About the Patient
JT is a 71-year-old male diagnosed with metastatic rectosigmoid adenocarcinoma (Table 1). Molecular testing of a biopsy specimen revealed microsatellite stable, RAS wild-type, BRAF V600E wild-type, HER2-negative and no other alterations.
JT initiated first-line therapy with leucovorin, 5-fluorouracil (5-FU), and irinotecan (FOLFIRI) plus panitumumab, to which he quickly achieved a near complete response and received up to 6 months of treatment. His treatment course was complicated within the first 2 months by development of a grade 2 rash on his face. Additionally, he developed diarrhea that rapidly worsened to grade 3, and neutropenia that also became grade 3. These toxicities ultimately necessitated a dose reduction of irinotecan. He maintained treatment with 5-FU and panitumumab, which he continued for the next 4 months until a laboratory workup revealed grade 3 hypomagnesemia.
In the face of these accumulating toxicities, JT requested a drug holiday, which continued for approximately 4 months while he maintained stable disease, until a computed tomography (CT) scan showed tumor progression. At that point, he initiated second-line treatment with leucovorin, 5-FU, and oxaliplatin (FOLFOX) plus bevacizumab, but developed grade 3 neutropenia and thrombocytopenia after the first cycle, prompting a 25% dose reduction of the FOLFOX regimen. Although his disease showed a partial response, he expressed dissatisfaction with his treatment and an inability to maintain his quality of life. Additionally, imaging revealed disease progression after 4 months.
Next-generation sequencing was performed on a liquid biopsy, which confirmed persistent RAS mutations. Based on this, it was discussed with JT that he did not qualify for an anti–epidermal growth factor receptor (anti-EGFR) treatment rechallenge. With his prior cytopenias and preference for oral medications, we instead discussed switching to a noncytotoxic therapy option given his prior cytopenias. We proceeded to switch him to fruquintinib. Baseline testing revealed he was slightly hypertensive, so he was referred to his primary care physician, who initiated him on metoprolol and continued to monitor him at regular intervals. While on fruquintinib, he experienced hand-foot syndrome, which was well controlled and did not progress past grade 1. After 10 months, JT remains on fruquintinib, and his disease continues to remain stable with no progression on CT scans every 8 weeks.
Overview of mCRC
In 2026 alone, 158,850 new cases of colorectal cancer (CRC) are estimated to be diagnosed in the United States.1 Increasingly, CRC is being diagnosed in younger adults, with patients under 65 years comprising nearly one-half (45%) of new diagnoses. Although the 5-year relative survival rate has gradually increased, it was estimated to be 65% in the period of 2015 to 2021. The expected mortality of CRC in 2026 is estimated to be 55,203, making it the second deadliest cancer, although it is the fourth most commonly diagnosed cancer (after breast, prostate, and lung cancers).
One of the reasons for the high mortality rate of CRC is its propensity for metastasis, with 7 out of 10 patients experiencing metastatic disease, occurring either at diagnosis (23%) or in disease recurrence following treatment (up to 50%).2,3 The liver is a frequent target for CRC metastatic spread.4 When present at initial diagnosis, metastatic CRC (mCRC) has a particularly poor prognosis, with a severely diminished 5-year relative survival rate of 16.2%.2
The standard treatment of mCRC in the first and second lines is based on the chemotherapy regimens FOLFOX and FOLFIRI, which combine 5-FU and leucovorin with either the platinum agent oxaliplatin or the topoisomerase I inhibitor irinotecan, respectively. The GOIM (Gruppo Oncologico dell’Italia Meridionale) and GERCOR (Groupe Coopérateur Multidisciplinaire en Oncologie) studies established that these 2 regimens achieve similar efficacy outcomes, including in time to progression, progression-free survival (PFS), and overall survival (OS).5 Alternatively, 5-FU and leucovorin can be replaced with capecitabine and added to oxaliplatin (CAPEOX) to achieve a regimen with similar efficacy and lower toxicity compared with FOLFOX.6 A third regimen, FOLFOXIRI, which combines 5-FU, leucovorin, oxaliplatin, and irinotecan, is associated with further prolongation of PFS and OS but at the cost of higher rates of toxicity.
The first- and second-line standard treatments of mCRC were significantly improved with the addition of vascular endothelial growth factor (VEGF) pathway inhibitors (bevacizumab, aflibercept, or ramucirumab) and EGFR pathway inhibitors (cetuximab or panitumumab). In pivotal trials in first-line mCRC, significant improvements in OS and PFS were demonstrated with the addition of these agents to standard chemotherapy.5,7 The efficacy of the anti-EGFR agents were further shown to be limited primarily to mCRC tumors harboring wild-type KRAS.
As patients with mCRC progress through multiple lines of therapy, there is a decline in the PFS interval between each subsequent line. In one retrospective study of 120 patients, the PFS interval was 8.5 months (range, 4-23) after first-line treatment; this decreased to 5 months (range, 4-7.5) and 3 months (range, 2-5.5) after second-line and third-line treatments, respectively.8 This is clinically relevant, as PFS is considered a surrogate endpoint for OS in patients with mCRC. Thus, there is a need for treatments aimed to prolong the duration of PFS.
A number of alternative treatment options are available for the treatment of mCRC tumors harboring actionable mutations.9 Immune checkpoint inhibitor therapy is also important in mCRC tumors that are characterized as microsatellite instability-high, mismatch repair deficient, or harboring POLE/POLD1 polymerase mutations.10 However, most patients with mCRC are not candidates for either targetable agents or immune checkpoint inhibitor therapy.
Issue of Chemotherapy-Associated Toxicity in mCRC Without Targetable Mutations
Chemotherapy remains an important component of treatment for mCRC, either alone or in combination with biologic agents such as anti-VEGF or anti-EGFR therapies. However, treatment benefit must be balanced against chemotherapy-associated toxicity (Table 2), which can affect quality of life, dose intensity, treatment duration, and overall patient management.
Common chemotherapy backbones in mCRC include fluoropyrimidines, oxaliplatin, and irinotecan. Fluoropyrimidines, such as 5-FU and capecitabine, are associated with gastrointestinal and mucocutaneous toxicities, including diarrhea, mucositis, nausea, anorexia, and hand-foot syndrome, particularly with capecitabine.11-13 Myelosuppression may also occur, although it is often less prominent than with some other cytotoxic agents. Rare but clinically important toxicities include cardiotoxicity and severe toxicity related to dihydropyrimidine dehydrogenase deficiency, which can lead to excessive fluoropyrimidine exposure.14,15
Oxaliplatin is strongly associated with peripheral neuropathy, which can become persistent and dose-limiting.16 Because neuropathy can interfere with daily function, oxaliplatin is often discontinued after a defined induction period, with continuation of maintenance therapy using a fluoropyrimidine with or without the biologic agent.
Irinotecan is commonly associated with diarrhea and myelosuppression.17 Diarrhea may occur early, as part of an acute cholinergic syndrome, or later, when it can be more prolonged and clinically significant. Neutropenia can increase infection risk and may require dose modification, treatment delay, or supportive care.
Therapeutic Goals and Patient-Centered Considerations With Third-Line Treatment
The goals of treatment in patients who have reached third-line or later therapy for mCRC primarily focus on prolonging survival while maintaining or improving quality of life.18 Patients at this stage have received several cycles of cytotoxic chemotherapies and other systemic agents of the first and second lines of treatment. As a result they often enter third-line treatment burdened with cumulative toxicities such as bone marrow suppression, anorexia, and fatigue. These patients may benefit from a break in cytotoxic treatments, opting instead for nonchemotherapy alternatives such as tyrosine kinase inhibitors (TKIs) that offer the potential for disease stabilization while extending survival. However, it is important to consider that these agents are not free from side effects; instead they are associated with a different and often manageable toxicity profile.
It is imperative that the selection of third-line treatment in patients with mCRC is made based on shared decision-making, considering the patient’s goals and preferences. Other patient considerations include their potential difficulties with adherence to the dosing schedule, the toxicity profile of the agent and its overlap with the patient’s existing comorbidities, and the potential impact on quality of life. Prolonging survival is an essential goal but should be carefully weighed against a drug’s tolerability and its impact on the patient’s daily activities. In some cases, disease stabilization together with a manageable toxicity profile can result in a meaningful survival advantage.
Post–Standard Therapy Third-Line Options for Patients With mCRC Without Targetable Mutations
Three agents (regorafenib, trifluridine/tipiracil with or without bevacizumab, and fruquintinib) are approved by the US Food and Drug Administration for patients who progress following standard combination chemotherapy regimens in the first- and second-line settings (Figure 1).19-21 All three have in common an indication for the treatment of patients with mCRC who have previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type, an anti-EGFR therapy. In the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines), all 4 regimens have a Category 2A recommendation for patients who are ineligible for or who have progressed on checkpoint inhibitor immunotherapy and have progressed through all available regimens, although the combination of trifluridine/tipiracil with bevacizumab is preferred over trifluridine/tipiracil alone.10
Mechanism of Action
Regorafenib and fruquintinib are targeted therapies, whereas trifluridine/tipiracil is generally classified as an oral cytotoxic chemotherapy agent.
Regorafenib and fruquintinib are both TKIs that target the tyrosine kinase receptor for VEGF, of which three exist: VEGFR-1, VEGFR-2, and VEGFR-3.19,21,22 When triggered by VEGF, activation of these receptors leads to intracellular signaling pathways that result in angiogenesis (VEGFR-1 and VEGFR-2) and lymphangiogenesis (VEGFR-3).22 Because fruquintinib is a TKI active against all 3 VEGFRs, it is able to inhibit both the angiogenesis pathways to restrict tumor growth and progression, as well as lymphangiogenesis pathways. Fruquintinib inhibits VEGFRs with limited off-target kinase activity, allowing for drug exposure achieving sustained target inhibition.22,23 In contrast, regorafenib is considered a multitargeted TKI, whereby in addition to all 3 VEGFRs, it inhibits the activity of several other kinases including RET, KIT, PDGFR-α, PDGFR-β, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAF V600E, SAPK2, PTK5, Abl, and CSF1R at concentrations that have been achieved clinically.19,22
Trifluridine/tipiracil is not a TKI; instead it is a small molecule comprised of trifluridine (a thymidine-based nucleoside analogue) and tipiracil (a thymidine phosphorylase inhibitor).20 Trifluridine becomes incorporated into DNA, interfering with its synthesis and inhibiting cell proliferation; tipiracil increases trifluridine exposure via inhibiting its metabolism by thymidine phosphorylase.
Pivotal Trials of Regorafenib and Trifluridine/Tipiracil in mCRC
Fruquintinib, regorafenib, and trifluridine/tipiracil were all approved based on their efficacy and safety demonstrated in similarly designed, phase 3, placebo-controlled pivotal trials (Table 3).24-31 The combination of trifluridine/tipiracil with bevacizumab was also evaluated in a phase 3 pivotal trial in which it was compared with trifluridine/tipiracil alone.31 Each study enrolled relatively large populations of patients with treatment-refractory mCRC.
Regorafenib was evaluated in the 2 phase 3 pivotal trials CORRECT (760 patients) and CONCUR (204 patients), and in a practice-changing randomized phase 2 study ReDOS (116 patients) comparing standard regorafenib dosing with a dose-escalation strategy.24-26 The international CORRECT trial enrolled patients from across North America, Europe, Asia, and Australia; thus the standard therapies patients had received as either first-line or second-line therapy were required to include as many of the following as were licensed locally: a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab, and either cetuximab or panitumumab (in patients with KRAS wild-type mCRC). Compared with placebo, regorafenib demonstrated significant improvements in both median OS (6.4 vs 5.0 months; hazard ratio [HR], 0.77; 95% CI, 0.64-0.94; P=.0052) and median PFS (1.9 vs 1.7 months; HR, 0.49; 95% CI, 0.42-0.58; P<.0001).
The CONCUR study was designed to extend the findings from CORRECT into a population of Asian patients enrolled from China, Hong Kong, South Korea, Taiwan, and Vietnam. Because of this geographic limitation, the CONCUR study allowed patients to enroll who had not received a biologic agent (40% of the study population), which were not widely available across Asian countries at the time of the trial. In this population, regorafenib also showed significant improvements in median OS (8.8 vs 6.3 months; HR, 0.55; 95% CI, 0.40-0.77; P=.00016) and median PFS (3.2 vs 1.7 months; HR, 0.31; 95% CI, 0.220.44; P<.0001). Grade 3 or higher adverse events (AEs) reported by patients in the regorafenib arm of CORRECT included hand-foot skin reaction (HFSR; 17%), fatigue (10%), diarrhea (8%), hypertension (7%), and rash/desquamation (6%), and in CONCUR included HFSR (16%), hypertension (11%), elevated alanine aminotransferase (ALT; 7%), and elevated aspartate aminotransferase (AST; 6%).
ReDOS was a randomized phase 2 study comparing standard regorafenib dosing (160 mg once daily) with a dose-escalation strategy (80 mg, increasing to 120 mg during week 2 and 160 mg during week 3 based on the patient’s tolerance and adverse events), both given 3 weeks on/1 week off. The dose-escalation arm significantly improved the likelihood of proceeding to cycle 3 (43% vs 26%; P=.043). Median OS favored dose escalation (9.8 vs 6.0 months; HR, 0.72; 95% CI, 0.47-1.10; P=.12), while median PFS was similar (2.8 vs 2.0 months; HR, 0.84; 95% CI, 0.57-1.24; P=.38). Grade 3/4 toxicities were generally lower with dose escalation, including fatigue (13% vs 18%), HFSR (15% vs 16%), and hypertension (7% vs 15%), except abdominal pain (17% vs 6%). These results were considered practice-changing and drive how regorafenib is currently administered in the clinic.
Like regorafenib, trifluridine/tipiracil was also evaluated in 2 pivotal phase 3 trials—the RECOURSE study (800 patients enrolled from the United States, Europe, Australia, and Japan) and TERRA (406 patients from across several Asian countries).27,28 The median OS achieved in the RECOURSE trial was prolonged with trifluridine/tipiracil compared with placebo (7.1 vs 5.3 months; HR, 0.68; 95% CI, 0.58-0.81; P<.001), as was the median PFS (2.0 vs 1.7 months; HR, 0.48; 95% CI, 0.41-0.57; P<.001). In the TERRA trial, trifluridine/tipiracil also significantly prolonged median OS (7.8 vs 7.1 months; HR, 0.79; 95% CI, 0.62-0.99; P=.035) and median PFS (2.0 vs 1.8 months; HR, 0.43; 95% CI, 0.34-0.54; P<.001). Grade 3 or higher AEs reported by patients in the trifluridine/tipiracil arm of the RECOURSE trial included neutropenia (38%), leukopenia (21%), anemia (18%), and thrombocytopenia (5%), and of the TERRA trial included neutropenia (33.2%), leukopenia (20.7%), anemia (17.7%), and lymphopenia (14.4%).
A third trial, SUNLIGHT, compared the addition of the anti-VEGF antibody bevacizumab with trifluridine/tipiracil versus trifluridine/tipiracil alone in 492 patients.31 This study demonstrated an improvement in both median OS (10.8 vs 7.5 months; HR, 0.61; 95% CI, 0.49-0.77; P<.001) and median PFS (5.6 vs 2.4 months; HR, 0.44; 95% CI, 0.36-0.54; P<.001) with the addition of bevacizumab. With the combination, grade 3 or higher AEs reported in patients included neutropenia (43.1%), anemia (6.1%), and hypertension (5.7%).
Fruquintinib in mCRC Without Targetable Mutations
Pivotal Trials of Fruquintinib in mCRC
The pivotal phase 3 FRESCO trial (416 patients) first evaluated fruquintinib in a population of patients from China who had mCRC treated with at least 2 prior lines of chemotherapy.29 Compared with placebo, fruquintinib significantly prolonged median OS (9.30 vs 6.57 months; HR, 0.65; 95% CI, 0.51-0.83; P<.001) as well as median PFS (3.71 vs 1.84 months; HR, 0.26; 95% CI, 0.21-0.34; P<.001). The results of the FRESCO trial led to the approval of fruquintinib for the treatment of mCRC in China. Notably, at the time of patient enrollment into the FRESCO study, neither VEGF pathway inhibitors nor EGFR pathway inhibitors were considered standard of care treatment for mCRC in China. Thus, just 30% of patients had previously received a VEGF inhibitor, and only 14% had been treated with an EGFR inhibitor. Additionally, neither regorafenib nor trifluridine/tipiracil was available for treatment at that time; none of the patients enrolled in the study had any prior treatment with regorafenib or trifluridine/tipiracil. In FRESCO, dose interruptions owing to AEs occurred in 35.3% of patients in the fruquintinib arm (vs 10.2% in the placebo arm). Dose reductions owing to AEs were also more common with fruquintinib compared with placebo (24.1% vs 4.4%), as were discontinuations owing to AEs (15.1% vs 5.8%), most frequently because of proteinuria.
To better understand the efficacy and safety of fruquintinib in a group of patients reflective of current real-world populations, the pivotal FRESCO-2 trial was designed.30 FRESCO-2 (691 patients) was an international, randomized, double-blind, placebo-controlled, phase 3 study that enrolled patients from across North America, Europe, Asia, and Australia. In particular, this study population was comprised of heavily pretreated patients (median of 4 prior lines of treatment for metastatic disease, and 73% had received more than 3 prior lines of therapy) with mCRC who were eligible only if they had received all standard treatments, including fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy, anti-VEGF therapy, and anti-EGFR therapy (if RAS wild-type). Indeed, most patients (96%) had received prior anti-VEGF therapy, and 39% had received prior anti-EGFR therapy. Additionally, patients were required to have either experienced disease progression on or been intolerant to trifluridine/tipiracil or regorafenib. At baseline, patients had received trifluridine/tipiracil (52%), regorafenib (8%), or both (39%). Median OS was significantly prolonged with fruquintinib compared with placebo (median OS, 7.4 vs 4.8 months; HR, 0.66; 95% CI, 0.55-0.80; P<.0001), as was median PFS (3.7 vs 1.8 months; HR, 0.32; 95% CI, 0.27-0.39; P<.0001). In FRESCO-2, 47% of fruquintinib-treated patients experienced dose interruption owing to AEs (compared with 27% in the placebo arm). Dose reductions owing to AEs were also reported with a higher frequency in the fruquintinib arm compared with the placebo arm (24% vs 4%), primarily because of hand-foot syndrome (5%), hypertension (4%), and asthenia (4%). However, discontinuations owing to AEs occurred at a similar rate between the 2 treatment arms (20% in the fruquintinib arm and 21% in the placebo arm), most frequently because of asthenia (2%). Table 4 summarizes the most common AEs reported in the FRESCO-2 trial.
Fruquintinib Dosing and Administration in mCRC
Fruquintinib is administered for the first 21 days of each 28-day cycle at a recommended dose of 5 mg orally once daily, given at approximately the same time each day.21 The recommended starting dose may be modified in the event of adverse reactions (Table 5). Dose modifications are recommended for specific AEs, including grade 3 hypertension, grade 2 hemorrhagic events, and grade 2 palmar-plantar erythrodysesthesia, as well as elevations of proteinuria (≥2 g
in 24 hours) or signs of hepatotoxicity (ALT or AST >3 times the upper limit of normal). The first recommended dose reduction is to 4 mg once daily, and the second recommended dose reduction is to 3 mg once daily. In the event that even the 3-mg dose cannot be tolerated, fruquintinib should be permanently discontinued.
Grade 3 adverse reactions are generally managed by temporarily withholding fruquintinib, then resuming it at a reduced dose after resolution of the AE to grade 1 or lower.21 Discontinuation of fruquintinib is recommended in patients with grade 4 adverse reactions, although resumption at a lower dose may be considered on an individual basis in the event of non–life-threatening toxicity.
Managing Potential Side Effects With Fruquintinib
The pivotal clinical trials of fruquintinib reported the toxicity profile of fruquintinib in patients with mCRC. Some of these AEs and their management are described in more detail in the fruquintinib prescribing information (Table 6).
Hypertension is a side effect common with fruquintinib; in clinical trials it was the most frequently reported AE with fruquintinib.21,29,30 When initiating treatment with fruquintinib, a baseline blood pressure should be determined, followed by weekly monitoring during the first month, then monthly thereafter and as clinically indicated. Antihypertensive therapy is initiated or adjusted as needed for patients who experience elevated blood pressure. Grade 3 hypertension is managed with dose interruption and resumption at a reduced dose; grade 4 hypertension requires discontinuation of fruquintinib.
Hand-foot syndrome can also be a side effect of fruquintinib, and is typically managed by decreasing dose intensity, as either a dose delay or dose reduction.21 To avoid patients having to decrease dose intensity, preventive measures may include loose-fitting clothes and shoes to reduce skin friction, avoiding heat, use of daily emollients and creams, and rapid treatment to skin erosions to prevent infection.
Diarrhea can also occur with fruquintinib.21 It is important to engage in patient education and communication to keep track of its severity, and initiate treatment before it becomes severe. Over-the-counter treatments, such as loperamide, can be used to manage diarrhea, and rehydration with liquids that contain electrolytes and water is also essential.
Proteinuria was reported in 36% of fruquintinib-treated patients in the pooled safety population, including 2.5% grade 3 or higher events.21 In patients who experience proteinuria of at least 2 g per 24 hours, fruquintinib should be withheld until the proteinuria is either fully resolved or dips below 1 g per 24 hours. Upon resolution, fruquintinib is then resumed at the next lower dose level. However, if the proteinuria does not recover to less than 1 g per 24 hours, or if the patient develops nephrotic syndrome, fruquintinib should be permanently discontinued.
Infections, including fatal infections, have been reported with fruquintinib.21 In the pooled safety population of fruquintinib-treated patients, the most common infections reported were urinary tract infections (6.8%), upper respiratory tract infections (3.2%), and pneumonia (2.5%); fatal infections included pneumonia (0.4%), sepsis (0.2%), bacterial infection (0.1%), lower respiratory tract infection (0.1%), and septic shock (0.1%). Fruquintinib is withheld for grade 3 or 4 infections, or worsening infection of any grade, but it can be resumed at the same dose upon resolution of the infection.
Monitoring Response to Treatment
In most cases, imaging is the primary modality for monitoring treatment response in patients receiving third-line therapy for mCRC.32 Imaging studies are typically performed with CT scans of the chest/abdomen/pelvis with contrast, although magnetic resonance imaging may be an alternative.33 Frequent imaging, such as every 2 months, can help catch those patients who will experience rapid disease progression.
Careful monitoring of patient symptoms may also be useful when determining a patient’s response to treatment.34 This is especially the case for patients with a heavy tumor burden, in whom symptom palliation is an important treatment goal. In contrast, symptom palliation as an assessment of treatment response is less useful in patients with more indolent disease.
Likewise, serial tumor biomarkers such as carcinoembryonic antigen may be useful to detect tumor control.10 Emerging biomarkers are under investigation; chief among these is circulating tumor, which may portend disease progression before radiological recurrence is observed.35,36
Bringing It All Together
For patients with mCRC, standard chemotherapy regimens can improve survival and disease control but can be associated with significant hematologic and nonhematologic toxicities. Nonchemotherapy options provide additional later-line treatment opportunities, particularly after progression on fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens. For patients who wish to avoid IV therapy or frequent clinic visits, oral agents are often favored. Common oral agents used in this setting include fruquintinib, regorafenib, and trifluridine/tipiracil alone.
Trifluridine/tipiracil is a combination antimetabolite with a dual mechanism of action that causes DNA dysfunction and is often administered with bevacizumab, a monoclonal antibody that targets the VEGF-A ligand. Fruquintinib and regorafenib are oral kinase inhibitors with antiangiogenic activity that interfere with signaling pathways involved in tumor vascularization and growth. Regorafenib is a “promiscuous” oral multikinase inhibitor that targets angiogenic, stromal, and oncogenic pathways, simultaneously blocking multiple distinct receptor tyrosine kinases. Fruquintinib is a highly selective inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3, targeting angiogenic and lymphangiogenic signaling pathways that support tumor progression. In our patient, we chose fruquintinib given prior cytopenias and patient preference based on the FRESCO studies. The phase 3 FRESCO and FRESCO-2 studies demonstrated the efficacy and safety of fruquintinib in heavily pretreated patients with mCRC, many of whom had liver metastases, microsatellite-stable disease, and multiple prior lines of therapy. Fruquintinib significantly improved both OS and PFS compared with placebo.29,30
Disclosures
Dr Bekaii-Saab has the following disclosures to report:
Research funding (to institution): Agios, Arrys Therapeutics, Arcus, Atreca, Boston Biomedical, Bayer, Eisai, Celgene, Eli Lilly, Ipsen, Clovis Oncology, Seagen, Genentech, Novartis, Mirati Therapeutics, Merus, AbGenomics, Incyte, Pfizer, Bristol Myers Squibb (BMS), and Revolution Medicines. Consulting (to institution): Servier, Ipsen, Arcus, Pfizer, Seagen, Bayer, Genentech, Incyte, Eisai, Merus, Merck KGaA, Revolution Medicines, and Merck & Co. Consulting (personal): Stemline Therapeutics, AbbVie, Blueprint Medicines, Boehringer Ingelheim, Janssen, Daiichi Sankyo, Natera, Takeda, Treos Bio, Celularity, Caladrius Biosciences, Exact Sciences, Sobi, BeiGene, Kanaph Therapeutics, AstraZeneca, Deciphera, Zai Lab, Exelixis, MJH Life Sciences, Aptitude Health, Illumina, Foundation Medicine, Sanofi, GlaxoSmithKline (GSK), ArsenalBio, Xilio Therapeutics, RYGHT AI, and Whitehawk Therapeutics. Independent Data Monitoring Committee (IDMC)/Data and Safety Monitoring Board (DSMB): The Valley Hospital, FibroGen, Suzhou Kintor, AstraZeneca, Exelixis, Merck/Eisai, PanCAN, and 1Globe. Scientific Advisory Boards: Imugene, Immuneering, Xilis, Replimune, and Artiva Biotherapeutics.Royalties: UpToDate. Patents/Inventions: WO/2018/183488: Human PD1 Peptide Vaccines and Uses Thereof (licensed to Imugene). WO/2019/055687: Methods and Compositions for the Treatment of Cancer Cachexia (licensed to Recursion).
References
1. American Cancer Society. Fast facts: colorectal cancer statistics, 2026. Accessed June 25, 2026. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/colorectal-cancer-facts-and-figures/crc-2026/crc-2026-fast-facts.pdf
2. National Cancer Institute. Surveillance, Epidemiology, and End Results. Cancer Stat Facts: Colorectal cancer. 2026. Accessed June 25, 2026. https://seer.cancer.gov/statfacts/html/colorect.html
3. Atreya CE, Yaeger R, Chu E. Systemic Therapy for Metastatic Colorectal Cancer: From Current Standards to Future Molecular Targeted Approaches. Am Soc Clin Oncol Educ Book. 2017;37:246-256.
4. Riihimäki M, Hemminki A, Sundquist J, Hemminki K. Patterns of metastasis in colon and rectal cancer. Sci Rep. 2016;6:29765.
5. Gustavsson B, Carlsson G, Machover D, Petrelli N, Roth A, Schmoll HJ, Tveit KM, Gibson F. A review of the evolution of systemic chemotherapy in the management of colorectal cancer. Clin Colorectal Cancer. 2015;14(1):1-10.
6. Kuang D, Xu H, Shen X. Oxaliplatin combined with capecitabine therapy and comprehensive nursing in advanced colorectal cancer patients. Front Med (Lausanne). 2025;12:1582683.
7. Pathak PS, Chan G, Deming DA, Chee CE. State-of-the-art management of colorectal cancer: treatment advances and innovation. Am Soc Clin Oncol Educ Book. 2024;44(3):e438466.
8. Cicero G, De Luca R, Dieli F. Progression-free survival as a surrogate endpoint of overall survival in patients with metastatic colorectal cancer. Onco Targets Ther. 2018;11:3059-3063.
9. Ciracì P, Studiale V, Taravella A, Antoniotti C, Cremolini C. Late-line options for patients with metastatic colorectal cancer: a review and evidence-based algorithm. Nat Rev Clin Oncol. 2025 Jan;22(1):28-45.
10. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.2.2026. © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed June 25, 2026. To view the most recent and complete version of the guideline, go online to NCCN.org
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. Reyhanoglu G, Smith T. Irinotecan. StatPearls [Internet]. 2023. Accessed June 25, 2026. https://www.ncbi.nlm.nih.gov/books/NBK554441/
18. Cann C, Zhao S, Khan N, O’Donnell M, Taylor M, Salimi T. Third-line treatment decision-making for metastatic colorectal cancer: a cross-sectional survey of US community physicians. Oncologist. 2026;31(3):oyag018.
19. Stivarga (regoranib). Prescribing Information. Bayer HealthCare Pharmaceuticals, Inc. 2026.
20. Lonsurf (trifuridine and tipiracil). Prescribing Information. Taiho Pharmaceutical Co., Ltd. 2023.
21. FRUZAQLA. Prescribing Information. Takeda Pharmaceuticals America, Inc; 2025.
22. Stucchi E, Bartolini M, Airoldi M, et al. Fruquintinib as new treatment option in metastatic colorectal cancer patients: is there an optimal sequence? Expert Opin Pharmacother. 2024;25(4):371-382.
23. Sun Q, Zhou J, Zhang Z, et al. Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy. Cancer Biol Ther. 2014;15(12):1635-45.
24. 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):303-12.
25. 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):619-29.
26. Bekaii-Saab TS, Ou FS, Ahn DH, et al. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. Lancet Oncol. 2019;20(8):1070-1082.
27. 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):1909-19.
28. 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.
29. 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.
30. 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.
31. 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.
32. Van Cutsem E, Verheul HM, Flamen P, et al. Imaging in colorectal cancer: progress and challenges for the clinicians. Cancers (Basel). 2016;8(9):81.
33. Cervantes A, Adam R, Roselló S, et al. Electronic address: clinicalguidelines@esmo.org. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(1):10-32.
34. Chiorean EG, Nandakumar G, Fadelu T, et al. Treatment of patients with late-stage colorectal cancer: ASCO Resource-Stratified Guideline. JCO Glob Oncol. 2020;6:414-438.
35. Reece M, Saluja H, Hollington P, et al. The use of circulating tumor DNA to monitor and predict response to treatment in colorectal cancer. Front Genet. 2019;10:1118.
36. Bartolomucci A, Nobrega M, Ferrier T, et al. Circulating tumor DNA to monitor treatment response in solid tumors and advance precision oncology. NPJ Precis Oncol. 2025;9(1):84.