had to have progressive unresectable mCRC and be exposed to available standard therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents and anti-EGFR agents if RAS/RAF wild-type. This group was defined as CDR patients. For CDR patients, ultrasound - or CT-guided biopsies were sampled from liver metastases. A 16-gauge needle was used (SuperCore TM , Argon Medical Devices, Athens, TX, USA). The biopsies were mechanically dissociated into tissue fragments and embedded in Matrigel (Corning Life Sciences, Merck, Germany). Screening of samples from CDR patients and chemonaive patients were done according to a modified version of a procedure previously described. The tumoroids were exposed to the drug treatments for seven days. Tumoroids growth was measured by taking brightfield images with a Cytation 1 (Biotek) imaging system and quantified using 2cureX’s artificial intelligence algorithm IndiNet TM. For all three treatment regimens, the IndiTreat ® test showed that the growth inhibition of tumoroids from CDR patients was significantly less compared to chemonaive patients. The clustering for the CDR patients showed that the IndiTreat ® test identified 81%-94% of the patients as having a low growth inhibition (FOLFIRI 94%, FOLFOX 81% and FOLFOXIRI 82%). Conversely, for chemonaive patients, the IndiTreat ® test identified 88%-100% of the patients presented high growth inhibition (FOLFIRI 88%, FOLFOX 100% and FOLFOXIRI 100%). - The IndiTreat ® test is with a high degree of precision able to identify patients that are clinically resistant to the regimens of FOLFOX, FOLFIRI and FOLFOXIRI. - The present study was performed retrospectively in first- and third-line patients. To investigate the general applicability of the IndiTreat ® test, we plan to perform a prospective study in first-line treatment of mCRC with resistance as the primary endpoint. - Ultimately, the IndiTreat ® technology will assist in the identification of the most efficacious chemotherapy treatment in first-line unresectable mCRC patients.

P-80 A multicenter randomized phase II study comparing CAPOXIRI plus bevacizumab and FOLFOXIRI plus bevacizumab as the first-line treatment for metastatic colorectal cancer: A safety analysis of the QUATTRO-II study

FOLFOXIRI plus bevacizumab (BEV) is the standard first-line treatment for metastatic colorectal cancer (mCRC) despite its association with a high incidence of neutropenia and diarrhea. In this study, capecitabine (CAP), oxaliplatin (OX), and irinotecan (IRI) (CAPOXIRI) plus BEV are hypothesized to be more feasible than FOLFOXIRI plus BEV, without compromising the efficacy. Here, results of safety analysis in the induction phase are reported in the randomized phase II QUATTRO-II study comparing CAPOXIRI plus BEV and FOLFOXIRI plus BEV as the first-line treatment for mCRC. This multicenter, open-label, randomized phase II study enrolled patients with the ECOG performance status of 0 or 1, without previous chemotherapy in the metastatic setting, with adequate organ function, and with UGT1A1 *6/*28 gene polymorphisms of wild-type or single heterozygous. Patients were randomized in a 1:1 ratio to FOLFOXIRI plus BEV (arm A) or CAPOXIRI plus BEV (arm B). As we previously reported, the recommended phase II doses of CAPOXIRI plus BEV were determined as CAP, 1,600 mg/m2; OX, 130 mg/m2; IRI, 200 mg/m2; and BEV, 7.5 mg/kg every 3 weeks from the results of Safety Lead-In of this study. FOLFOXIRI plus BEV or CAPOXIRI plus BEV in the induction phase was continued until 8/6 (arm A/B) cycles (maximum, 12/8 cycles), followed by 5-FU/l-LV plus BEV or CAP plus BEV in the maintenance phase at the investigator’s discretion. The primary endpoint was progression-free survival, and secondary endpoints were overall response rate, overall survival, and safety. The completion of the induction phase was defined as meeting both of the following two criteria in all cycles: all drugs are administered (dose reduction was permitted); and the cycle was started within 28 days of the planned start date. A total of 103 patients (arm A/B, 51/52) were enrolled from June 2020 to June 2021. Baseline patient characteristics (arm A/B), including the median age (range), 60 (38–75)/60 (35–77) years; the ECOG performance status of 0, 46 (90%)/49 (94%); and UGT1A1 *6/*28 gene polymorphisms, wild-type 30 (59%)/29 (56%) were similar between the two treatment arms. At the data cutoff of December 17, 2021, the incidence of grade >3 major adverse events (AEs) in the induction phase was as follows (arm A/B): neutropenia (65%/39%), febrile neutropenia (10%/12%), diarrhea (8%/17%), and anorexia (8%/17%). No treatment-related deaths occurred. Among patients in arms A and B, 26 (51%) and 30 (58%) patients achieved the completion of the induction phase, respectively. The main reasons for incompletion of the induction phase (arm A/B) were treatment discontinuation due to resection (9/9), disease progression (2/5), and adverse events (5/1) and not meeting the definition of completion of the induction phase (6/6). This safety analysis showed that both CAPOXIRI plus BEV and FOLFOXIRI plus BEV were safe and tolerable with differences in AE incidences and toxicity profiles. The QUATTRO-II study is still in the follow-up phase, and the efficacy data will be reported in next year’s scientific meeting.

Using cell-free circulating tumor DNA (cfDNA) to identify guideline-relevant biomarkers for therapy selection in 14,000 patients (pts) with metastatic colorectal cancer (mCRC).

3601 Background: Two cfDNA assays are FDA-approved for use in advanced cancer pts across solid tumors. While several NCCN guidelines recommend cfDNA as a valid and useful method for molecular testing, the utility varies by cancer type. Despite the growing number of molecular alterations pertinent to first-line treatment in mCRC, current guidelines offer little guidance on the use of cfDNA in mCRC. Here we assess the ability of cfDNA to detect guideline-relevant actionable biomarkers informative for first-line therapy selection and beyond in patients with mCRC. Methods: We queried consecutive samples from advanced cancer pts with a diagnosis of CRC who underwent testing via a commercially available cfDNA assay (Guardant360) from September 2018 to January 2022. Validation and content of this assay has been previously described. To enrich for less heavily treated pts, we limited analysis to those whose first cfDNA test was done during the study period and only included the pt’s first test. The maximum variant allele fraction (maxVAF) for each test was used as a proxy for tumor shed and was compared between cancers with a Mann-Whitney test. The frequency of suspected germline alterations was assessed only in pts who received testing via a panel version with expanded mismatch repair (MMR) gene coverage. Tissue frequencies for select biomarkers were obtained from the MSK-IMPACT Clinical Sequencing Cohort in cBioPortal. Results: In total, 14,345 pts with mCRC received their first cfDNA test during the study period, with 92% of pts (13,190) having &gt;1 cfDNA alteration detected. Median age was 62 and 44% of pts were female. The frequencies of key biomarkers are listed in Table 1. The median maxVAF was 5.6%, compared to 2.5% and 1.8% for pts with advanced gastric and NSCLC, respectively (p = &lt; 0.0001 for both). The average turnaround time (TAT) for tests was 7 calendar days. Conclusions: cfDNA results from pts with mCRC demonstrated detection of biomarkers essential to first-line treatment decisions at a frequency comparable to what has been reported via tissue genotyping. mCRC pts had significantly higher tumor shed compared to other cancer types with guidelines that recommend cfDNA as an option for molecular testing, suggesting a potential gap in coverage. Tissue availability in mCRC does not guarantee comprehensive testing is completed quickly (compared to the 7-day TAT seen for cfDNA here), making it an attractive alternative strategy for first-line therapy selection in mCRC. [Table: see text]

P-280 Can immune checkpoint inhibitors plus surgery cure advanced mismatch repair-deficient cancer?

There is a strong body of evidence supporting use of immune checkpoint inhibitors (ICI) in unresectable mismatch repair-deficient (MMRd) / microsatellite unstable (MSI) high colorectal cancer (mCRC); anti-PD-1 therapy is the standard of care for first-line treatment of mCRC (Andre, NEJM 2021). Emerging evidence also demonstrates high rates of complete pathological response (pCR) following neoadjuvant ICI in patients with stage I-III MSI colon cancer (Chalabi, Nature 2020) and in MSI gastric cancer (Andre, ASCO GI 2022). This leads to the question of whether ICI with or without surgery could lead to cures in advanced MSI cancers. Herein we describe our single institutional experience of immunotherapy followed by surgery in MSI intestinal cancers. In this retrospective series the institutional electronic health record was reviewed for patients with ICI treated MSI intestinal cancers with subsequent surgical resection. Demographics and clinicopathological characteristics were collected, with ICI therapy details and toxicity, radiological response and operative details. Post-operative histology was reviewed. Overall survival was calculated using the Kaplan-Meier method. Five patients were identified; 5 (100%) female. Mean/median age was 37/46 years (range 22-78). Four (80%) had MLH1/PMS2 deficient cancers, 1 was MSH2/MSH6 deficient. One had germline MLH1 mutation, one germline pending. Two (40%) had concurrent tumour BRAF V600E mutation, two (40%) had KRAS G12D mutation. Four (80%) had colon cancer (1 ascending colon, 1 synchronous ascending colon and hepatic flexure, 1 transverse colon, 1 rectosigmoid); 1 patient jejunal adenocarcinoma. Three colon cancer patients had lymph node metastases distant from the primary, one had local pelvic side wall recurrence, one had direct invasion of liver and pancreas. All patients received ICI with initial palliative intent (1 ascending colon 2nd line nivolumab, 1 synchronous tumours 1st line nivolumab/ipilimumab, 1 rectosigmoid 2nd line nivolumab/ipilimumab, 1 transverse 1st line pembrolizumab, jejunal 1st line nivolumab). Two patients had admissions with ICI related fevers, 1 experienced ICI G3 pneumonitis and 1 experienced G3 hepatitis. All patients had radiological response to ICI. Two patients (transverse colon / jejunal cancer) experienced stricture in responding primary tumour and required surgery. One ascending colon cancer had surgery a symptomatic PET-avid mass, 1 synchronous cancer patient had right total mesocolic excision, partial hepatectomy and Whipples. One recurrent rectosigmoid colon cancer had total pelvic exenteration following ICI and radiotherapy. All patients had R0 resection. Two patients had pCR (ypT0N0) (ascending colon, rectosigmoid colon); both complete responders had experienced ICI related toxicity. Other patients’ stage were transverse colon (ypT3N0), jejunal cancer (ypT0N1) and synchronous tumours (ypT4N0 and ypT2N0). After median follow up of 15 months, no patient has recurrent disease. Median overall survival is not reached. In this series we demonstrate that a combination of ICI and surgery can render patients with advanced MSI cancers disease free by downstaging previously unresectable cancers and eliminating distant metastases. As complete responses were demonstrated in two patients with suspicious pre-operative radiological findings on resection, improved imaging techniques or ctDNA may be helpful in guiding which patients require surgery in future.

P-230 The effect of duration of induction therapy on survival in patients receiving maintenance therapy in the first line for metastatic colorectal cancer: A single-center retrospective analysis

Standard first-line treatment of metastatic colorectal cancer (mCRC) is combination chemotherapy with the addition of a biological agent. Several randomized clinical trials have investigated different strategies of continuing chemotherapy until progression compared with a period of either treatment break or the use of various maintenance therapies. In this retrospective, observational, single-center study conducted in the University Hospital Centre Zagreb in Zagreb, Croatia, data were retrieved from medical records on 95 patients (59% men, 41% women) who began first-line treatment for mCRC between Jan 1, 2016 and Dec 31, 2018. The therapy regimen was chosen by the attending physician and depended on the patient's overall health, RAS/BRAF status and preferences. The duration of induction chemotherapy in patients who have responded depended on the attending physician choice and the patient’s preferences. Maintenance therapy consisted of fluoropyrimidine +/- bevacizumab, and patients who received anti-EGFR were deescalated to mono fluoropyrimidines. The objectives of this study were to compare the effectiveness in terms of overall survival (OS) and progression-free survival (PFS) with regard to the duration of the induction treatment period in the real-world setting. The follow-up was set at 36 months. Survival (OS and PFS) was estimated using the Kaplan-Meier method and curves of the different treatment groups were compared using the log-rank test. Cox regression analysis was used to examine the association between survival and other influencing factors (age, ECOG performance status, RAS/BRAF status, location of the primary tumor, local ablative treatment including surgical resection of metastases). Results were expressed as hazard ratios (HR) with 95% confidence interval (CI) with statistical significance set at a confidence level of P < 0.05. Patients were divided into two groups based on the duration of the induction therapy. There were 51 patients (54%) in group A with short induction period (≤6 months) and 44 patients (46%) in group B with long induction period (>6 months). Median age was 65 years. Patients in group B had significantly longer PFS than in group A, 25.8 vs. 18.7 months (p=0.005), respectively. However, there was no difference in OS between these two groups of patients, although there was a numerical trend in favor of group B (50.0 vs 35.8 months, p=0.056). Cox regression analysis showed longer OS in patients with RAS/BRAF wild type tumours (HR 0.49, 95% CI 0.24-1.02, p=0.005) and in those who underwent local ablative treatments (HR 0.52, 95% CI 0.33-0.89, p=0.017). Significantly more patients in group B had RAS/BRAF wild type tumours, compared to the group A (52.3 % vs. 27.5 %, p=0.019). With all the limitations due to the retrospective nature of the study, our results suggest that patients could benefit from a longer induction period in terms of survival. However, this may be influenced by the different treatment approach between RAS mt and wt tumours. Considering patients heterogeneity and multiple factors that might influence OS further trials and real-world data are needed.

The Role of Anti-EGFR Monoclonal Antibody in mCRC Maintenance Therapy.

Background: Epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) combined with chemotherapy in patients with RAS (rat sarcoma viral oncogene homolog) wild-type metastatic colorectal cancer (mCRC) can alleviate and stabilize the disease, effectively prolong the progression-free survival (PFS) and overall survival (OS), and improve the overall response rate (ORR), which is the first-line treatment standard scheme for RAS wild-type mCRC currently. However, whether anti-EGFR mAb can be used for the maintenance treatment after the first-line treatment of mCRC remains controversial. We reviewed the recent studies on anti-EGFR mAb. The contents include five parts, introduction, anti-EGFR mAb in mCRC and its status in first-line therapy, establishment of the maintenance treatment pattern after the standard first-line treatment for mCRC, research progress of anti-EGFR mAb in mCRC maintenance therapy, and conclusion. More studies support the maintenance treatment of anti-EGFR mAb, but some researchers raise the problems about high cost and drug resistance. Despite lack of the maintenance evidence of anti-EGFR mAb, especially lack of large-scale phase III prospective clinical trials, with the emergence of new evidence and more accurate screening of treatment-dominant groups, maintenance therapy with anti-EGFR mAb monotherapy or anti-EGFR mAb combined with fluorouracil-based schemes after first-line chemotherapy combined with anti-EGFR mAb therapy might strive for more treatment opportunities, optimize treatment strategies and prolong treatment continuity, and finally, lead to more survival benefit for suitable patients.

The role of germline polymorphisms in genes involved in the antioxidant system to predict the efficacy of cetuximab for patients with metastatic colorectal cancer (mCRC) enrolled in FIRE-3 trial.

143 Background: Reactive oxygen species activate RAS/MAPK signaling either through inactivation of phosphatases or by direct oxidation of kinases. We hypothesized that functional genetic variants in genes involved in the antioxidant system may be associated with the efficacy of cetuximab in mCRC patients. Methods: We analyzed genomic and clinical data from FIRE-3, a phase III trial which compared cetuximab and bevacizumab in combination with FOLFIRI in untreated mCRC patients. Genomic DNA extracted from blood samples was genotyped using an OncoArray (Illumina, Inc., San Diego, CA, USA). Candidate 13 functional single nucleotide polymorphisms (SNPs) ( TXN rs2301242, TXN rs2301241, TXN2 rs4821494, TXN2 rs9619611, TXN2 rs59841625, CAT rs7943316, CAT rs564250, CAT rs11604331, CAT rs1001179, CAT rs769217, GPX4 rs757229, GPX4 rs4807542, and GPX4 rs713041) were tested for association with progression-free survival and overall survival (OS), using log-rank test and Cox proportional hazards model. To confirm the predictive value, the treatment-by-SNP interaction was tested. Results: A total of 236 patients were available for the SNP analyses (cetuximab arm, n = 129; bevacizumab arm, n = 107). In the cetuximab arm, two SNPs were significantly associated with clinical outcomes in univariate analyses: TXN2 rs4821494 (T/T vs any G allele, hazard ratio [HR] on OS = 2.17, 95% confidence interval [CI] = 1.04–4.56, log-rank p = 0.04) and GPX4 rs4807542 (G/G vs any A allele, HR on OS = 2.04, 95% CI = 1.05–3.98, log-rank p = 0.03). Multivariate analysis confirmed the significance in TXN2 rs4821494 (T/T vs any G allele, HR on OS = 2.47, 95% CI = 1.06–5.72, p = 0.03). In the bevacizumab arm, univariate analyses did not detect any significant associations between the SNPs and clinical outcomes. Treatment-by-SNP interaction test showed the significant predictive value of TXN2 rs4821494 in terms of OS ( p = 0.03). Conclusions: TXN2 rs4821494 involved in the antioxidant system may predict the efficacy of cetuximab, in comparing with bevacizumab, in the first-line treatment of mCRC. Our novel findings warrant further validation studies.

Economic Evaluation of Monoclonal Antibodies in Metastatic Colorectal Cancer: A Systematic Review.

Colorectal cancer (CRC) is one of the major causes of mortality and morbidity worldwide. The median overall survival (OS) of patients with metastatic CRC (mCRC) has doubled over the last 20 years partly due to the introduction of advanced biologic therapies. However, these treatment modalities bear significant costs on healthcare systems globally, and may jeopardize their fiscal sustainability. The aim of this systematic review was to critically appraise the economic evaluations of monoclonal antibodies in mCRC. A literature search was performed in the electronic databases of: Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, EMBASE, EMBASE Alert, PUBMED, NHS Economic Evaluation and Health Technology Assessment Database for full articles published from 1 January 2013 to 31 December 2020. Twenty economic analyses were identified in the literature that fulfilled the inclusion criteria and evaluated the cost-effectiveness of (a) bevacizumab as first-line treatment for mCRC and as maintenance treatment, (b) cetuximab as first-line treatment, (c) panitumumab versus bevacizumab and cetuximab versus bevacizumab as first-line treatment, (d) aflibercept and ramucirumab as second-line treatment, (e) cetuximab and panitumumab as third-line treatment, (f) cetuximab versus panitumumab as later lines of treatment, and (g) RAS testing prior to anti-epidermal growth factorreceptor (EGFR) treatment. Bevacizumab in combination with chemotherapy is cost-effective as neither first-line treatment nor maintenance treatment. Sequential treatment with bevacizumab in first-line and second-line treatment was also not cost-effective. Testing for KRAS and extended RAS mutations is cost-effective and should be performed prior to anti-EGFR treatment. In the RAS wild-type subgroup of mCRCs the use of anti-EGFR (panitumumab or cetuximab) in first-line treatment leads to a more favorable cost-effectiveness profile than the corresponding anti-VEGF (bevacizumab). Cetuximab is not cost-effective as a first-line treatment. Anti-EGFR administration is not a cost-effective strategy in third-line treatment, even for RAS wild-type mCRCs, compared to best supportive care. Aflibercept was superior to ramucirumab and costed less, but neither were cost-effective compared to standard care.