Strategies for the Management of Relapsed/Refractory Metastatic Colorectal Cancer: From Landmark Trials to Precision Medicine

Introduction

COLORECTAL CANCER (CRC) is the fourth most common cancer diagnosis in the United States with over 36.5 new cases per 100,000 people per year; further, it is the second leading cause of cancer-related death.^1,2 Prognosis deteriorates as the disease spreads, with approximate 5-year survival rates of 91% for localized disease, 74% for regional disease, and 15% for metastatic disease.¹ Over 20% of newly diagnosed patients have metastatic disease, and approximately 50% of patients with locoregional CRC will develop distant recurrence.^1,3 Currently, with the exception of a small subset of patients with resectable isolated lung or liver metastases, metastatic CRC (mCRC) is incurable and is associated with a median overall survival (OS) of 1.7 years.^4-6

The 3 main categories of systemic therapies used in mCRC are immunotherapy, conventional chemotherapy, and targeted therapy. Current guidelines for mCRC recommend immune checkpoint inhibitors (ICI) as first-line therapy for patients with mismatch repair-deficient/microsatellite instability–high (dMMR/MSI-H) mCRC.^7-9 Fluoropyrimidine-based doublet therapy (oxaliplatin or irinotecan) with an epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) inhibitor is recommended as first-line therapy for patients who need conventional chemotherapy.^7,9 Patients who progress through fluoropyrimidine-based therapy are considered to have refractory disease, and subsequent therapy options depend on prior therapy and tumor biomarkers. Unfortunately, only 10% to 16% of CRCs have mutations (KRAS, BRAF, or HER2) for which targeted therapy can be used.¹⁰ For most patients, the only salvage regimens available are regorafenib, fruquintinib, trifluridine/tipiracil (FTD/TPI), or FTD/TPI plus bevacizumab.⁹

Efficacy and Safety Profiles of Treatment Options for Relapsed/Refractory mCRC

FTD/TPI is an oral therapy that combines trifluridine, a thymidine-based nucleic acid analog, and tipiracil, a potent thymidine phosphorylase inhibitor that prevents enzymatic breakdown of trifluridine.¹¹ FTD/TPI has been approved for use as monotherapy and in combination with intravenous infusion of bevacizumab, a VEGF inhibitor with antiangiogenic effects.¹¹ Regorafenib is an oral multikinase inhibitor that blocks protein kinases involved in angiogenesis (VEGF1, VEGF2, VEGF3, and TIE2), oncogenesis (KIT, RET, RAF1, and BRAF), and the tumor microenvironment (PDGFR and FGFR).¹² Fruquintinib is a tyrosine kinase inhibitor that is a highly selective and potent inhibitor of VEGF, which downregulates tumor growth and metastasis through inhibition of VEGF-mediated endothelial cell proliferation.¹³

Clinical Trial Data

FTD/TPI was originally approved as monotherapy for mCRC based on an improvement in OS compared with placebo in the RECOURSE study (NCT01607957).¹⁴ approval based on the SUNLIGHT trial (NCT04737187), a phase 3 study from November 25, 2020 to February 18, 2022.¹⁵ The study evaluated the efficacy and safety of combination therapy with FTD/TPI plus bevacizumab (35 mg/m2 on days 1 through 5 and 8 through 12, and 5 mg/kg on days 1 and 15, respectively, in a 28-day cycle) versus FTD/TPI monotherapy in patients with relapsed or refractory mCRC. Four hundred ninety-two patients were enrolled (246 patients in each group), and 72.0% of participants received prior anti-VEGF monoclonal antibody treatment. The combination therapy group, when compared with the monotherapy group, demonstrated improvement in median OS (10.8 months [95% CI, 9.4-11.8 months] vs 7.5 months [95% CI, 6.3-8.6 months], respectively) (HR, 0.61; 95% CI, 0.49-0.77; P < .001) and median progression-free survival (PFS) (5.6 months [95% CI, 4.5-5.9 months] vs 2.4 months [95% CI, 2.1-3.2 months]) (HR, 0.44; 95% CI, 0.36-54; P < .001).¹⁵

Adverse events (AEs) commonly observed in both groups included neutropenia, nausea, and anemia. The AEs attributed to the addition of bevacizumab in the combination group were marginal, as grade 3 or higher toxicities were comparable. Still, there were higher overall rates of hypertension (any grade, 10.2% vs 2.0%; grade ≥ 3, 5.7% vs 1.2%), nausea (any grade, 37.0% vs 27.2%; grade ≥ 3, 1.6% vs 1.6%), and neutropenia (any grade, 62.2% vs 51.2%; grade ≥ 3, 43.1% vs 32.1%) in the combination therapy group vs the FTD/TPI monotherapy group, respectively. No treatment-related deaths were reported.¹⁵

These findings suggest that combination therapy with FTD/TPI plus bevacizumab provides enhanced efficacy with a manageable safety profile.¹⁵ The benefits were observed despite prior anti-VEGF therapy in more than 70% of patients.¹⁵ Based on these outcomes, the combination therapy may be considered as standard of care over FTD/TPI alone for this patient population, although FTD/TPI monotherapy may be preferred to mitigate serious AEs with bevacizumab in patients who have preexisting risk factors such as uncontrolled hypertension.^9,16

Regorafenib gained FDA approval through the CORRECT study (NCT01103323) in 2013, which demonstrated improvement in OS, although a majority of patients experienced AEs.¹⁷ To improve tolerability, an alternative dosing strategy for regorafenib was evaluated in the ReDOS study (NCT02368886), a randomized, open-label phase 2 study comparing 2 dosing strategies for regorafenib.¹⁸ For cycle 1, the dose-escalation group received regorafenib starting at 80 mg daily for 1 week, then 120 mg daily for 1 week, then 160 mg daily for 1 week if no significant drug-related toxicities were observed.¹⁸ For subsequent cycles, patients received the highest tolerated dose from cycle 1. The standard-dose group started regorafenib at 160 mg daily for 21 days of a 28-day cycle until dose modification or discontinuation.¹⁸

One hundred sixteen patients were enrolled; there were 54 patients in the dose-escalation group and 62 patients in the standard-dose group. More patients in the dose-escalation group initiated cycle 3 compared with the standard-dose group (43% vs 26%; P = .043). The median OS was 9.8 months (95% CI, 7.5-11.9 months) for the dose-escalation group and 6.0 months (95% CI, 4.9-10.2 months) for the standard-dose group (HR, 0.72; 95% CI, 0.47-1.10; P = .12). Median PFS was 2.8 months (95% CI, 2.0-5.0 months) in the dose-escalation group and 2.0 months (95% CI, 1.8-2.8 months) in the standard-dose group (HR, 0.84; 95% CI, 0.57-1.24; P = .38).¹⁸

AEs were similar between the 2 dosing strategies. The most common grade 3/4 AEs were fatigue (15.5%), hand-foot syndrome (15.5%), hypertension (11.2%), and abdominal pain (11.2%).¹⁸ This was consistent with the known safety profile of regorafenib. However, in cycle 1, fewer patients in the dose-escalation group had grade 2/3 hand-foot syndrome compared with the standard-dose group. Quality of life (QOL) scores were significantly higher at week 2 in the dose-escalation group compared with the standard-dose group for fatigue (5.30 [95% CI, 4.48-6.12] vs 4.25 [95% CI, 3.55-4.95], respectively; P = .046), general activity interference (5.59 [95% CI, 4.73-6.45] vs 4.31 [95% CI, 3.48-5.14]; P = .032), mood interference (6.22 [95% CI, 5.35-7.09] vs 4.92 [95% CI, 4.07-5.77]; P = .038), walking ability interference (5.96 [95% CI, 5.07-6.85] vs 4.50 [95% CI, 3.68-5.32]; P = .019), and normal work interference (5.48 [95% CI, 4.58-6.38] vs 4.17 [95% CI, 3.34-5.00]; P = .039) as measured by the Brief Fatigue Inventory questionnaire. At weeks 4, 6, and 8, the QOL scores were no longer significantly different between dosing strategies.¹⁸ Overall, the dose-escalation strategy was associated with some improvement in tolerability and QOL in the ramp-up phase and allowed more patients to initiate cycle 3 without significant differences in efficacy.

Fruquintinib received FDA approval through the FRESCO-2 trial (NCT04322539), a randomized, doubleblind, placebo-controlled, phase 3, international study in patients with mCRC after prior standard treatments including fluoropyrimidine-based chemotherapy, anti-VEGF therapy, anti-EGFR therapy, and either FTD/TPI or regorafenib.¹⁹ Patients were randomly assigned to receive fruquintinib 5 mg or placebo orally once daily on days 1 through 21 in 28-day cycles. A total of 691 patients were enrolled; 461 patients received fruquintinib, and 230 patients received placebo. The overall population was heavily pretreated; the median number of lines of therapy for metastatic disease was 4 (IQR, 3-6); 96% of patients received prior anti-VEGF therapy, 39% of patients received prior anti-EGFR agents, 92% of patients received prior FTD/TPI, and 48% of patients received prior regorafenib.¹⁹

The median OS was 7.4 months (95% CI, 6.7-8.2 months) in the fruquintinib group compared with 4.8 months (95% CI, 4.0-5.8 months) in the placebo group (HR, 0.66; 95% CI, 0.55-0.80; P < .0001). The median PFS was 3.7 months (95% CI, 3.5-3.8 months) in the fruquintinib group compared with 1.8 months (95% CI, 1.8-1.9 months) in the placebo group (HR, 0.32; 95% CI, 0.27-0.39; P < .001). The improvements in OS and PFS were consistent in subgroup analyses involving patients with prior anti-VEGF therapy, prior FTD/TPI, and prior regorafenib. Although no patients achieved complete response, the median duration of response in the fruquintinib group was 10.7 months (95% CI, 3.9 months to not estimable). Patients who received fruquintinib more frequently experienced hypertension (any grade, 37% vs 9%; grade 3 or more, 14% vs 1%), asthenia (any grade, 34% vs 23%; grade 3 or more, 8% vs 4%), and hand-foot syndrome (any grade, 19% vs 3%; grade 3 or more, 6% vs 0%) compared with those in the placebo group, respectively. Each group had 1 patient death related to treatment. One patient in the fruquintinib group developed intestinal perforation, and 1 patient in the placebo group died from cardiac arrest. The discontinuation rate due to AEs was similar between the fruquintinib and placebo groups (21% vs 20%).¹⁹

Fruquintinib was well tolerated and associated with prolonged OS and PFS in patients with refractory mCRC.¹⁹ The demonstrated benefit of fruquintinib despite prior FTD/TPI or regorafenib therapies may influence decisions on therapy sequencing.

European Society for Medical Oncology (ESMO) guidelines recommend regorafenib and FTD/TPI as third-line therapies for mCRC following oxaliplatin- and irinotecan-based regimens, but fruquintinib is not yet included, as it was approved after the latest guideline update.^7,13 Other guidelines offer broader recommendations supporting the use of fruquintinib, regorafenib, and FTD/TPI with or without bevacizumab after all other treatment lines have failed. Combination FTD/TPI with bevacizumab is preferred over FTD/TPI monotherapy.⁹ These differences underscore the evolving nature of cancer treatment guidelines as new evidence emerges and therapy options expand.

Real-World Evidence

There are no prospective head-to-head studies comparing any of the aforementioned therapies. Real-world studies are available comparing regorafenib and FTD/TPI, although US-based studies are limited. In a retrospective, longitudinal cohort study at a US tertiary oncology center, 221 patients with mCRC were treated with FTD/TPI (n = 126) or regorafenib (n = 95).²⁰ Most patients received FTD/TPI or regorafenib after 3 lines of therapy, but 37.3% and 34.7% of patients received FTD/TPI or regorafenib, respectively, as second- or third-line therapy. Best real-world overall response rate was higher with FTD/TPI compared with regorafenib (52.5% vs 34.2%; P = .012).²⁰

Among patients who received either FTD/TPI or regorafenib earlier in their treatment course (as second- or third-line therapy), those who received FTD/TPI were more likely to respond to treatment (54.8% vs 25.9%; P = .018) and achieve disease control (69.0% vs 37.0%, P = .009), defined as at least stable disease for 6 weeks. OS was not different between groups (7.5 months [95% CI, 6.0-8.8 months] vs 7.1 months [95% CI, 5.0-8.2 months]; P = .312) nor the subgroup of patients who received these therapies in the second or third line (7.7 months [95% CI, 4.4-11.5 months] vs 5.1 months [95% CI, 2.9-7.9 months]; P = .073). Patients who received FTD/TPI were more likely to experience neutropenia (incidence rate ratio [IRR], 5.35; 95% CI, 2.01-14.21) but less likely to experience hand-foot syndrome (IRR, 0.06; 95% CI, 0.01-0.27) compared with patients who received regorafenib.²⁰

Notably, all patients used the standard-dose strategy of regorafenib 160 mg daily, as the results from the ReDOS trial were not available until after data collection was completed.²⁰ Even so, use of the regorafenib dose-escalation strategy would likely have more effect on initial tolerability and would not be expected to change the results of efficacy outcomes.¹⁸ Results are also limited to interpretation for FTD/TPI monotherapy only. If combination therapy with bevacizumab was evaluated, it may have favored FTD/TPI, as it had demonstrated greater efficacy over FTD/TPI monotherapy in the SUNLIGHT trial; however, additional analyses would be needed to evaluate this directly.¹⁵

Another study evaluated real-word data of patients with de novo or recurrent mCRC who received FTD/TPI or regorafenib as third-line or later therapy from more than 800 sites, including both academic and community oncology settings.²¹ A total of 1937 patients were included in the analysis, with 1016 patients (52.5%) receiving FTD/TPI alone or prior to regorafenib and 921 patients (47.5%) receiving regorafenib alone or prior to FTD/TPI.²¹ Of these, 111 patients (10.9%) in the FTD/TPI group and 99 patients (10.7%) in the regorafenib group went on to receive the alternate therapy. Median OS was 6.66 months (95% CI, 6.16-7.18 months) for the FTD/TPI group compared with 6.30 months (95% CI, 5.80-6.79 months) in the regorafenib group (HR, 0.99; 95% CI, 0.90-1.09; P = .82). An exploratory analysis comparing patients who received FTD/TPI prior to regorafenib and those who received regorafenib prior to FTD/TPI showed similar OS regardless of sequence of therapy (HR, 0.98; 95% CI, 0.83-1.14).²¹ Contrary to the previously discussed real-world study of a single academic center, this study did not find any differences in efficacy between FTD/TPI and regorafenib.^20,21 Interestingly, a decreased risk of death was observed in patients on FTD/TPI who developed neutropenia within the first 4 weeks of therapy (HR, 0.56; 95% CI, 0.37-0.84).²¹ Real-world data in this study were comparable to data presented in clinical trials that led to FDA approval.^14,17,21

Discussion thus far is limited to currently available data. Data are lacking in comparing FTD/TPI in combination with bevacizumab to other therapy options, and the regorafenib dose-escalation strategy has not been compared with other options. Future US-based study of fruquintinib will also be useful in guiding sequencing decisions within a US population.

Precision Oncology and Personalized Medicine in mCRC Management

There are many targetable mutations for mCRC. Although the incidence is low, existence of targetable mutations allows for additional therapy options.¹⁰

RAS

KRAS/NRAS status is of particular importance, as these are downstream of the EGFR pathway, and mutations of RAS are predictive of insensitivity to anti-EGFR therapy.⁹ Additionally, tumors with the KRAS G12C mutation may be treated with a KRAS inhibitor along with an anti-EGFR agent.⁹ KRAS G12C mutation is found in approximately 2% to 4% of CRC patients and can be targeted with sotorasib or adagrasib, small-molecule KRAS G12C inhibitors.¹⁰ These therapies may be used in combination with cetuximab or panitumumab every 2 weeks for KRAS G12C–mutated CRC.^9,22,23 Patients who cannot tolerate the AEs of anti-EGFR therapy may be eligible for anti-KRAS monotherapy, although these still carry potential serious AEs.^24,25 Sotorasib and adagrasib may cause hepatotoxicity and pneumonitis, whereas adagrasib puts patients at additional risk of significant gastrointestinal toxicity (eg, nausea, vomiting, or diarrhea) and QTc prolongation.^26,27

BRAF V600E

BRAF V600E mutation is identified in roughly 5% to 9% of CRC patients and can be treated with encorafenib in combination with cetuximab or panitumumab.^7,9,10 Some notable AEs associated with encorafenib include risk of new primary malignancy, cardiomyopathy, hepatotoxicity, hemorrhage, uveitis, and QTc prolongation.²⁸

HER2

HER2 amplification occurs in 3% of CRC and 5% to 14% of RAS/BRAF wild-type CRC.¹⁰ The majority of patients with strong HER2 overexpression have rectal cancer and left-sided colon cancer, emphasizing the importance of HER2 testing in this patient cohort. HER2 overexpression predicts evasion of EGFR inhibitor therapy given the overlapping downstream signaling pathways.¹⁰ Guidelines recommend HER2-directed therapy, namely trastuzumab in combination with pertuzumab, lapatinib, or tucatinib, for HER2-amplified and RAS/BRAF wild-type CRC, and fam-trastuzumab deruxtecan for HER2-amplified CRC.⁹ Despite the availability of and recommendation to use HER2-directed therapies, a real-world data study of US patients with HER2-positive mCRC using a health claim clinical-genomic dataset from January 2014 to September 2020 found that not all patients receive anti-HER2 therapy.²⁹ Even though usage increased from 22.8% prior to 2018 to 36.5% post-2018, considerable opportunity remains to increase access to these therapies for appropriate patients.²⁹

From a safety perspective, each of the HER2-targeted therapies carry distinctive AE risks. Trastuzumab has the risk of cardiomyopathy and requires regular echocardiogram monitoring.³⁰ Pertuzumab carries the risk of infusion reactions and diarrhea.³¹ Lapatinib may cause hepatotoxicity, diarrhea, pneumonitis, QTc prolongation, and severe cutaneous reactions.³² Fam-trastuzumab deruxtecan is associated with pneumonitis, neutropenia, and left ventricular dysfunction.³³

NTRK

NTRK fusion is found in 0.2% to 1% of CRCs.¹⁰ Guidelines recommend anti-NTRK therapy, such as entrectinib or larotrectinib, for NTRK-mutated CRC, although both are associated with central nervous system effects and hepatotoxicity.^9,34,35 Entrectinib has additional risks of congestive heart failure, skeletal fractures, QTc prolongation, and vision disorders.³⁴

RET

RET gene fusion is identified in less than 1% of CRCs; selpercatinib, a kinase inhibitor of wild-type RET and VEGF, may be used to target the gene fusion.^9,36 Selpercatinib has notable AEs of hepatotoxicity, pneumonitis, hypertension, QTc prolongation, hemorrhage, hypersensitivity, and impaired wound healing.³⁶

Patient-Centered Treatment Approaches

Despite improvement in OS, mCRC is still an incurable disease, underscoring the importance to shift treatment priority to improving QOL while involving patients in the decision-making process.^37,38 The impact of mCRC and its treatment on QOL can be very different from patient to patient.³⁸ Patient-centered care and prioritization of patient preferences, needs, values, and obligations are crucial to minimize the impact of the disease on the patient’s life.³⁸

Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events classification helps assess treatment-related AEs that affect the patient and may be a more patient-centered way to measure the tolerability profile of a therapy throughout its development process. Many tools have been developed to assess QOL including some specific to mCRC, but additional questionnaires may be needed to assess other possible AEs related to treatment.³⁸

Older adults represent a substantial portion of patients with CRC, as the median age of diagnosis is 66 years.¹ Adults 75 years or older with CRC were 43% less likely to receive chemotherapy despite growing evidence that older patients are interested in and may still benefit from these therapies.^39,40 A comprehensive geriatric assessment rather than chronological age and performance status alone may more accurately predict how an older patient may tolerate therapy, because it evaluates the patient’s past medical history, nutritional reserve, sensory function, support network, psychological stability, and mental capacity.^39,41

Economic Impact Analysis

The US spending on oncologic care for CRC increased from $22.3 billion in 2015 to $24.3 billion in 2020, making CRC the second most expensive malignancy.⁴² Caring for mCRC is especially costly in later lines of therapy, as the average per-patient cost for medical services and oral prescription drugs were highest for the last year of life ($110,100 and $1400, respectively) compared with the first year of diagnosis ($66,500 and $400, respectively) and the continuing care phase ($6200 and around $200, respectively).⁴³

Value-Based Care

The American Society of Clinical Oncology (ASCO) and ESMO value frameworks are valuable tools for evaluating antineoplastic therapy. These frameworks quantify the overall clinical benefit of a therapy based on clinical outcomes, QOL measures, and reported toxicity.⁴⁴ A 2017 study applied the value frameworks on oncology drugs approved by the FDA from 2004 to 2015.⁴⁴ FTD/TPI was superior to regorafenib based on both the ASCO and ESMO scores; however, FTD/TPI combination therapy with bevacizumab and the dose-escalation strategy for regorafenib were not evaluated.⁴⁴ A 2022 value-based analysis study found that a regorafenib dose-escalation strategy was more cost effective based on quality-adjusted life-year than was FTD/TPI with or without bevacizumab.^44,45

Health care utilization studies have been done to compare the value of treatment options in mCRC. A modeling analysis of treatments for dMMR/MSI-H mCRC found that ICIs were more effective based on OS and quality-adjusted life-year but less cost-effective compared with FTD/TPI due to high drug costs and the long-term cost of maintenance therapy.⁴⁶ Another modeling analysis compared the cost-effectiveness of therapies used for BRAF V600E-mutated mCRC.⁴⁷ Encorafenib and cetuximab with or without binimetinib were effective in improving quality-adjusted life-year but not cost-effective compared with cetuximab plus chemotherapy.⁴⁷

Medication Adherence

From an adherence perspective, a retrospective study using US claims data from the Symphony Health Solutions Integrated Dataverse database from October 2014 to July 2016 evaluated adherence of patients with mCRC to FTD/TPI and regorafenib. Medication adherence was assessed using medication possession ratio (MPR), defined as total number of days supplied divided by number of days between medication fill dates, and proportion of days covered (PDC), defined as the number of unique days with medication divided by the length of a fixed time interval (3 and 6 months). The study evaluated 1630 patients receiving FTD/TPI and 1425 patients receiving regorafenib.⁴⁸ FTD/TPI had higher mean MPR (0.91 vs 0.87; P < .001), proportion of MPR of at least 0.80 (84.5% vs 74.0%; P < .001), MPR of at least 0.90 (71.2% vs 55.1%; P < .001), mean PDC at 3 months (0.71 vs 0.59; P < .001), and mean PDC at 6 months (0.57 vs 0.45; P < .001) compared with regorafenib.⁴⁸

A similar study using IQVIA Real-World Data Adjudicated Claims in the US from October 2015 to July 2017 evaluated the adherence to FTD/TPI and regorafenib treatment regimens in patients with mCRC.⁴⁹ Patients receiving FTD/TPI (n = 469) had higher mean MPR (0.93 vs 0.86; P < .001), proportion of MPR of at least 0.80 (87.1% vs 72.6%; P < .001), MPR of at least 0.90 (74.6% vs 54.3%; P < .001), mean PDC at 3 months (0.72 vs 0.60; P < .001), and mean PDC at 6 months (0.56 vs 0.48; P = .020) compared with patients receiving regorafenib (n = 311).⁴⁹ These real-world studies suggest that patients on FTD/TPI were more likely to be adherent to therapy compared with those on regorafenib, although both studies were conducted prior to the ReDOS study.^18,48,49

Precision Medicine Considerations

Beyond the value of the treatment itself, an additional consideration for precision medicine approaches is the cost of universal testing for targetable biomarkers. When looking specifically at RAS testing, the cost of up-front testing was found to be lower than the cost of treating all patients without testing.⁵⁰ However, broader screening of all targetable mutations will help ensure patient access to all appropriate therapies, and broad molecular testing panels are significantly more costly than individual target testing according to a model analysis of reimbursement data.⁵¹ However, in a model analysis of patients with non–small cell lung cancer in Canada, up-front panel testing prevented the need for sequential individual target testing and was associated with less cost of delay in care.⁵² Thus, it is important to consider broad molecular profiling biomarker testing for KRAS/NRAS, BRAF, HER2, and MSI/MMR status for mCRC if not previously done in accordance with guideline recommendations.⁹

Conclusion

A diagnosis of mCRC presents complex challenges, driving the need for innovative strategies to improve outcomes while managing costs. Precision oncology testing may allow additional targeted treatment options in mCRC.

Further research is needed to understand optimal sequencing of available therapies as well as value-based comparisons that incorporate precision-medicine approaches. Newer analyses that incorporate modern-day approaches, such as the dose-escalation strategy for regorafenib or the combination of FTD/TPI with bevacizumab, are imperative to further optimize value-based care.

The financial impact of mCRC treatment demands a careful examination of payer reimbursement policies and their role in sustaining a functional health care system. Although it is critical to consider a drug’s clinical effectiveness, safety, and likelihood for adherence, payer decisions should also reflect individual patient values and treatment goals. These considerations are particularly vital, because insurance coverage can influence treatment accessibility and affordability, shaping the patient’s journey through a challenging disease. Furthermore, a one-size-fits-all reimbursement approach may inadvertently create barriers to care, disproportionately affecting those with lower socioeconomic status.⁵³ To avoid exacerbating health disparities, health care systems are encouraged to design reimbursement strategies that support personalized treatment while ensuring equitable access for all patients regardless of their socioeconomic background.

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