New dosing schedules in pre-treated patients with metastatic colorectal cancer

We commend the authors, Zhang et al., for their valuable contribution, “Efficacy and safety of dose adjustment for fruquintinib in the third-line treatment of metastatic colorectal cancer: a retrospective study with real-world settings”, published in a recent issue of the Journal of Gastrointestinal Oncology (1). Zhang et al. presented clinical experience with an alternative dosing schedule of fruquintinib in patients with metastatic colorectal cancer (mCRC). Colorectal cancer ranks as the third most common cancer worldwide, with over 1.9 million new cases diagnosed annually (2). Nearly half of these patients experience mCRC, either at initial diagnosis or after disease recurrence. Consequently, approximately 900,000 individuals die each year, posing a significant challenge for oncology.

Since the early 2000s, the treatment landscape for mCRC has evolved considerably (3,4). Irinotecan and oxaliplatin were approved soon after the turn of the millennium, and the current standard for first- and second-line therapy involves the sequential use of doublet (often FOLFOX, CapOx, or FOLFIRI) or triplet chemotherapy (FOLFOXIRI) combined with targeted agents. In brief, 5-fluorouracil (5-FU) monotherapy prolonged median survival from around 6 to 12 months, and the sequential use of combination chemotherapy prolonged median survival further to around 24 months.

Unfortunately, 20–40% of patients become ineligible for further treatments after each line of therapy. This rate largely depends on patient selection, as those enrolled in clinical trials are more likely to receive multiple lines of therapy compared to unselected patient populations. European Society for Medical Oncology (ESMO) aims for 50% of “fit” patients starting first-line therapy to be eligible for third-line treatment (3). However, in real-world clinical practice, only 25–30% of first-line patients receive third-line therapy, and just 10–15% proceed to fourth-line treatments (5,6). In this editorial, we will use the phrase “chemorefractory mCRC” for patients who previously received standard chemotherapy, including fluoropyrimidine, oxaliplatin, and irinotecan.

The treatment approach for cancer, including mCRC, is shifting from a “one strategy fits all” model towards a more personalized strategy. However, this shift has not yet been fully realized in an anti-angiogenic therapy because there are, so far, no validated predictive biomarkers (7,8). Angiogenic inhibition remains a key component in the therapeutic arsenal of mCRC, including in the case of chemorefractory disease. Anti-angiogenic drugs primarily fall into two main categories: the monoclonal antibodies (mAbs) and the small molecules, tyrosine kinase inhibitors (TKIs). The mAbs act by directly binding to vascular endothelial growth factor (VEGF)-A or by blocking the extracellular binding domain of its receptor. In contrast, TKIs are internalized into the cell, where they inhibit the extracellular kinase domain of the various receptors involved in angiogenesis.

In patients with chemo-refractory mCRC, survival without active treatment is short. Multiple randomized trials comparing investigational agents to placebo consistently report a median progression-free survival (PFS) of less than 2 months and an overall survival (OS) of 4 to 6 months (9).

Until 2012, no approved treatment options were available for this patient population. This changed with the publication of the CORRECT trial, which demonstrated that monotherapy with regorafenib significantly extended OS from 5.0 to 6.4 months (10). Regorafenib is an oral multikinase inhibitor that blocks numerous protein kinases including VEGFR1. The most common grade 3 or more symptomatic adverse events were hand-foot skin reaction (17%), fatigue (10%), diarrhea (7%), and rash (6%).

Since then, a number of randomized trials, chiefly with similar inclusion and exclusion criteria, have confirmed the benefit of new drugs, mainly as monotherapy but also in combinations, in patients with chemo-refractory mCRC (11-15). As summarized in Table 1, landmark studies such as CORRECT (10), RECOURSE (11), SUNLIGHT (15) (mainly 3rd line trials), and FRESCO-2 (14) (4th line trial) have demonstrated statistically significant improvements in survival among unselected patients. The results from these well-conducted randomized trials have formed the basis for regulatory approval of agents like regorafenib, trifluridine/tipiracil (FTD/TPI), FTD/TPI plus bevacizumab, and fruquintinib. However, it must also be emphasized that several TKIs (e.g., vatalanib, cediranib, sunitinib, sorafenib tested as monotherapy or in combinations as first or second line therapy) did not show any survival benefit in patients with mCRC (8).

A prolonged PFS and OS in these pivotal randomized trials formed the basis for approval of new drugs. However, definitive regression of the tumour burden was seldom achieved and therefore other options, even though the scientific evidence is lower, might be the preferred option for patients with distinct tumour symptoms and a demand for shrinkage (9,19). Several prospective trials, mainly phase 2, have evaluated the efficacy of promising targeted therapies in molecularly selected subgroups of chemorefractory mCRC and found an encouraging OS, but also importantly, a response rate of up to 50%. So far, these novel options are only sparsely approved, but if the drugs are available, patients should be tested for RAS and BRAF status (including KRAS^G12C mutations), human epidermal growth factor receptor 2 (HER2) overexpression or amplification, deficient mismatch repair (MMR), and NTRK gene fusions (9,19).

Fruquintinib

Fruquintinib, a pan-VEGF inhibitor, was developed to improve kinase selectivity, aiming to maintain clinical efficacy while enhancing tolerability. The randomized FRESCO trial, a phase 3 study conducted in China, enrolled 416 patients with chemo-refractory mCRC, who were randomized to receive either fruquintinib or placebo. Treatment with fruquintinib led to a significant prolonged median OS with 2.7 months (from 6.6 to 9.3 months). Based on findings of FRESCO trial (13), in September 2018, fruquintinib was approved in China for mCRC patients who failed fluoropyrimidine, oxaliplatin, and irinotecan, with or without prior use of anti-VEGF or anti-epidermal growth factor receptor (EGFR) therapies.

In comparison, based on FRESCO-2 (14), fruquintinib was approved by the US Food and Drug Administration (US FDA) in November 2023 and by the European Commission in June 2024. After the approval of fruquintinib in China, several Chinese real-world third-line studies have been published, and basically these trials confirmed efficacy and safety with major grade 3 adverse events being hypertension, hand and foot skin reactions, and fatigue (20). Zhang et al. had observed that the standard dosing of fruquintinib (5 mg) was frequently associated with a high incidence of adverse effects, which led to discontinuation of therapy, particularly in elderly individuals (1). In case of severe adverse events during treatment with fruquintinib, the recommended dose modification is a reduction from 5 to 4 mg daily and, if still not tolerated, a second reduction from 4 to 3 mg daily (14). Once a dose is reduced, it should not be re-escalated. Instead of using the standard dosing schedule, Zhang et al. used a new dose reduction strategy by skipping completely the dosing in the second week of therapy, reducing the overall dose-intensity to two-thirds.

In clinical practice, physicians have frequently created and implemented new and innovative dosing or interval schedules to improve tolerability, despite the lack of high-quality evidence or supportive clinical data. The novelty and major strength of the present paper is that a new investigator invented dose adjustments that may inspire other physicians to handle adverse events in a new way that might be more advantageous. Alternative dosing schedules have also been suggested for reforafenib and FTD-TPI (21-24).

The efficacy outcomes reported by Zhang et al. should be interpreted with caution, as retrospective studies often overestimate efficacy due to multiple inherent limitations. The present retrospective analysis shows several of these methodological issues, highlighting why efficacy data from retrospective studies should not be compared with data from large, randomized trials.

Zhang et al. only included patients who started full-dose fruquintinib (5 mg daily for days 21 every 4 weeks) but then continued with a reduced dose, potentially implying that patients with the worst prognosis, e.g., patients with clinical deterioration or patients who decided to discontinue for any reason, were excluded.

Starting dose and dose adjustments in elderly or frail patients is another important topic that the authors mention in their abstract, but actually, they do not present any analysis of outcome according to age. The median age was 59 years, like patients in the Chinese FRESCO trial but younger than the median age in the international FRESCO-2 trial (13,14). In the FRESCO trial, only 18% of patients receiving fruquintinib were aged ≥65 years, and there is an absolute need for more information on tolerability and efficacy in elderly patients. In the global FRESCO-2 trial, 46% and 25% were aged ≥65 years and ≥70 years, respectively. Survival outcomes for younger patients (aged <65 years) were comparable to older patients (≥65 years), with an OS of 7.3 and 7.6 months, respectively. In contrast, adverse events grade 3–4 were significantly higher in elderly patients, especially hypertension and hand-foot syndrome.

A small phase 2 trial including 29 patients aged ≥65 years used a dose escalation strategy starting with fruquintinib 3 mg/day and increasing the dose weekly to 5 mg/day in the third week of therapy (25). Around 50% were escalated to 4 mg (week 2), but only 4 patients (14%) were escalated to the recommended dose of 5 mg/day. As may be expected, the most frequently occurring TRAEs of greater grade 3–4 were hand-foot syndrome (20.7%), hypertension (17.2%), and diarrhea (10.3%). The median OS was 7.6 months, numerically somewhat shorter than the 9.3 months in FRESCO.

FTD-TPI

Multiple dosing schedules of FTD-TPI were evaluated in phase I trials, ending up with the recommended dose of 35 mg/m² twice daily on days 1–5 and days 8–12 of 28-day cycles, as monotherapy or in combination with bevacizumab. The major severe adverse event is grade 3–4 neutropenia, which often requires dose delays/reductions and may require granulocyte colony stimulating factors (GCSF) support. Several investigators have used an alternative (biweekly) dosing schedule where FTD/TPI is given days 1–5 every 2 weeks, maintaining the dose-intensity but apparently with less hematological toxicity, but a maintained PFS and OS (21).

Biweekly FTD/TPI with bevacizumab was also tested in the randomized JCOG2014, which was prematurely terminated, in consideration of the results of the SUNLIGHT trial. However, 152 chemo-refractory mCRC patients were randomized to biweekly FTD/TPI plus bevacizumab or standard FTD-TPI monotherapy (26). The biweekly regimen resulted in fewer grade 3–4 neutropenia (47% vs. 24%) and longer PFS but no significant difference in OS.

Regorafenib

The CORRECT (10) and the CONCUR studies (16) showed prolonged OS, but unfortunately, many patients experienced severe adverse events that required dose delays or modifications, often during the first months of therapy. The adverse event profile of regorafenib has limited its use in some countries. Despite limited evidence, various dosing schedules have been used to relieve toxicities.

In the 3-arm REARRANGE trial (23), patients were randomized to receive the approved dose of regorafenib of 160 mg daily for 21 days of a 28-day cycle, a reduced dose of 120 mg, or a schedule of 160 mg daily for 7 days every 2 weeks. For the two alternative schedules, a planned dose escalation to the standard dose was planned from cycle 2. The REARRANGE trial aimed to reduce the percentage of patients with grade 3–4 treatment-related adverse events; however, the study failed to meet its primary endpoint.

In the randomized ReDOS trial (24), patients were randomized to the approved dose of regorafenib of 160 mg daily or a reduced starting dose of 80 mg daily with weekly dose escalation to 120 mg in week 2 and 160 mg in week 3 if no significant drug-related toxicities were observed. More patients in arm B (reduced starting dose) continued with therapy in cycle 3 (43% vs. 26%), and thus the primary endpoint was met. PFS (2.0 vs. 2.8 months) and OS (6.0 vs. 9.8 months) were numerically but not significantly longer. The safety profile was comparable with prior experience and with no important differences between the two dosing strategies.

Conclusions

Recommended doses of TKIs are often based on small phase 1 trials, aiming to define the maximum tolerated dose for further evaluation in phase 2 and 3 studies. While this approach prioritizes safety thresholds, it may not always reflect the optimal balance between efficacy and tolerability in broader patient populations. An alternative strategy—identifying the minimum effective dose—would be more clinically relevant in many cases but requires larger, more complex trials. Consequently, further studies exploring alternative dosing and scheduling strategies that maintain efficacy while improving tolerability are highly valuable.

Fruquintinib has demonstrated a favorable toxicity profile as monotherapy and is currently being investigated in combination with other agents in ongoing clinical trials. The current study adds new insight into potential dose modifications, including how treatment can be adjusted in clinical practice to reduce toxicity without compromising efficacy. However, data on quality of life (QoL) remains limited and should be prioritized in future research.

It is also important to acknowledge that various dosing regimens of TKIs are already being used across different solid tumors, underlining the need for individualized treatment strategies based on both tumor biology and patient tolerance.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-492/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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