Treatment sequencing in metastatic colorectal cancer

ACHAIKI IATRIKI | 2025; 44(1):45–54

Review

George Zarkavelis1,2, Nanteznta Torounidou1, Melina Yerolatsite1, Anna-Lea Amylidi1, Athanasia Karavasili1, Varvara Keramisanou1, Eleftherios Kampletsas1,2


1University Hospital of Ioannina, Medical Oncology Clinic, Ioannina, Greece
2Society for the Study of Clonal Heterogeneity of Neoplasia (EMEKEN), Ioannina, Greece

Received: 25 May 2024; Accepted: 29 Jul 2024

Corresponding author: George Zarkavelis, University Hospital of Ioannina, Oncology Department, E-mail: gzarkavelis@outlook.com

Key words: Metastatic colorectal cancer, molecular characteristics, sequential therapy, pMMR tumors, dMMR tumors

 


Abstract

Colorectal cancer management remains a significant challenge in contemporary oncology. Although current therapies have improved median survival rates, the overall prognosis for patients with stage IV disease remains dismal. Over the past decade, significant advances have expanded the available therapeutic options. The molecular characteristics of the tumor now play a pivotal role in therapy selection, both in the first line and subsequent lines of treatment in the metastatic setting. Chemotherapy remains the cornerstone of therapeutics for the disease while immunotherapy and targeted therapies implementation in the treatment algorithm continues to evolve rapidly. The idea of a “continuum of care” is currently fundamental, aiming at providing all the available therapeutic options to our patients to maximize the derived clinical benefit. Ongoing research efforts aim at further elucidating the underlying molecular biology of the tumor and eventually addressing the optimal sequencing of therapies in patients with metastatic colorectal cancer.

INTRODUCTION

Colorectal cancer ranks third among the most common types of cancer and is the second leading cause of cancer deaths globally [1]. 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 [2,3]. Although current therapies have led to improved median overall survival (OS) rates in patients with early colon cancer, a considerable proportion will eventually develop metastatic disease. Additionally, approximately 25% of patients are diagnosed with metastatic spread of the disease upon presentation [3]. The 5-year OS of patients with stage IV disease is estimated at 15%. However, with the advent of new therapeutic strategies, patients may achieve a median survival that exceeds 30 months according to current published data [4,5].

During the last decade, major advances have been made towards expanding the available therapeutic choices for patients with metastatic colorectal cancer. Tumor sidedness, extent of the disease, molecular characteristics of the tumor, aim of the applied therapy, patients’ overall needs, and performance status are some of the key factors to be considered when deciding on the optimal therapeutic approach, ideally in the context of a multidisciplinary team [6]. When the disease is deemed incurable, the aim is to prolong life expectancy and palliate symptoms. The continuum of care concept, where all available therapies are applied serially, may improve survival rates and extend disease control [7].

First line therapy for pMMR tumors

It has been historically established that 5-fluorouracil (5-FU) is the cornerstone of stage IV colorectal cancer treatment. Both intravenous 5-FU and oral capecitabine have been shown to provide comparable results regarding their estimated survival benefit [8]. Further improvements in survival rates and progression-free survivals (PFS) estimates can be achieved by incorporating oxaliplatin and/or irinotecan with 5-FU in the first-line setting, using doublets or triplets i.e., FOLFOX, FOLFIRI or FOLFOXIRI [9].

Numerous clinical trials have explored the role of anti-EGFR targeted therapy in therapeutic regimens for metastatic disease. Results have clearly demonstrated that the presence of KRAS/NRAS and BRAF mutations precludes the use of EGFR monoclonal antibodies due to lack of efficacy and even detrimental effects in this population. On the other hand, in patients with tumors harboring RAS/RAF wild-type tumors, the addition of either cetuximab or panitumumab provides significant clinical benefits. The combination of FOLFIRI plus panitumumab in patients without KRAS mutations led to a significantly reduced risk of disease progression and improved OS compared to FOFLIRI alone [10]. Furthermore, the combination of FOLFOX plus cetuximab led to improved response rates and PFS in patients with RAS wild-type metastatic colorectal cancer [11]. Thus, the combination of 5-FU based doublets with the addition of anti-EGFR targeted therapy has been established as a valid first-line option for patients with KRAS/NRAS/BRAF wild type tumors.

Apart from targeting the EGFR axis, the benefits of antiangiogenic compounds have also been explored and incorporated in current treatment algorithms. Bevacizumab, a selective VEGF-A inhibitor, has been investigated in numerous clinical trials. When combined with capecitabine, its addition led to improved PFS, and when combined with irinotecan plus 5-FU plus leucovorin positive results in terms of OS were demonstrated [12,13]. Taken together, although bevacizumab provides modest results, it is a valid option in the treatment of patients with metastatic colorectal cancer, as it can be used for all patients regardless of molecular status.

At the time point of first-line therapy selection, the absence of mutations in both KRAS/NRAS and BRAF genes allows for the addition of EGFR monoclonal antibodies whereas their presence precludes their administration, and then bevacizumab is selected along with backbone cytotoxic chemotherapy if not contraindicated. However, primary tumor sidedness has also emerged as a key factor that affects the treatment strategy. Combined analyses from studies investigating anti-EGFRs highlighted the benefit of cetuximab or panitumumab addition in patients with left sided primary tumors [14]. On the contrary, patients with right-sided primary tumors fared better with the addition of bevacizumab to first-line therapy, while the use of anti-EGFR antibodies had limited impact in this population [15]. Recently, the question of how primary tumor sidedness impacts the selection of optimal therapy was investigated in a phase III clinical trial. PARADIGM confirmed the added benefit of anti-EGFR antibodies in left sided primary tumors while also providing better results in the entire population of the study regardless of primary tumor location. Improved OS was recorded mainly in patients with left sided primaries. Thus, it is wise to provide anti-EGFR targeted therapy in patients with left-sided primaries that are KRAS/NRAS/BRAF wild type based on the aforementioned data [16]. For patients with right-sided tumors or those harboring KRAS/NRAS/BRAF mutations, bevacizumab can be incorporated into the applied regimen.

First line in dMMR tumors

Current guidelines advise checking the microsatellite instability (MSI) status at presentation of any patient with colorectal cancer. MSI, when present, is the result of either sporadic events or Lynch syndrome. Genetic testing to confirm or exclude possible Lynch syndrome is of utmost importance for both patients and their families. Apart from familial and personal medical history, MSI status is characteristic of hypermutated tumors that usually also have higher tumor mutational burden, making them the perfect candidates for immunotherapy application [6,17,18].

In cases of early colon cancer, MSI status may have both prognostic and predictive role when it comes to adjuvant therapy selection [6,17]. However, this molecular feature, encountered in approximately 5% of patients with metastatic disease, is indicative of immunotherapy application in the first-line setting, or in later lines if not previously given. The results of KEYNOTE 177, where patients with MSI metastatic colorectal cancer tumors had significantly improved PFS with pembrolizumab versus chemotherapy, established immunotherapy as the ideal option for this subset of patients [18]. Furthermore, recent data of CHECKMATE 8HW confirmed the superiority of immunotherapy versus chemotherapy, in patients with MSI/dMMR stage IV colon cancer [19].

In addition, DNA polymerase epsilon (POLE) mutations, which lead to DNA-repair deficiencies, have been associated with high tumor mutational burden. POLE mutated colorectal cancers have a hypermutated profile, and their microenvironment is rich in neoantigens. They are usually present in male patients of younger age, with a higher incidence reported in right-sided primaries [20]. Somatic POLE mutations are present in less than 1% of colon cancer cases and are associated with microsatellite stable (MSS)/pMMR tumors whereas germline POLE mutations correlate with MMR germline variants in MSI 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 [21.22].

To conclude, in the first line setting of therapy for patients with metastatic colorectal cancers, Either chemotherapy plus targeted therapy or immunotherapy alone can be offered according to the molecular characteristics of the tumor. For pMMR/MMS tumors backbone chemotherapy consisting of 5-FU-based doublet may be selected with either anti-EGFR antibody addition if KRAS/NRAS/BRAF wild-type tumor is identified, especially if left-sided, or bevacizumab when mutations are present. If MSI/dMMR status is identified during molecular testing, then immunotherapy is the optimal treatment choice.

Further lines of therapy

After the failure of first-line therapy, patients proceed with second and further lines while aiming to receive all available antineoplastic agents under a continuum of care in order to prolong their life expectancy and palliate their symptoms. The optimal treatment choice and sequence rely on tumor mutational profile that is ideally acquired at presentation. Recent advances in colorectal cancer therapeutics have led to the incorporation of further targeted agents according to druggable mutations discovered when sequencing the tumor. BRAF inhibitors, anti-HER2 targeted agents, KRAS inhibitors, NTRK gene fusion therapies are among the available further treatment choices [23-26].

Targeting BRAF V600E mutation

BRAF mutations are usually present in right-sided colorectal cancers with an estimated incidence of 10-15%. BRAF mutant right-sided cancers may also have a MSI high/dMMR status due to MLH1 promoter methylation. For patients with metastatic disease, this mutation confers a poor prognosis and relative resistance to chemotherapy, while clinical trials conducted in the past, clearly demonstrate a lack of anti-EFGR antibody efficacy in this subset of patients. The most common BRAF mutation is V600E accounting for approximately 80% of all BRAF mutations in metastatic colorectal cancers [23,24].

Until today, patients presenting with BRAF-mutated tumors undergo standard first-line therapy, as already analyzed, mainly the combination of backbone cytotoxic chemotherapy plus bevacizumab with chemotherapy triplets leading to higher response rates in numerous clinical trials [6]. Although anti-EGFR resistance is expected when BRAF V600E mutation is present, the combination of a BRAF inhibitor plus anti-EGFR therapy has become a standard treatment in the second or further line. The combination of a BRAF inhibitor plus a MEK inhibitor and anti-EGFR antibody overcomes the reported resistance in patients with BRAF V600E mutated tumors. Based on the results of BEACON study, encorafenib plus cetuximab plus binimetinib versus FOLFIRI or irinotecan plus cetuximab resulted in improved OS and response rates [25]. Moreover, the doublet consisting of encorafenib plus cetuximab provided comparable median OS to the triplet combination with fewer toxicities. Both the doublet and triplet combination therapy are approved choices for patients harboring BRAF V600E mutated tumors [25,26].

As expected, triplet targeted therapy has also been investigated in the first line setting in a phase II clinical trial with promising results, while phase III clinical trials are underway to explore the administration of encorafenib plus anti-EGFR as the first-line treatment choice. Initial data have also emerged regarding the combination of BRAF inhibitor plus anti-EGFR plus immune checkpoint inhibitors in an attempt to investigate the impact of immunotherapy when combined with BRAF inhibitors in this population [27,28].

Targeting KRAS G12C mutation

Novel potent KRAS inhibitors have come into the spotlight recently, rendering the once undruggable KRAS mutation sensitive to selective inhibition. KRAS G12C mutated metastatic colorectal cancers account for approximately 2-4% of all metastatic colon cancers. Both sotorasib and adagrasib have been investigated in clinical trials with positive results. In CodeBreak 100 phase I clinical trial sotorasib provided low response rates in patients with KRAS G12C tumors [29]. However, when combined with the anti-EGFR antibody panitumumab improved response rates of 30% and a 5,7-month median PFS were recorded in CodeBreak 101 clinical trial [30]. In parallel, adagrasib alone provided a response rate of 19% in pretreated patients, but when combined with cetuximab the responses improved, climbing up to 46%, with a median PFS of 6,9 months [31].

Thus, the combination of targeted KRAS G12C inhibition along with anti-EGFR monoclonal antibodies seems to overcome the upstream signaling of EGFR activation. Recently the results of CodeBreak 300 phase III clinical trial depicted that the combination of sotorasib plus panitumumab resulted in tumor shrinkage in 81% of the patients and led to 51% reduction in the risk of disease progression. Skin-related toxicities and hypomagnesemia were the most common adverse events noted, with no new safety signals raised [32]. The scientific data provide a new therapeutic option for previously treated patients with KRAS G12C mutated metastatic colon cancer.

HER2 amplification targeting

HER2 amplification can be detected in 1-5% of all metastatic colorectal cancers, primarily in RAS/RAF wild-type tumors. Both immunohistochemistry (IHC) and next generation sequencing (NGS) can be applied to tumor specimens as detection methods [33]. Multiple clinical trials have explored the potency of sole anti-HER2 directed therapies with initially modest results. On the other hand, dual anti-HER2 targeting is approved for previously treated patients having HER2-positive tumors. The MOUNTAINEER clinical trial investigated the efficacy of tucatinib plus trastuzumab in 117 patients with response rates of 38% [34]. In addition, the combination of trastuzumab plus lapatinib provided an overall response rate of 30% in patients with HER2-positive tumors that were previously treated according to the results of HERACLES [35]. In the MyPathway phase II clinical trial, trastuzumab plus pertuzumab combined resulted in 32% overall response rates [36].

In DESTINY-CRC01 phase II clinical trial, previously treated patients with HER2 IHC +3 metastatic colorectal cancer underwent therapy with trastuzumab deruxtecan (T-Dxd), an HER2 antibody and topoisomerase inhibitor conjugate. The results were very promising with overall response rates of 45,3% and a median PFS of 6,9 months. Approximately one-third of those patients had already received prior anti-HER2 targeted therapy. Apart from the positive results, higher rates of T-Dxd-related pneumonitis were also announced [37]. The overall positive results of these studies, indicative of anti-HER2 targeted therapy efficacy, led to the approval of trastuzumab with either pertuzumab, lapatinib or tucatinib in the treatment algorithm of metastatic colon cancer, along with trastuzumab deruxtecan for chemotherapy-refractory HER2-positive patients. Ongoing clinical trials are aiming to assess the efficacy of anti-HER2 therapy in the first line setting [34-37].

NTRK and RET gene fusions

NTRK and RET gene fusions are rare, accounting for less than 1% of mutations in metastatic colorectal cancer. When present, targeted therapy can lead to high objective responses [38]. In particular, for patients harboring NTRK fusions that lead to activation of the chimeric tropomyosin receptor kinase, larotrectinib and entrectinib provide promising results. In 19 patients with metastatic colon cancer, larotrectinib resulted in responses reaching up to 47%, a median PFS of 5,6 months, and OS of 12 months [39]. Furthermore, entrectinib, tested in 10 patients, provided response rates of 20%, a PFS of three months and 16 months OS [40]. Both agents have been approved for use in patients with previously treated metastatic colon cancers. 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 median duration of response of 9,4 months, leading to approval for RET-positive pretreated patients with metastatic colorectal cancer [41].

MSI in the non-first line setting

Since MSI high/dMMR tumors respond to immunotherapy, monoclonal antibodies targeting the PD1/PD-L1 axis have been incorporated in the first-line therapy setting of metastatic colorectal cancer therapy. However, if for any reason patients with dMMR tumors were not initially treated with immune checkpoint inhibitors, immunotherapy should be provided in the second or further lines of therapy. According to KEYNOTE 164, in pretreated patients with metastatic colon cancer pembrolizumab resulted in overall response rates of 33% [42]. Nivolumab also led to response rates of 30% when tested alone, while the combination of nivolumab plus ipilimumab provided higher responses of 55% with significantly improved quality of life [43]. Dostarlimab-gxly was also investigated in the COARNET phase I clinical trial where the cohort of patients with dMMR or POLE mutated tumors achieved response rates of 36% [44]. Hence, immune checkpoint inhibitors should be part of the treatment sequence if not contraindicated, in previously treated metastatic colorectal cancer patients who have not already received immunotherapy.

Anti-EGFR targeted therapy in subsequent therapy lines

Patients who have KRAS/NRAS/BRAF wild-type tumors and who have not, for any reason, received anti-EGFR targeted therapy in the first line, the combination of cetuximab or panitumumab with chemotherapy is a valid option in further lines. The addition of panitumumab to FOLFIRI as a second line option resulted in improved PFS with evident differences in OS versus chemotherapy alone [45]. When tested as monotherapy, panitumumab led to improved OS versus best supportive care (BSC) after oxaliplatin and irinotecan failure [46]. Cetuximab, when combined with irinotecan also led to improved PFS however, without OS benefit versus irinotecan alone [47].

Whether anti-EGFR therapy is more effective after prior anti-angiogenesis administration or vice versa has been an area of investigation and controversy, with more recent studies indicating that anti-EGFR after a prior bevacizumab-containing regimen results in no difference in PFS compared to bevacizumab continuation therapy [48]. The concept of anti-EGFR rechallenge strategies in further lines of therapy has been extensively investigated in recent years due to the advent of liquid biopsies. Several clinical trials have led to the conclusion that acquired anti-EGFR resistance may be overcome upon anti-EGFR therapy withdrawal since resistant clones tend to decay exponentially [49]. The use of liquid biopsies for applying anti-EGFR is compelling and data demonstrating high response rates and prolonged PFS, compared to historical benchmarks, have come to spotlight further supporting the notion of anti-EGFR rechallenge when patients are found to carry RAS/Raf wild-type tumors using peripheral blood [48,49].

Anti-angiogenesis in subsequent lines of therapy

Bevacizumab continuation combined with standard second-line chemotherapy led to improved OS when compared to chemotherapy alone, according to the results of ML18147 study [50]. The same conclusion has been drawn by the GONO phase III BEBYP clinical study. Although modest, these results indicate that continuing anti-VEGF therapy can lead to marginal improvements in survival. The addition of bevacizumab after the failure of the first-line bevacizumab-free regimen also led to modest improvements [51]. Apart from bevacizumab, ziv-aflibercept, which functions as a VEGF trap and inhibits angiogenesis, is also approved as a component of second and further line of therapy in metastatic colorectal cancer patients. The VELOUR trial met its primary endpoint, providing improved OS even in patients previously treated with bevacizumab-containing regimen [52,53].

Ramucirumab, a monoclonal anti-VEGFR2 antibody, blocks VEGF signaling. The phase III RAISE clinical study investigated the addition of ramucirumab to FOFLIRI versus FOLFIRI plus placebo and resulted in improved OS in the experimental arm [54]. It is of note that angiogenic agents may lead to thromboembolic events, hypertension, or bleeding. However, a meta-analysis performed on this subject concluded that ramucirumab administrations did not increase the probability of thromboembolic or bleeding events [55].

Regorafenib is a multiple kinase inhibitor including VEGFR, that is incorporated in the treatment algorithm in the metastatic setting. In the phase III CORRECT trial, regorafenib led to improved survival (rates) compared to placebo, as well as in the phase III CONCUR trial. Main adverse events included hand-foot skin reaction, fatigue, hypertension, and diarrhea [57]. The subsequent phase II ReDOS trial evaluated an alternative dose-escalating schedule for regorafenib making it a valid option [58].

FRESCO and FRESCO2 are two phase clinical studies that explored the use of fruquintinib, an oral VEGFR 1,2,3 inhibitor, in patients with metastatic colon cancer who had undergone at least two prior lines of therapy, with a median of four lines in FRESCO2. When compared to placebo, fruquintinib improved OS including patients with prior anti-VEGF therapy exposure. Hypertension was the most reported adverse event [59,60].

TAS-102

Trifluridine tipiracil consists of trifluridine and tipiracil hydrochloride which block the degradation of the trifluridine component. This oral combination was evaluated in the phase III RECOURSE trial providing improved overall survival compared to placebo [61]. Furthermore, the combination of TAS-102 plus bevacizumab led to improved PFS when tested in a phase I/II clinical trial in patients previously treated with chemotherapy and anti-VEGF therapy or anti-EGFR monoclonal antibodies [62,63].

Continuum of care

Recent advances in colorectal cancer therapy have improved patents’ OS with metastatic disease. In some studies, survival that exceeds 32 months has been reported. However, the overall prognosis of patients with stage IV disease remains dismal. Contrary to previous scientific research aimed at addressing the optimal sequence of therapies, the idea of a “continuum of care” is gaining grounds, aiming to provide all the available therapeutic options to maximize the derived clinical benefit [64].

The issue of first-line therapy has been extensively studied and clearly addressed. It is wise to test patients at presentation for possible KRAS/NRAS/BRAF mutations, as well as for MSI status, to implement the appropriate therapy. It would be wise for both time and cost-effectiveness to evaluate a larger gene panel for existing mutations before the initiation of therapies, which can also assist in determining a median or long-term therapeutic plan. The molecular signature of the tumor seems to evolve as the cornerstone for both first and subsequent lines of therapy [6].

Among strategies to prolong patients’ PFS, one might also opt for maintenance therapy after first-line application. This subject has been evaluated in different clinical trials, including CAIRO3, AIO 0207, PRODIGE9 amongst others [65,66,67]. According to the results of a systematic review, maintenance therapy with a fluoropyrimidine combined or not with bevacizumab improves PFS but has no impact on OS of patients [68]. Thus, one might opt for chemotherapy break based on scientific data from eleven randomized clinical trials where intermittent versus continuous systemic therapy was investigated. Opting for therapy holidays and intermittent treatment delivery did not lead to significant effects on OS when compared to continuous therapy administration [69].

Ongoing research

Despite the significant advances in the therapeutic landscape of colorectal cancer with the application of a more personalized pattern of therapy, unexplored areas still exist. Clustered regularly interspaced short palindromic repeat (CRISPR)- associated protein 9 can be used to identify previously undiscovered cancer genes in colorectal cancer based on genome editing techniques [70]. Epigenetic modifications have also been associated with colorectal cancer incidence and development [71]. Recently, scientific data highlighted the impact of microbiota in colorectal cancer and may unfold to a field of active research to further expand therapy armamentarium [72].

The relatively accessible next-generation sequencing platforms make it much more possible to identify new targets and unravel ways to inhibit signaling pathways and proteins such as TGFβ, p53, PI3K/AKT/mTOR [73]. It is of note though, that apart from the ongoing attempts to identify new targets and refine metastatic colorectal cancer therapy, resistance to currently available regimens remains a big subject. A gap in our knowledge regarding biomarker-based therapy sensitivity should be a primary focus of scientific research [74].

Under this scope, circulating tumor DNA (ct-DNA) may become a valuable tool in metastatic colorectal cancer therapeutics. Although of currently limited clinical use, the possible applications in patients’ management are further investigated. Apart from mutation identification in cases where little time to therapy initiation is available or when anti-EGFR rechallenge strategies are applied, ct-DNA may be used to identify mechanisms of resistance to applied therapy or even detect the upcoming disease progression months before it is clinically evident. Monitoring the patient’s journey from diagnosis of metastatic colorectal cancer throughout the application of different therapeutic regimens is an area of intense scientific research that aims to highlight ct-DNA as a useful biomarker in everyday clinical practice [75].

CONCLUSION

Metastatic colorectal cancer therapeutics have substantially evolved over the years, with new treatment options now readily available in clinical practice. Despite these advancements, conventional chemotherapy remains the mainstay of treatment across the various lines of therapy. Table 1 shows the line of therapy depending on the tumor mutations. However, with the advent of immunotherapy as well as new targeted therapies, regimen sequencing in the era of personalized metastatic colorectal cancer therapy can be rather challenging. In order to facilitate therapy sequencing and application, an in-depth comprehension of underlying molecular biology of the tumor as well as patients’ characteristics and available treatment options is a fundamental prerequisite. Exposing the patient to all accessible options should remain the primary focus of clinicians in order to maximize the derived benefit for their patients while waiting for results of continuing research to refine the optimal sequencing of therapies and improve outcomes for patients with metastatic colorectal cancer.

Conflict of interest disclosure: None to declare.

Declaration of funding sources: None to declare.

Author contributions: All authors contributed equally to the study as well as to the preparation of the manuscript for publication.

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