In the Clinic . . .
Consider the following patient cases encountered in my clinic.
Case 1: Indolent Disease, Long-Term Disease Control
A 59-year-old male was originally diagnosed with stage 2 colorectal cancer (CRC) 3 years ago. He did not receive adjuvant therapy. He then presented with small lung lesions and tested circulating tumor DNA (ctDNA)–positive. Molecular testing showed RAS wild-type, BRAF V600E wild-type, microsatellite-stable (MSS), and HER2-negative. Biopsy results were positive and the patient was considered unresectable.
As first-line therapy for metastatic CRC (mCRC), he received capecitabine and bevacizumab, which induced a response. At a 3-year follow-up, the patient remained asymptomatic, but several new lesions were detected, indicating progressive disease. After considering the available options, the patient was started on trifluridine/tipiracil plus bevacizumab and has had stable disease (SD) for 12 months.
Case 2: Balancing Tumor Response With Quality of Life
A 45-year-old female, working full time and married with 2 children, was diagnosed with recto-sigmoid colon cancer after developing rectal bleeding and narrowing of stool. A positron emission tomography (PET) scan detected liver and lung metastases. A multidisciplinary team considered the tumor not resectable. Molecular testing showed MSS, a RAS mutation, BRAF V600E wild-type, and HER2-negative.
Her induction treatment consisted of leucovorin, fluorouracil (5-FU), irinotecan, and oxaliplatin (FOLFIRINOX) plus bevacizumab, which induced a strong response by 6 cycles but with some neurologic toxicity. The oxaliplatin and irinotecan were discontinued, and capecitabine and bevacizumab were added. The patient’s symptoms resolved and she returned to work and parenting duties. She received capecitabine/bevacizumab maintenance therapy for 9 months, then imaging revealed minor progressive disease. She had no change in bowel symptoms and no neuropathy. She was started on trifluridine/tipiracil plus bevacizumab and has had SD for 6 months.
Case 3: Molecularly Driven Treatment and Sequencing
A 72-year-old female presented with ascending colon cancer. Initial staging was negative. Surgery showed T3N2M1 with small peritoneal lesions. Molecular testing revealed a BRAF V600E mutation. A postoperative PET scan was positive for peritoneal lesions and para-aortic nodes. She received leucovorin, 5-FU, and oxaliplatin (FOLFOX), panitumumab, and encorafenib, which induced a near radiographic complete response (CR) but caused a minor rash. The oxaliplatin and fluorouracil were discontinued and the patient continued panitumumab and encorafenib. After 6 months of SD, scans revealed progressive disease but no new symptoms. The patient was started on trifluridine/tipiracil plus bevacizumab and has had SD for 8 months.
The Common Thread: Approaching mCRC Treatment as Chess, Not Checkers
With the availability of varied therapies, including chemotherapeutic agents, targeted agents, and immunotherapy, management of mCRC has evolved to be more strategic, analogous to a game of chess rather than checkers (Figure 1). These cases illustrate that mCRC management requires an individualized approach, taking into account disease-related factors (location, resectability, molecular factors, and the pace of progression), patient-related factors (fitness, preferences, and symptoms), and treatment-related factors (efficacy, toxicity, prior treatments received, and the type of response to prior treatments) at each decision step.
It is important that clinicians understand all the “chess pieces” available and learn to use them strategically for the best outcome across the treatment journey of the patient.
Overview of mCRC and Initial Assessment
CRC is one of the most common cancer types in the United States; an estimated 158,850 new cases will be diagnosed in 2026, and 55,230 individuals will die from the disease.1 The age range at diagnosis has shifted, with CRC increasingly affecting younger adults. Although the median age at diagnosis is 66 years, 23.5% of cases occur in adults younger than age 55. Early-onset CRC, defined as occurring in individuals younger than 50 years of age, is among the fastest growing cancers in young people in the United States, with a current incidence rate of 14.8 cases per 100,000 population.2 There appear to be biological differences among these cancers that may affect the treatment approach, highlighting the importance of molecular testing.
CRC is somewhat unique among cancer types in that some patients with metastatic disease are eligible for curative therapy with surgery or other ablative techniques.3 As a result, it is essential to conduct a thorough baseline assessment of the location of metastases and to ensure the patient is evaluated by a multidisciplinary tumor board to assess eligibility for potentially curative treatment.
Molecular profiling is another essential element of the workup. Clinicians tend to be familiar with testing for microsatellite instability (MSI), but it is also important to test for other markers, including BRAF V600E, HER2 (ERBB2), and KRAS/NRAS, as the number of actionable alterations increases.4
The location of the primary tumor is another key factor; epidermal growth factor receptor (EGFR)-targeted therapy has demonstrated a significant overall survival (OS) benefit in patients with left-sided RAS wild-type mCRC.5
My Approach to Initial Treatment of mCRC
Initial lines of therapy are determined by tumor location, resectability, and molecular factors. First-line chemotherapy is usually a combination of chemotherapies, typically 5-FU (oral or intravenous) combined with oxaliplatin, irinotecan, or both, usually administered in combination with a biologic agent. It should be noted that these chemotherapy agents are associated with significant hematologic and nonhematologic toxicities (Table 1).6-11
For most patients, the added biologic agent is bevacizumab, but EGFR-targeted agents are used in selected patients, and BRAF-targeted drugs are incorporated for patients with a BRAF V600E mutation. The treatment approach for patients with deficient mismatch repair (dMMR) and high microsatellite instability (MSI-H) is different and beyond the scope of this article.
When I see a patient with unresectable mCRC, my first question is not simply which regimen to use. It is identifying what the treatment needs to accomplish. I consider multiple factors, including the size of the tumor, types of metastases, and the extent of symptoms. For most patients, I use a 3-drug regimen, typically 5-FU, oxaliplatin, and bevacizumab. However, I may consider a 2-drug regimen of 5-FU and bevacizumab for a patient with small, slow-growing lung metastases, and a 4-drug regimen in a patient with bulky, symptomatic tumors.
The induction regimen is administered for approximately 3 to 6 months, at which point the patient switches to maintenance therapy, typically consisting of a 2-drug regimen of 5-FU and bevacizumab. I tend to use the oral formulation of 5-FU (capecitabine). Usually, this induction strategy helps patients for the first year or more.
Conventional Approaches to Second-Line Therapy: Time to Rethink?
When tumor growth occurs, and the patient is ready for second-line therapy, the reflexive next step has been to administer whichever drugs had not been used in the first-line setting. Typically, this includes irinotecan if not used in induction. The regimen used may vary depending on the presence of targetable alterations such as mutations in KRAS/NRAS/BRAF or HER2 overexpression/amplification. Historically, second-line irinotecan-based regimens have yielded only modest efficacy, with objective response rates (ORR) ranging from 4% to 12.5%, increasing to 5% to 24.2% with the addition of a vascular endothelial growth factor (VEGF) inhibitor (bevacizumab, ramucirumab, or aflibercept).12-16
The development of disease progression after receiving standard chemotherapy and targeted therapies is considered to be refractory mCRC. Multiple newer agents have demonstrated a significant OS benefit in these patients, including the coformulated chemotherapeutic combination of trifluridine and tipiracil (initially evaluated alone but shown to have a further OS benefit when used in combination with bevacizumab), the VEGF inhibitor fruquitinib, and the multikinase inhibitor regorafenib.17-20
Although conventionally patients are considered for these newer approaches only after the standard first-line and second-line regimens, there may be a role for rethinking this paradigm, and considering using these chess pieces earlier in the game. First, let us review the evidence for these newer therapies.
Therapies for Refractory mCRC: A Review of the Evidence
Today the treatment options available for patients with mCRC who have received prior oxaliplatin and irinotecan and are not eligible for targeted therapy include trifluridine/tipiracil with or without bevacizumab (with the bevacizumab combination preferred), fruquitinib, and regorafenib (Figure 2).21-23 An overview of the clinical trial data leading to the United States Food and Drug Administration (FDA) approval of these regimens is shown in Table 2 (dosing summary in Table 3).17-19,20,24-27
Regorafenib
The first drug to receive FDA approval in refractory mCRC was the oral multitargeted tyrosine kinase inhibitor (TKI) regorafenib, which was compared against placebo in the randomized, phase 3 CORRECT trial in 760 patients with mCRC previously treated with standard therapies.17 The trial was conducted across 16 countries and included 111 Asian patients, primarily Japanese. Patients were randomly assigned 2:1 to best supportive care plus regorafenib 160 mg (n=505) or placebo (n=255) once daily for 3 weeks of every 4-week cycle.
The CORRECT trial met its primary endpoint, demonstrating a significant improvement in OS with regorafenib compared with placebo (median, 6.4 months vs 5.0 months, respectively; hazard ratio [HR], 0.77; 95% CI, 0.64-0.94; P=.0052). The most common grade 3 or higher adverse events (AEs) related to regorafenib were hand-foot skin reaction (HFSR, 17%), fatigue (10%), diarrhea (8%), hypertension (7%), and rash/desquamation (6%).
A second phase 3 trial, CONCUR, evaluated regorafenib in a broader population of Asian patients—204 patients in China, Hong Kong, South Korea, Taiwan, and Vietnam.24 Patients were randomly assigned 2:1 to regorafenib 160 mg (n=136) or placebo (n=68) once daily for 3 of 4 weeks with best supportive care. After a median follow-up of 7.4 months, regorafenib was associated with a significant improvement in OS over placebo (median, 8.8 months vs 6.3 months, respectively; HR, 0.55; 95% CI, 0.40-0.77; P=.00016). The most frequent treatment-related AEs in the regorafenib arm were HFSR (16%), hypertension (11%), hyperbilirubinemia (7%), hypophosphatemia (7%), increased alanine aminotransferase (7%), increased aspartate aminotransferase (6%), increased lipase (4%), and rash (4%).
Trifluridine/Tipiracil
The second regimen to receive FDA approval in refractory mCRC was trifluridine/tipiracil (TAS-102), an orally administered combination of the thymidine-based nucleic acid analogue trifluridine and the thymidine phosphorylase inhibitor tipiracil. The cytotoxic effects of the compound are exerted by trifluridine, which incorporates into DNA; the addition of tipiracil prevents trifluridine degradation, which stabilizes the active drug.28
The randomized, phase 3 RECOURSE trial compared trifluridine/tipiracil against placebo in a global population of patients with refractory mCRC.25 A total of 800 patients were randomly assigned 2:1 to trifluridine/tipiracil (n=534) or placebo (n=266); patients received trifluridine/tipiracil (35 mg/m2) or placebo twice daily for 5 days a week with 2 days of rest for 2 weeks, followed by a 14-day rest period, in 4-week cycles. The trial demonstrated a significant improvement in OS with trifluridine/tipiracil vs placebo (median, 7.1 months vs 5.3 months, respectively; HR, 0.68; 95% CI, 0.58-0.81; P<.001). The most frequent clinically significant AEs associated with trifluridine/tipiracil were neutropenia (38%), leukopenia (21%), febrile neutropenia (4%), and 1 death. The median time to worsening of Eastern Cooperative Oncology Group (ECOG) performance status from 0 or 1 to 2 or higher was significantly longer with trifluridine/tipiracil vs placebo (5.7 vs 4.0 months; HR, 0.66; 95% CI, 0.56-0.78; P<.001).
Trifluridine/tipiracil was also evaluated in the randomized, phase 3 TERRA trial, which focused on an Asian patient population.26 The trial enrolled 406 patients with mCRC refractory or intolerant to 3 or more prior chemotherapy regimens who were randomly assigned to trifluridine/tipiracil (n=271) or placebo (n=135). Trifluridine/tipiracil was associated with a significant improvement in OS over placebo (median, 7.8 months vs 7.1 months, respectively; HR, 0.79; 95% CI, 0.62-0.99; P=.035). The rate of serious AEs was similar between arms (23.2% and 23.7%, respectively).
Trifluridine/Tipiracil + Bevacizumab
The demonstrated benefit of continuing antiangiogenesis therapy after progression, and the demonstration of OS benefit with VEGFR targeting via regorafenib and fruquitinib in refractory mCRC, provided a rationale for evaluating the addition of bevacizumab to trifluridine/tipiracil in this setting.12,17,19,20,24 Several phase 1/2 trial and investigator-initiated studies demonstrated encouraging efficacy with the addition of bevacizumab to trifluridine/tipiracil, warranting a larger trial.29-31
The randomized, phase 3 SUNLIGHT trial was undertaken to evaluate the efficacy and safety of adding bevacizumab to trifluridine/tipiracil in patients with refractory mCRC.19 The trial enrolled 492 patients who had received up to 2 prior chemotherapy regimens for advanced CRC; patients were randomly assigned 1:1 to trifluridine/tipiracil alone or with bevacizumab administered at 5 mg/kg intravenously on days 1 and 15 every 28 days. The trial met its primary endpoint, demonstrating a significant improvement in OS with trifluridine/tipiracil plus bevacizumab vs trifluridine/tipiracil alone (median, 10.8 vs 7.5 months; HR, 0.61; 95% CI, 0.49-0.77; P<.001). The median PFS was 5.6 months and 2.4 months, respectively (HR, 0.44; 95% CI, 0.36-0.54; P<.001).
The most common grade 3 or 4 AEs in both arms were neutropenia (43.1% vs 32.1%), neutrophil count reduction (8.9% vs 5.3%), anemia (6.1% vs 11.0%), hypertension (5.7% vs 1.2%), and asthenia (4.1% vs 4.1%). The median time to worsening of ECOG performance status from 0 or 1 to 2 or higher was 9.3 months with trifluridine/tipiracil plus bevacizumab vs 6.3 months with trifluridine/tipiracil alone (HR, 0.54; 95% CI, 0.43-0.67).
The OS benefits observed with trifluridine/tipiracil over placebo in the RECOURSE and TERRA trials and with the addition of bevacizumab to trifluridine/tipiracil in the SUNLIGHT trial were sustained across subgroups, including whether patients had KRAS-mutated disease.18,19,25
Fruquitinib
The oral VEGFR inhibitor fruquitinib was evaluated in patients with refractory mCRC in 2 randomized, phase 3 trials: the FRESCO trial, conducted in China, and the FRESCO-2 trial, which enrolled a broader population.20,27 In the FRESCO trial, 416 patients in China with mCRC previously treated with at least 2 lines of chemotherapy but not VEGFR inhibitor therapy were randomly assigned to fruquitinib 5 mg (n=278) or placebo (n=138) once daily for 21 days followed by 7 days off in 28-day cycles.27 Fruquitinib was associated with a significant improvement over placebo in OS (median, 9.3 vs 6.6 months; HR, 0.65; 95% CI, 0.51-0.83; P<.001). The rates of serious AEs with fruquitinib and placebo were 15.5% and 5.8%, respectively, and rates of hospitalization were 14.4% and 5.1%, respectively.
The FRESCO-2 trial enrolled patients across 14 countries with mCRC who had received all approved cytotoxic and targeted therapies and progressed on, or were intolerant of, trifluridine/tipiracil, regorafenib, or both.20 Patients were randomly assigned to fruquitinib 5 mg (n=461) or placebo (n=230) once daily on days 1 to 21 every 28 days with best supportive care. Median OS was significantly longer with fruquitinib compared with placebo (7.4 vs 4.8 months; HR, 0.66; 95% CI, 0.55-0.80; P<.0001). Grade 3 or higher AEs occurred in 63% and 50% of patients, respectively. The most frequent grade 3 or higher AEs in the fruquitinib arm were hypertension (14%), asthenia (8%), and hand-foot syndrome (6%). There was 1 treatment-related death reported in each arm: intestinal perforation in the fruquitinib arm and cardiac arrest in the placebo arm.
Strategically Approaching mCRC Across Lines of Therapy
The introduction of newer effective therapies provides options for patients with refractory mCRC. However, simply following the sequential first-line, second-line, and third-line continuum is more of a checkers-type approach. Rethinking this convention and instead using the available agents strategically based on the disease profile, symptoms, and other factors is needed.
Reconsidering Treatment Sequencing
In some cases, an intensive second-line-type regimen is urgently needed for tumor shrinkage. This is akin to using the most powerful chess pieces to counter a strong opponent. However, similar to risks with playing powerful chess pieces, there are downsides with using intensive regimens in terms of tolerability, quality of life (QOL), and potentially losing out on later options. Thus a strategic approach is knowing when to use the most intensive regimens and when instead to use a less-intensive regimen with a primary aim of tumor stabilization and saving the more aggressive regimens when regression is needed. This maximizes the tolerability, QOL, and OS benefits of these regimens, and increases the likelihood of a patient being able to receive all available therapies over the course of their treatment.
Let us consider a patient who develops low-level progressive disease while receiving post-induction maintenance therapy. If the patient is asymptomatic with a good QOL, I will often hold off on irinotecan and other more intensive regimens and instead bring in one of the newer third-line regimens such as trifluridine/tipiracil plus bevacizumab in a second maintenance-type approach.
Locoregional therapy is increasingly being used in the setting of mCRC and highlights the importance of multidisciplinary care. For patients with unresectable colorectal liver metastases, locoregional options that may be considered include hepatic artery infusion pump therapy, stereotactic body radiation therapy, image-guided ablation, and transarterial chemoembolization or radioembolization.32
Lack of Evidence for Chemotherapy Rechallenge
Chemotherapy rechallenge is often used in managing mCRC. However, whether oxaliplatin was held in the prior course to avoid neuropathy or whether the patient discontinued oxaliplatin after attaining a response to first-line therapy, oxaliplatin rechallenge is not an evidence-based strategy. Historical data suggest relatively limited response rates and a lack of OS benefit.33-36 As a result, using rechallenge before third-line therapy is not a good chess move compared with using a later-line therapy with a demonstrated OS benefit.
Looking Ahead: Clinical Trials and Emerging Strategies
The treatment landscape could change further with the introduction of additional agents. In the STELLAR-303 trial, the investigational multitargeted TKI zanzalintinib plus atezolizumab provided a significant OS improvement over regorafenib in patients with refractory mCRC that is not dMMR/MSI-H, with a median OS of 10.9 vs 9.4 months (HR, 0.80; P=.0034).37
In May 2026, the Colorectal Cancer Alliance and the Global Coalition for Adaptive Research announced a collaboration to establish an adaptive clinical trial platform called KLEOS that will allow for more rapid and efficient study of new therapies and combinations.38 I am pleased to be serving as the principal investigator of this initiative, which also plans to assess the potential role of early interventions, including the use of perioperative chemotherapy and treatment upon detection of ctDNA-positive minimal residual disease prior to full disease progression.
Back to the Clinic . . .
To summarize, the management of mCRC continues to evolve, with several newer options that have been evaluated in the third-line setting and beyond. Although the treatment algorithm for mCRC conventionally involves the sequential use of the most intensive chemotherapy-based regimens at each step, this may not be the optimal approach for each patient, because the goal is not always immediate tumor shrinkage; maintaining disease control, QOL, and access to effective therapies over time can be equally important.
This approach is seen in the 3 cases discussed initially, in which treatment decisions were individualized. In Case 1, less-intensive therapy was shown to preserve QOL and future treatment options in asymptomatic, indolent disease. In Case 2, de-escalation after response preserved QOL, highlighting the use of less-intensive therapies strategically when immediate tumor shrinkage is not required. In Case 3, molecular profile, treatment response, and toxicities determined the treatment strategy.
Furthermore, collaboration with a multidisciplinary team is essential to ensure patients are considered for curative therapy and for potentially beneficial locoregional therapy. Novel therapies and use of innovative clinical trial platforms to evaluate new therapies and combinations will further improve outcomes for patients with mCRC.
For practicing community oncologists faced with a continually evolving treatment landscape, the challenge in mCRC treatment is to move beyond awareness of individual therapies and toward strategic use the available approaches throughout the course of disease.
Disclosures
Dr Marshall has advisory/consulting relationship with Caris, Astellas, Takeda, and Taiho.
References
1. National Cancer Institute. Surveillance, Epidemiology, and End Results. Cancer Stat Facts: Colorectal cancer. 2026. Accessed September 8, 2026. https://seer.cancer.gov/statfacts/html/colorect.html
2. Abraham A, Jayakrishnan T. Early-onset colorectal cancer: understanding risk factors, biology, and management considerations-toward a framework for improving care. JCO Oncol Pract. Published online April 20, 2026.
3. Hitchcock KE, Romesser PB, Miller ED. Local therapies in advanced colorectal cancer. Hematol Oncol Clin North Am. 2022;36(3):553-567.
4. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.2.2026. Accessed September 8, 2026. To view the most recent and complete version of the guideline, go online to NCCN.org
5. Watanabe J, Muro K, Shitara K, et al. Panitumumab vs bevacizumab added to standard first-line chemotherapy and overall survival among patients with RAS wild-type, left-sided metastatic colorectal cancer: a randomized clinical trial. JAMA. 2023;329(15):1271-1282.
6. Kadoyama K, Miki I, Tamura T, et al. Adverse event profiles of 5-fluorouracil and capecitabine: data mining of the public version of the FDA Adverse Event Reporting System, AERS, and reproducibility of clinical observations. Int J Med Sci. 2012;9(1):33-39.
7. Negarandeh R, Salehifar E, Saghafi F. et al. Evaluation of adverse effects of chemotherapy regimens of 5-fluoropyrimidines derivatives and their association with DPYD polymorphisms in colorectal cancer patients. BMC Cancer. 2020;20(1):560.
8. Hwang JJ. Irinotecan and 5-FU/ leucovorin in metastatic colorectal cancer: balancing efficacy, toxicity, and logistics. Oncology (Williston Park) 2004;18(14 suppl 14):26-34.
9. Cordier PY, Nau A, Ciccolini J. et al. 5-FU-induced neurotoxicity in cancer patients with profound DPD deficiency syndrome: a report of two cases. Cancer Chemother Pharmacol. 2011;68(3):823-826.
10. Lestuzzi C, Stolfo D, De Paoli A, et al. Cardiotoxicity from capecitabine chemotherapy: prospective study of incidence at rest and during physical exercise. Oncologist. 2022;27(2):e158-e167.
11. Cheng F, Zhang R, Sun C, et al. Oxaliplatin-induced peripheral neurotoxicity in colorectal cancer patients: mechanisms, pharmacokinetics and strategies. Front Pharmacol. 2023;14:1231401.
12. Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14(1):29-37.
13. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30(28):3499-3506.
14. Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16(5):499-508.
15. Xu RH, Muro K, Morita S, et al. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2018;19(5):660-671.
16. Kuboki Y, Terazawa T, Masuishi T, et al. Trifluridine/tipiracil+bevacizumab (BEV) vs fluoropyrimidine-irinotecan+BEV as second-line therapy for metastatic colorectal cancer: a randomised noninferiority trial. Br J Cancer. 2023;128(10):1897-1905.
17. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-312.
18. Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909-1919.
19. Prager GW, Taieb J, Fakih M, et al. Trifluridine-tipiracil and bevacizumab in refractory metastatic colorectal cancer. N Engl J Med. 2023;388(18):1657-1667.
20. Dasari A, Lonardi S, Garcia-Carbonero R, et al. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Lancet. 2023;402(10395):41-53.
21. Stivarga (regorafenib) [Prescribing Information]. Bayer HealthCare Pharmaceuticals, Inc. 2025.
22. Lonsurf (trifuridine and tipiracil) [Prescribing Information]. Taiho Pharmaceutical Co., Ltd. 2023.
23. Fruzaqla (fruquintinib) [Prescribing Information]. Takeda Pharmaceuticals America, Inc. 2025.
24. Li J, Qin S, Xu R, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015;16(6):619-629.
25. Van Cutsem E, Mayer RJ, Laurent S, et al. The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo with best supportive care in patients with metastatic colorectal cancer. Eur J Cancer. 2018;90:63-72.
26. Xu J, Kim TW, Shen L, et al. Results of a randomized, double-blind, placebo-controlled, phase III trial of trifluridine/tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: the TERRA Study. J Clin Oncol. 2018;36(4):350-358.
27. Li J, Qin S, Xu RH, et al. Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial. JAMA. 2018;319(24):2486-2496.
28. Fukushima M, Suzuki N, Emura T, et al. Structure and activity of specific inhibitors of thymidine phosphorylase to potentiate the function of antitumor 2’-deoxyribonucleosides. Biochem Pharmacol. 2000;59(10):1227-1236.
29. Pfeiffer P, Yilmaz M, Möller S, et al. TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Lancet Oncol. 2020;21(3):412-420.
30. Takahashi T, Yamazaki K, Oki E, et al. Phase II study of trifluridine/tipiracil plus bevacizumab by RAS mutation status in patients with metastatic colorectal cancer refractory to standard therapies: JFMC51-1702-C7. ESMO Open. 2021;6(2):100093.
31. Ishizaki T, Mazaki J, Enomoto M, et al. Prospective multicenter phase II study of biweekly TAS-102 and bevacizumab for metastatic colorectal cancer. Anticancer Res. 2021;41(4):2157-2163.
32. Song Y, Jeeva M, Liddell RP, et al. Liver-directed therapy for colorectal cancer: where are we now?. Am Soc Clin Oncol Educ Book. 2026;46(1):e515562.
33. Maindrault-Goebel F, Tournigand C, André T, et al. Oxaliplatin reintroduction in patients previously treated with leucovorin, fluorouracil and oxaliplatin for metastatic colorectal cancer. Ann Oncol. 2004;15(8):1210-1214.
34. Suenaga M, Mizunuma N, Matsusaka S, et al. Phase II study of reintroduction of oxaliplatin for advanced colorectal cancer in patients previously treated with oxaliplatin and irinotecan: RE-OPEN study. Drug Des Devel Ther. 2015;9:3099-3108.
35. Matsuda C, Honda M, Tanaka C, et al. Multicenter randomized phase II clinical trial of oxaliplatin reintroduction as a third- or later-line therapy for metastatic colorectal cancer-biweekly versus standard triweekly XELOX (The ORION Study). Int J Clin Oncol. 2016;21(3):566-572.
36. Amatu A, Mauri G, Tosi F, et al. Efficacy of retreatment with oxaliplatin-based regimens in metastatic colorectal cancer patients: the RETROX-CRC retrospective study. Cancers (Basel). 2022;14(5):1197.
37. Hecht JR, Park YS, Tabernero J, et al. Zanzalintinib plus atezolizumab versus regorafenib in refractory colorectal cancer (STELLAR-303): a randomised, open-label, phase 3 trial. Lancet. 2025;406(10517):2360-2370.
38. Colorectal Cancer Alliance. Alliance and GCAR announce collaboration to advance a groundbreaking adaptive clinical trial platform for CRC: KLEOS. https://colorectalcancer.org/article/alliance-and-gcar-announce-collaboration-advance-groundbreaking-adaptive-clinical-trial. Accessed September 10, 2026.