Introduction
Colorectal cancer (CRC) is a very common and aggressive type of cancer, often diagnosed in a metastatic setting. It is the third most common type of cancer worldwide and the second most common cause of death related to cancer. Fortunately, there is a positive trend for mortality, with both incidence and mortality rates having declined over the past decades [1]. Peak mortality rates have decreased by more than 50% over those 40 years. Current estimates foresee an increase of incidence reaching up to 3 million deaths by 2040 with a concurrent decline in the age-standardized mortality rate. The reason for this trend is the improvement in screening and treatments, as well as the identification of biomarkers [2–6].
At the time of CRC diagnosis, up to 23% of patients are found to have metastatic CRC (mCRC). Additionally, an estimated 25% to 50% of patients initially diagnosed with lymph node-positive CRC may eventually develop metastases. The outcome for patients with localized CRC is much better than for those with mCRC. Specifically, the 5-year survival rate for mCRC is 15.6%, compared to localized CRC [1, 7].
Thus, the management of mCRC remains challenging due to its heterogeneous nature and the development of resistance to therapy. Treatment sequencing plays a crucial role in optimizing outcomes for patients with mCRC, as the order in which therapies are administered can impact efficacy, toxicity, and overall survival [7–9].
The molecular profile of cancer is potentially an important part of the treatment for any type of cancer. Specifically, it seems that the mole-cular profile of CRC plays a pivotal role in the development of the cancer and provides crucial knowledge for therapy decisions [9–11].
Approximately 85% of CRCs result from alterations in the number and structure of chromosomes, a phenomenon known as chromosomal instability. The most clinically significant pathways involved in chromosomal instability in colorectal tumors are the Wnt and MAPK pathways. In CRCs developing through the Wnt pathway, Wnt proteins bind to Frizzled family receptors, leading to the accumulation of β-catenin, which activates transcription and promotes uncontrolled cell proliferation. In MAPK-activated CRCs, receptor tyrosine kinases are activated, causing signaling molecules such as RAS and RAF to become constitutively active, thereby driving uncontrolled cell proliferation [9–12].
The remaining 15% of CRCs, not attributed to chromosomal instability, result from microsatellite instability (MSI), which involves a general instability of DNA sequences, known as microsatellites. MSI can occur due to mutations in mismatch repair (MMR) genes or hypermethylation and subsequent silencing of the MLH1 promoter. In the absence of mutations in any of the 5 MMR genes of interest (i.e., MLH1, MSH2, MSH6, or PMS2) or hypermethy-lation of MLH1, the tumor is considered microsatellite stable (MSS). If at least 2 of these MMR genes are mutated, the tumor is classified as microsa-tellite instability-high (MSI-H) [9–12].
In this review, we discuss the rationale behind treatment sequencing in mCRC and summarize the current evidence supporting various therapeutic strategies. At the beginning of this review, we examine each category of therapy, and then we explain the therapeutic choices in the first and subsequent lines of treatment.
Chemotherapy-based sequencing
Historically, chemotherapy has been the cornerstone of treatment for mCRC, with regimens such as FOLFOX (folinic acid, fluorouracil, oxaliplatin) and FOLFIRI (folinic acid, fluorouracil, irinotecan) demonstrating efficacy in both first-line and subsequent lines of therapy [7, 8, 14].
The GERCOR group conducted a comparison among patients with advanced colorectal cancer who were randomized to receive either FOLFIRI followed by FOLFOX6 or the reverse sequence. A total of 230 patients were randomly assigned to either group. No significant differences were observed between the FOLFIRI-first and FOLFOX-first groups in terms of median overall survival (21.5 vs. 20.6 months, p = 0.99) or median second progression-free survival (14.2 vs. 10.9 months, p = 0.64). Additionally, the response rate as first-line therapy was similar between the FOLFIRI-first and FOLFOX-first groups (56% vs. 54%; p-value was not significant) [8, 14, 15].
Furthermore, the toxicity profiles differed between the two chemotherapy options. FOLFIRI was more commonly associated with gastrointestinal symptoms, whereas FOLFOX was more frequently linked with thrombocytopenia and neurosensory symptoms [7, 8].
The choice of chemotherapy regimen and sequencing strategy depends on various factors, including prior treatment exposure, tumor response, and toxicity profiles. Recent studies have explored the role of maintenance chemotherapy, alternating regimens, and dose-intensified approaches in optimizing treatment outcomes and prolonging progression-free survival (PFS) in mCRC patients [7, 8].
Targeted therapy sequencing
mCRC treatment has evolved significantly with the introduction of targeted therapies, which specifically target molecular pathways implicated in tumor growth and progression [9].
Epidermal growth factor receptor (EGFR) inhibitors, such as cetuximab and panitumumab, block EGFR signaling. Both cetuximab and panitumumab are only effective against tumors with wild-type (non-mutated) KRAS and BRAF oncogenes, observed in approximately 60% of mCRC patients [10, 11]. Cetuximab, FDA-approved in 2004, attaches to the external domain of EGFR, promoting its internalization and degradation. Another EGFR inhibitor, panitumumab, approved for mCRC treatment, received FDA approval in 2006. By binding directly to EGFR and competitively inhibiting the binding of other ligands, panitumumab prevents ligand-induced receptor autophosphorylation and the activation of receptor-associated kinases [16].
EGFR inhibitors were examined both as subsequent-line and as first-line therapy. More specifically, the CRYSTAL multi-center phase III trial compared first-line FOLFIRI with or without cetuximab. The addition of cetuximab was associated with improved PFS (HR = 0.85, 95% CI: 0.72–0.99, p = 0.048), although overall survival (OS) was not different between groups (HR = 0.93, 95% CI: 0.81–1.07; p = 0.31). After further analysis of KRAS status (89% of patients were tested), KRAS wild-type patients were found to have an improved response rate (57 vs. 40%; p < 0.001), PFS (median, 9.9 vs. 8.7 months, p = 0.02), and OS (median, 23.5 vs. 20.0 months, HR 0.796; p = 0.009) [9, 11, 17].
The FIRE-3 trial examined the combination of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab in patients with RAS wild-type tumors. FOLFIRI plus cetuximab resulted in a significantly higher objective response rate (ORR) and longer OS compared to FOLFIRI plus bevacizumab among patients with left-sided tumors [18]. The TAILOR trial, a phase III study, investigated the efficacy and tolerability of first-line cetuximab plus FOLFOX-4 versus FOLFOX-4 in patients with RAS wild-type mCRC. The results showed that the combination therapy improved PFS (HR = 0.69; 95% CI: 0.54–0.89, p = 0.004; median, 9.2 vs. 7.4 months, respectively), OS (median, 20.7 vs. 17.8 months, respectively), and ORR (95% CI: 1.61–3.61, p < 0.001; 61.1% vs. 39.5%, respectively) [19].
When the CAPOX (capecitabine and oxaliplatin) combination was evaluated alongside cetuximab in the COIN trial, no significant benefit in PFS or OS was observed, except for an increased response rate in the RAS-wild type population treated with cetuximab. Consequently, combining anti-EGFR with capecitabine-based chemotherapy is not recommended [20]. Similarly, the FLOX regimen (LV, bolus 5-fluorouracil [5-FU], oxaliplatin) with cetuximab also showed no benefit. Therefore, anti-EGFR with bolus 5-FU-based chemotherapy is not recommended [20].
Moreover, in the OPUS phase II trial, previously untreated mCRC patients were randomly assigned to receive FOLFOX4 either with or without cetuximab. KRAS wild-type patients treated with cetuximab plus FOLFOX4 demonstrated a higher response rate (57 vs. 34%; p = 0.0027) and prolonged PFS (median, 8.3 vs. 7.2 months, p = 0.0064) compared to those who received FOLFOX4 alone. However, the difference in overall survival did not reach statistical significance (median, 22.8 vs. 18.5 months, p = 0.39) [7, 17].
In addition, in the multicenter phase III PRIME trial, 1,183 previously untreated patients with mCRC were randomized to receive either panitumumab plus FOLFOX4 or FOLFOX4 alone. Upon analysis of KRAS wild-type patients (n = 656), panitumumab plus FOLFOX4 demonstrated prolonged progression-free survival (median, 10.0 vs. 8.6 months, p = 0.01) without a significant improvement in overall survival (median, 23.9 vs. 19.7 months, p = 0.17). However, survival analysis indicated that the panitumumab regimen was associated with improved overall survival (HR = 0.83, 95% CI: 0.70–0.98, p = 0.03) [7, 8, 18, 19].
Furthermore, the PEAK trial examined OS and tumor responses in the first-line treatment of RAS wild-type mCRC with FOLFOX6, combined with either panitumumab or bevacizumab. The trial showed that the addition of panitumumab resulted in longer PFS than the addition of beva-cizumab [21].
The Origami trial, a phase Ib/II study, examined amivantamab either as monotherapy or in combination with standard-of-care chemotherapy. Amivantamab, an EGFR-MET bispecific antibody, is potentially beneficial in refractory mCRC, as MET overexpression or amplification is a known mechanism of resistance to anti-EGFR therapy. The results of this trial show that amivantamab monotherapy demonstrates promising antitumor activity and a manageable safety profile in refractory mCRC, including in patients previously treated with anti-EGFR therapy and those with right-sided disease [22].
KRAS G12C mutations occur in approximately 2–4% of mCRCs. Clinical trials have investigated both sotorasib and adagrasib, with promising outcomes. In the CodeBreak 100 phase I clinical trial, sotorasib showed low response rates in patients with KRAS G12C tumors. However, in the CodeBreak 101 clinical trial, combining sotorasib with the anti-EGFR antibody panitumumab improved response rates to 30% and achieved a median PFS of 5.7 months. Similarly, adagrasib alone showed a 19% response rate in pretreated patients, but when combined with cetuximab, the response rate increased to 46% with a median PFS of 6.9 months [23, 24].
The combination of targeted KRAS G12C inhibition with anti-EGFR monoclonal antibodies appears to effectively counteract the upstream signaling of EGFR activation. Recently, the CodeBreak 300 phase III clinical trial results indicated that combining sotorasib with panitumumab led to tumor shrinkage in 81% of patients and resulted in a 51% reduction in the risk of disease progression. Skin- related toxicities and hypomagnesemia were the most common adverse events, with no new safety concerns identified. These findings offer a new therapeutic option for previously treated patients with KRAS G12C-mutated mCRC [25].
Vascular endothelial growth factor (VEGF) inhibitors, including bevacizumab, aflibercept, and ramucirumab, disrupt tumor angiogenesis. Bevacizumab, approved for mCRC treatment in 2004, has shown effectiveness in extending survival when used in combination with various first-line regimens for mCRC [9–11, 14–16].
In a phase III study (NO16966), CAPEOX (capecitabine and oxaliplatin) with bevacizumab or placebo was compared with FOLFOX with bevacizumab or placebo in 1400 patients with unresectable metastatic disease. The addition of bevacizumab to oxaliplatin-based regimens was associated with a modest increase of 1.4 months in PFS compared to these regimens without bevacizumab (HR = 0.83, 97.5% CI: 0.72–0.95, p = 0.0023), and the difference in OS, also modest at 1.4 months, did not reach statistical significance (HR = 0.89, 97.5% CI: 0.76–1.03, p = 0.077). The continuation of bevacizumab in the second line after progression with first-line bevacizumab-containing regimens has also been studied and found to be beneficial [7, 8, 18, 19].
Moreover, AVEX trial, a phase III trial examined the addition of bevacizumab in capecitabine therapy versus capecitabine alone in patients aged 70 years or older and who were not candidates for either oxaliplatin-based or irinotecan-based treatment. The results of this trial showed that PFS was significantly longer with bevacizumab plus capecitabine instead of capecitabine monotherapy [26]. The TRICOLORE phase III trial compared mFOLFOX6 or CAPOX combined with bevacizumab to irinotecan and S-1 (IRIS) plus bevacizumab. The study concluded that IRIS plus bevacizumab is non-inferior to mFOLFOX6 or CAPOX plus bevacizumab in terms of PFS, with comparable OS [27, 28].
Furthermore, in a randomized controlled trial involving 1,226 mCRC patients who had progressed on or after previous treatment with an oxaliplatin-based chemotherapy regimen, participants were randomly assigned to receive either aflibercept or placebo in combination with FOLFIRI. The addition of aflibercept was linked to an enhanced response rate (19.8% vs. 11.1%, p < 0.001), improved progression-free survival (HR = 0.76, 95% CI: 0.66–0.87, p < 0.001), and better overall survival (HR = 0.82, 95% CI: 0.71–0.94, p = 0.003) [7, 8, 11, 18].
An international multicenter randomized controlled trial demonstrated the effectiveness of ramucirumab. In this trial, 1,072 patients with mCRC, experiencing disease progression during or within 6 months of the last dose of first-line therapy, were randomly assigned to receive either ramucirumab or placebo in combination with FOLFIRI. While there was no difference in response rate (13.4% in the ramucirumab group vs. 12.5% in the placebo group, p = 0.63), both progression-free survival (HR = 0.79, 95% CI: 0.70–0.90, p < 0.001) and overall survival (HR = 0.84, 95% CI: 0.73–0.98, p = 0.022) were better in the ramuciru-mab group compared to the placebo group. Among VEGF inhibitors, bevacizumab has shown a favorable toxicity profile, making it a more commonly utilized agent [8, 9, 11].
Moreover, other anti-angiogenic agents such as regorafenib and fruquintinib offer additional options for refractory disease. Regorafenib is an orally active multikinase inhibitor that blocks several protein kinases, including receptors associated with angiogenesis (VEGFR1, VEGFR2, VEGF3, and TIE2), oncogenesis (KIT, RET, RAF1, and BRAF), and the tumor microenvironment (PDGFR and FGFR). It is used for the treatment of patients with mCRC who have progressed after fluorouracil, oxaliplatin, and irinotecan-based chemotherapy, as well as monoclonal antibodies including anti-VEGF and anti-EGFR agents. The phase III multicenter CORRECT trial demonstrated an increase in OS in patients who received regorafenib compared to those who received placebo [11, 19].
BRAF-mutated colon tumors indicate poorer outcomes compared to BRAF wild-type tumors. In the FOCUS study involving 711 patients, the median OS after standard treatment was approximately 12 months, contrasting with nearly 30 months in patients with BRAF wild-type tumors. BRAF inhibitors such as vemurafenib and encorafenib are used in BRAF-mutant mCRC, often in combination with MEK inhibitors such as cobimetinib or binimetinib [29].
The phase III BEACON study randomized 665 pre-treated mCRC patients into three arms: triplet therapy of BRAF inhibitor, EGFR inhibitor, and MEK inhibitor (encorafenib + cetuximab + binimetinib) or the doublet encorafenib + cetuximab versus the control arm (investigator’s choice of chemotherapy). The study demonstrated clear clinical benefit in both targeted therapy arms compared to the control arm, with patients treated with cetuximab + encorafenib showing PFS of 4.3 vs. 1.5 months (HR = 0.44) and OS of 9.3 vs. 5.9 months (HR = 0.61), while those treated with cetuximab + encorafenib + binimetinib had PFS of 4.5 vs. 1.5 months (HR = 0.42) and OS of 9.3 vs. 5.9 months (HR = 0.60). Upon analysis, it was concluded that the doublet had similar overall efficacy to the triplet. Both regimens improved OS, ORR, and PFS with manageable toxicity. Additionally, there are studies examining BRAF inhibitor and MEK inhibitor as first-line therapy. However, these combinations have not yet been included in clinical practice [7, 29].
The phase 3 Breakwater study evaluated the combination of encorafenib and cetuximab, with or without chemo-therapy, compared to standard-of-care chemotherapy in patients with BRAFV600E-mutated mCRC. Updated results presented at ESMO 2024 showed that the ORR confirmed by blinded independent central review (BICR) was 83.3% in first-line treatment and 44.4% in second-line treatment. Median progression-free survival (mPFS) by BICR was not estimable (NE) for the first line (95% CI: 13.8) and was 12.6 months (95% CI: 6.9–18.0) for the second line. Median overall survival (mOS) was NE (95% CI: 23.7, NE) for first line and 19.7 months (95% CI: 13.9–25.1) for the second line. In conclusion, the combination of encorafenib with cetuximab and chemotherapy is a safe regimen, and the results support the continuation of the trial [30].
Targeted sequential therapy with anti-HER2 agents in mCRC presents a promising strategy for patients with HER2 mutations. HER2-targeted agents, such as trastuzumab, pertuzumab, and lapatinib, have demonstrated promising efficacy, especially in those with wild-type RAS tumors. In the phase II MyPathway clinical trial, the duplet of trastuzumab and pertuzumab was investigated in pre-treated HER2-amplified mCRC. The trial demonstrated that the duplet is well tolerated and could potentially represent a therapeutic opportunity for patients with heavily pretreated, HER2-amplified metastatic colorectal cancer [31–35].
Zanidatamab is a humanized, bispecific monoclonal antibody targeting two non-overlapping domains of HER2. A phase II trial examined zanidatamab as a first-line the-rapy in patients with unresectable, advanced, or mCRC with HER2 overexpression or amplification. A mini-oral presentation at ESMO 2024 showcased the primary encouraging results of this trial. Specifically, zanidatamab combined with chemotherapy ± bevacizumab demonstrated promising antitumor activity and a generally manageable safety profile as a first-line treatment for patients with HER2- positive mCRC [36].
NTRK and RET gene fusions are rare, occurring in less than 1% of metastatic colorectal cancer cases. However, when present, targeted therapies can lead to high objective response rates. For patients with NTRK fusions, which result in the activation of the chimeric tropomyosin receptor kinase, the drugs larotrectinib and entrectinib have shown promising results. In a study involving 19 patients with metastatic colon cancer, larotrectinib achieved a response rate of up to 47%, a median PFS of 5.6 months, and an OS of 12 months [35]. Similarly, entrectinib, tested in 10 patients, provided a response rate of 20%, a PFS of 3 months, and overall survival of 16 months. Both agents have been approved for use in patients with previously treated metastatic colorectal cancers [37]. Additionally, the LIBRETO-001 basket trial investigated the efficacy of selpercatinib in patients with RET gene fusions, resulting in an overall response rate of 20% and a median duration of response of 9.4 months. These findings led to the approval of selpercatinib for RET-positive, previously treated patients with metastatic colorectal cancer [38].
Other targeted therapies include PI3K/AKT/mTOR pathway inhibitors (e.g., everolimus), Wingless/Integrated signaling pathway inhibitors and DNA damage repair inhibitors (e.g., PARP inhibitors. Multi-kinase inhibitors such as sorafenib and lenvatinib, as well as agents such as trifluridine/tipiracil (TAS-102) and Hsp90 inhibitors (e.g., TAS-116), further broaden the therapeutic armamentarium for mCRC, highlighting the diverse approaches aimed at improving outcomes for patients with this challenging disease [9–11].
A phase I trial investigated the safety, tolerability, pharmacokinetics, and preliminary clinical activity of M9140 as monotherapy in patients with mCRC who had received two prior lines of therapy. M9140 is the first anti-CEACAM5 antibody-drug conjugate (ADC) with a topoisomerase 1 inhibitor (Top1i) payload (exatecan). The trial showed that M9140 demonstrated promising activity in heavily pretreated patients with advanced CRC, along with a manageable and predictable safety profile. Unlike other approved ADCs with Top1i payloads, no interstitial lung disease (ILD) or ocular toxicities were observed [39].
Immunotherapy sequencing
Immunotherapy has emerged as a promising treatment modality for mCRC, particularly in patients with MSI-H or dMMR tumors. Immune checkpoint inhibitors (ICIs), such as pembrolizumab, nivolumab, and ipilimumab, have demonstrated efficacy in this subset of patients by unleashing the body’s immune system to target and destroy cancer cells. Specifically, pembrolizumab and nivolumab are anti-PD-1 monoclonal antibodies, and dostarlimab is an anti-PD-1 monoclonal antibody [9, 11].
In addition, DNA polymerase epsilon (POLE) mutations, which lead to DNA-repair deficiencies, have been associated with a high tumor mutational burden. POLE mutated colorectal cancers have a hypermutated profile and their micro-environment is rich in neoantigens. They usually are present in male patients of younger age, with higher incidence reported in right-sided primaries [34]. Somatic POLE mutations are present in less than 1% of colon cancer cases and are associated with microsatellite stable/pMMR tumors, whereas germline POLE mutations correlate with MMR germline variants in microsatellite instability high/dMMR tumors. According to recently published data, patients with tumors harboring POLE mutations may be candidates for immunotherapy due to the expected high response rates [40, 41, 42].
Pembrolizumab was approved for the treatment of MSI-H/dMMR mCRC as a first-line therapy. The phase III randomized open-label KEYNOTE-177 study investigated the use of pembrolizumab compared to chemotherapy with or without be-vacizumab or cetuximab as first-line therapy for 307 patients with MSI-H/dMMR mCRC. The study found that the median PFS was longer with pembrolizumab compared to chemotherapy (16.5 vs. 8.2 months; HR = 0.60; 95% CI: 0.45–0.80, p = 0.0002). Additionally, the confirmed ORR was 43.8% with pembrolizumab versus 33.1% with chemotherapy [7, 8]. Furthermore, recent data of CHECKMATE 8HW confirmed superiority of immunotherapy versus chemotherapy in patients with dMMR/MSI-H stage IV colon cancer [43].
Other ICIs such as nivolumab and dostarlimab are also recommended for the treatment of dMMR/MSI-H mCRC. Additionally, nivolumab can be used in combination with ipilimumab (an anti-CTLA4 antibody) either in the first or subsequent lines of therapy. Specifically, CheckMate 142, a phase II trial, examined monotherapy with nivolumab in patients with dMMR/MSI-H mCRC. The results of this trial showed promising efficacy of nivolumab in prolonging OS and, more specifically, demonstrated an mPFS of 14.3 months (95% CI: 4.30–NE), a 12-month PFS of 50% (95% CI: 38–61), and a 12-month OS of 73% (95% CI 62–82) [44]. Ongoing research is focused on expanding the utility of immunotherapy in mCRC, including investigating combination therapies with other agents and identifying predictive biomarkers to guide patient selection and optimize treatment outcomes [7–9, 11].
Personalized medicine and sequential therapy
Advances in molecular profiling techniques, such as next-generation sequencing (NGS) and liquid biopsies, have paved the way for personalized medicine in mCRC, enabling clinicians to identify actionable genetic alterations and tailor treatment regimens accordingly. In addition, there is a possibility to detect circulating tumor DNA (ctDNA) through liquid biopsy, and this may become a valuable tool in the treatment of metastatic colorectal cancer. Although its current clinical use is limited, its potential applications in patient management are under extensive investigation. Beyond identifying mutations in urgent cases or when anti-EGFR rechallenge strategies are used, ctDNA can be utilized to detect resistance mechanisms to ongoing therapies or even predict disease progression months before clinical symptoms appear. Monitoring the patient’s journey from the diagnosis of metastatic colorectal cancer through various therapeutic regimens is an area of intense scientific research, aiming to establish ctDNA as a useful biomarker in everyday clinical practice [45].
Sequential therapy approaches, incorporating targeted therapies, immunotherapies, and novel agents, based on real-time molecular profiling and disease evolution, hold promise in optimizing treatment outcomes and overcoming resistance mechanisms in mCRC. However, the inte-gration of complex genomic data into clinical practice poses challenges in terms of cost, accessibility, and inter-pretation, underscoring the need for multidisciplinary colla-boration and evidence-based decision making [22].
First-line therapy
The initial treatment regimen is pivotal in effectively managing systemic treatment in mCRC. Its significance lies in its longer duration, greater efficacy in terms of response and PFS, and its administration to all treated patients. Moreover, first-line therapy is crucial because some patients may later become candidates for metastatic resection and initially receive combination therapy [7, 8, 22, 46, 47].
Multiple factors influence the choice of first-line treatment in mCRC, including both clinical factors and molecular markers. The specific extent of the disease, distinguishing between oligo- and poly-metastatic disease and identifying the organs affected, significantly influences the decision regarding first-line treatment. Moreover, it is important to note that left-sided tumors are more likely to respond to anti-EGFR therapy and immunotherapy, while right-sided tumors may have better responses to VEGF inhibitors [7, 8, 13, 22]. Specifically, the PARADIGM study confirmed the additional benefit of anti-EGFR antibodies in treating left-sided primary tumors, showing better results across the entire study population regardless of primary tumor location. Improved overall survival was notably observed in patients with left-sided primary tumors. Based on these findings, it is advisable to provide anti-EGFR targeted therapy to patients with left-sided primaries that are KRAS/NRAS/BRAF wild type [48]. For patients with right-sided tumors or those with KRAS/NRAS/BRAF mutations, incorporating bevacizumab into the treatment regimen is recommended [47].
For patients who are unable or unwilling to undergo combination chemotherapy, particularly elderly individuals, treatment alternatives may consist of a dose-adjusted regimen involving fluoropyrimidine plus oxaliplatin, or alternatively, a combination of fluoropyrimidine plus bevacizumab [7, 8].
For the majority of patients with mCRC, therapy typically involves a cytotoxic doublet (such as FOLFOX, FOLFIRI, or CAPOX) combined with an anti-EGFR agent, a doublet with bevacizumab, or a triplet regimen with or without bevacizumab. In cases of RAS wild-type and BRAF wild-type left-sided tumors, the recommended therapy entails a doublet chemotherapy combined with an anti-EGFR agent. In RAS wild-type right-sided tumors, chemotherapy with bevacizumab is the preferred option. However, in cases requiring a more robust response for conversion therapy, a doublet regimen with cetuximab or panitumumab can be considered. Moreover, for specific patients with good performance status and no comorbidities, a triplet regimen comprising FOLFOXIRI plus bevacizumab could also be considered as an option. In dMMR/MSI-H mCRC patients, the immune checkpoint inhibitor pembrolizumab is recommended as the standard of care [7, 8].
Maintenance therapy
Both anti-EGFR and anti-VEGF therapies can be utilized as maintenance therapy in conjunction with fluoropyrimidine. Reintroducing an initial successful induction therapy should be considered after experiencing progressive disease while on maintenance therapy [7, 8].
The CAIRO3 phase 3 trial examined maintenance treatment with capecitabine and bevacizumab versus observation in mCRC. The primary endpoint of median PFS was significantly improved in patients receiving maintenance treatment, with 8.5 months in the observation group and 11.7 months in the maintenance group [49]. The PANAMA trial investigated the addition of panitumumab to maintenance therapy with fluorouracil and folinic acid (FU/FA) in patients with RAS wild-type metastatic colorectal cancer (mCRC). In these patients, FU/FA combined with panitumumab during maintenance therapy resulted in significantly improved PFS compared to FU/FA alone. For those seeking active maintenance therapy following induction with FU/FA, oxaliplatin, and panitumumab, the combination of FU/FA and panitumumab appears to be the most favorable option [50].
Second-line therapy
The decision of second therapy is dependent on the choice of the first-line therapy. Either FOLFIRI or FOLFOX can be used as a subsequent therapy. Bevacizumab can be added to chemotherapy regardless of its use as a first-line therapy. Aflibercept or ramucirumab in combination with FOLFIRI could be used as an alternative to bevacizumab with FOLFIRI in patients progressing on first-line treatment with oxaliplatin-based chemotherapy [7, 8].
For pre-treated mCRC patients with BRAF V600E muta-tion, encorafenib-cetuximab is advised as the optimal choice in the second line. For dMMR/MSI-H tumors progressing after first-line chemotherapy, ipilimumab- nivolumab is recommended [7, 8].
Third-line and subsequent therapies
In patients previously treated with fluoropyrimidines, oxaliplatin, irinotecan, and bevacizumab, as well as in RAS wild-type patients previously treated with EGFR antibodies, either regorafenib or the antimetabolite trifluridine/tipiracil (TAS-102) is recommended. Similarly, cetuximab or panitumumab is suggested, ideally combined with irinotecan, for KRAS/NRAS wild-type patients who have not received prior EGFR antibodies. Moreover, in HER2-positive patients with mCRC, treatment with HER2 dual blockade is optionally recommended, particularly in RAS wild-type tumors [7, 8, 30–32].
Discussion
The landscape of the sequencing of treatments in mCRC constitutes a multi-faceted challenge that involves a profound understanding of multiple factors that may impact the choice of therapy and the patient’s outcomes. Table 1 summarizes the lines of therapy based on tumor mutations. The crucial influence of the first-line therapy and its impact on the further course of treatment creation includes the consideration of the extent of mCRC and molecular profiling, which may inform the choice of the regimen, such as anti-EGFR or anti-VEGF agents in doublet with chemotherapy [7–9, 11].
Table 1
Therapy depends on gene mutations
Maintenance therapy and careful introduction of successful induction agents in cases of disease progression further exemplify the importance of the strategy-based approach. Second-line treatments, meanwhile, expand the range of available options, including chemotherapy and emerging immunotherapies, the use of which should be maximally effective with minimal toxic influence. Moreover, the evolving landscape of targeted therapies, including HER2 dual blockade and BRAFV600E inhibition, holds pro-mise for personalized treatment approaches. As research continues to uncover novel biomarkers and therapeutic strategies, the future of treatment sequencing in mCRC lies in its ability to adapt to patient-specific factors, mole-cular characteristics, and emerging therapeutic modalities, ultimately striving for improved patient outcomes and enhanced quality of life [7, 8, 23, 30].
Finally, the progression of molecular profiling techno-logies such as NGS and liquid biopsies has revolutionized the landscape of treatment for mCRC. These advancements help clinicians identify actionable genetic alterations and tailor treatment strategies accordingly, potentially improving patient outcomes. Sequential therapy approaches, guided by real-time molecular profiling and disease evolution, offer promise in optimizing treatment efficacy and overcoming resistance mechanisms. However, the integration of complex genomic data into clinical practice presents challenges related to cost, accessibility, and interpretation. Addressing these challenges will require concerted efforts in multidisciplinary collaboration and evidence-based decision- making to ensure the effective translation of molecular insights into improved patient care. The era of personalized medicine has already begun to reshape the therapeutic progression of mCRC, leading to continual improvements in patient outcomes [22, 49, 51].
Conclusions
Optimizing treatment sequencing in mCRC requires a thorough understanding of tumor biology, patient charac-teristics, and available treatment options. While conventional chemotherapy remains a mainstay of treatment, the advent of targeted therapies and immunotherapy has expanded therapeutic possibilities and introduced new challenges in treatment decision-making. Personalized approaches, informed by molecular profiling and clinical evidence, are essential for tailoring treatment strategies to individual patients and maximizing clinical benefit. Conti-nued research and collaboration are needed to define the optimal sequencing of therapies and improve outcomes for patients with mCRC [7–9, 12].
