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Ma L, Liu X, Zhang Y, Luo Y. Clinical advances in later-line therapy for metastatic or refractory colorectal cancer. World J Gastroenterol 2027; 33(2): 123996 [DOI: 10.3748/wjg.123996]
Li Ma, Xia Liu, Division of Abdominal Tumor, Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
Ying Zhang, Division of Internal Medicine, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
Yong Luo, Cancer Center, West China Hospital, Sichuan University, Chengdu 610065, Sichuan Province, China
Author contributions: Ma L and Liu X contributed equally as co-first authors. Ma L was involved in the collection and organization of the literature and the writing of the article; Liu X contributed to the collection and organization of the literature and the drafting of the tables; Zhang Y undertook the review of the figures and text; Luo Y was responsible for the review and revision of the article and tables. All authors approved the final version to publish.
AI contribution statement: We have thoroughly revised the language expression to improve its readability and academic fluency. It should be clearly stated that no AI-generated writing content was used throughout the entire writing and revision process.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Yong Luo, Cancer Center, West China Hospital, Sichuan University, No. 37 Guo Xue Alley, Chengdu 610065, Sichuan Province, China. luoyong@wchscu.edu.cn
Received: June 5, 2026 Revised: August 10, 2026 Accepted: September 24, 2026 Published online: January 14, 2027 Processing time: 161 Days and 17.1 Hours
Abstract
Metastatic colorectal cancer still ranks among the leading causes of cancer-related death globally owing to its poor treatment response. For patients with progression after first-line therapy, especially those with microsatellite-stable/proficient mismatch repair tumors or tumors harboring BRAF V600E or KRAS G12C mutations, high-quality evidence for optimal therapies remains scarce. This review summarizes clinical studies from the past 5 years on second-line and subsequent therapies for metastatic colorectal cancer, covering optimized combinations of chemotherapy, targeted therapy, immunotherapy, and radiotherapy, along with evaluations of novel agents. A review of these clinical advances reveals that chemotherapy regimens based on raltitrexed or trifluridine/tipiracil hydrochloride mixture (TAS-102) have demonstrated favorable efficacy in patients with fluoropyrimidine resistance. Antiangiogenic agents, epidermal growth factor receptor/human epidermal growth factor receptor 2/mesenchymal-epithelial transition factor blockade, BRAF inhibitors, and KRAS G12C inhibitors prolong survival. Immunotherapy yields durable responses in microsatellite instability-high/deficient mismatch repair metastatic colorectal cancer, especially with dual immune checkpoint inhibition. Combinations of drugs with different mechanisms of action may treat refractory microsatellite-stable/proficient mismatch repair disease. Novel antibody-drug conjugates and other antitumor agents offer new options for previously treated patients. Limited high-quality evidence hinders optimal regimen selection. Future work should focus on improving individualized therapy and multidisciplinary management.
Core Tip: This narrative review synthesizes the latest literature from PubMed and other databases published in the past 5 years. It mainly analyzes trial design, enrolled populations, and primary endpoints. By reviewing outcomes of combination regimens and phase I/II trials of novel agents, we evaluate the clinical applicability of various later-line therapies for colorectal cancer. Our team emphasizes combination strategies using existing drugs, highlighting that improved efficacy does not solely rely on new drug development.
Citation: Ma L, Liu X, Zhang Y, Luo Y. Clinical advances in later-line therapy for metastatic or refractory colorectal cancer. World J Gastroenterol 2027; 33(2): 123996
Globally, colorectal cancer (CRC) ranks third in incidence based on recent epidemiological data[1]. Beyond the known contributions of smoking, alcohol consumption, and obesity[2], genetic susceptibility has frequently been associated with the disease. Notably, the mortality rate of CRC is significantly higher than that of many other malignant tumors. According to statistical data published in The Lancet in 2025, CRC mortality ranks second among global cancer-related deaths[1].
For patients with advanced metastatic CRC (mCRC), the first-line treatment regimen is well defined according to the National Comprehensive Cancer Network guidelines, primarily consisting of fluoropyrimidine-based chemotherapy with or without targeted agents against vascular endothelial growth factor (VEGF) or epidermal growth factor receptor (EGFR)[3]. However, CRC is highly prone to drug resistance, and the prognosis after disease progression is generally poor. Particularly for patients with microsatellite stable (MSS)/mismatch repair proficient (pMMR) status[4], BRAF V600E mutation[5], or KRAS G12C mutation[6], although regorafenib, trifluridine/tipiracil hydrochloride mixture (TAS-102), and novel targeted agents have extended survival to some extent, how to further prolong survival while maintaining patients’ quality of life remains a key challenge (Figure 1).
To this end, we searched PubMed, Web of Science, and the Cochrane Library for literature published within the past 5 years focusing on disease progression after first-line therapy for mCRC. Unlike conventional reviews, our research team included not only phase III clinical trials and real-world studies but also phase I and II clinical trials. We acknowledge that phase I and II trials yield lower levels of clinical evidence. Nevertheless, for this narrative review, incorporating their data into our analytical assessment is valuable for optimizing clinical diagnosis and treatment strategies for CRC. Based on a systematic summary of clinical trials on second- and later-line treatments for mCRC, we conducted a rational analysis and in-depth assessment. This narrative review aims to provide potential strategies and insights for the formulation of later-line treatment regimens for mCRC. In the subsequent therapeutic sections, we describe and analyze the advantages and disadvantages of various drug combination regimens in chronological order.
CHEMOTHERAPY REGIMEN INNOVATIONS AND THERAPEUTIC PROGRESS OF TAS-102
Combination of chemotherapeutic agents
For patients with mCRC who have progressed on first-line 5-fluorouracil (5-FU)-containing regimens, rechallenge with 5-FU is often of limited value, representing a recurring clinical hurdle. In irinotecan-based second-line strategies, Chinese investigators have turned to agents other than 5-FU. Raltitrexed, a thymidylate synthase inhibitor, has drawn interest for its mechanism of action, which differs from that of 5-FU, and for its convenient biweekly administration.
A phase II study[7] from West China Hospital, Sichuan University of Sichuan University enrolled 35 patients with mCRC who had progressed after first-line therapy with 5-FU or its derivatives. They received irinotecan plus raltitrexed on a biweekly schedule. The objective response rate (ORR) was 8.6%, and the disease control rate (DCR) was 71.4%. Median progression-free survival (mPFS) was 4.5 months [95% confidence interval (95%CI): 3.8–5.2], and median overall survival (mOS) was 12.0 months (95%CI: 8.5–15.5); 4 patients achieved no evidence of disease. This doublet regimen appeared feasible in this setting.
In another prospective phase II trial[8], raltitrexed was combined with S-1 (tegafur/gimeracil/oteracil) as third-line treatment. The reported ORR was 7.62%, DCR was 48.57%, mPFS was 2.5 months, and mOS was 8.0 months. Subgroup analysis suggested that the 5-FU dose used during second-line therapy was a prognostic factor for outcomes with this combination.
The 2 phase II clinical trials described above provide new efficacy data for second- and third-line treatment of advanced CRC. However, because both studies were single-arm phase II trials, they lack head-to-head comparisons and validation in multicenter populations, resulting in a low level of evidence. Furthermore, the ORRs for both regimens were low, which may be related to the low tumor regression rates. Therefore, the true clinical benefits of these 2 regimens remain to be evaluated.
Application of TAS-102 in the later-line setting
Phase III trials[9] have established the efficacy of TAS-102 monotherapy in refractory mCRC. To improve its modest efficacy, investigators are actively exploring combination strategies. The combination of TAS-102 plus bevacizumab is currently a focus of research. One protocol[10] prospectively evaluated this combination in the third-line setting. A real-world study[11] in chemotherapy-refractory patients confirmed its clinical value, with an mPFS of 4.3 months (95%CI: 3.4–5.1) and mOS of 9.3 months (95%CI: 6.6–12.1). Subsequent data showed that a biweekly schedule achieved comparable efficacy to the conventional regimen, yielding an mPFS of 4.6 months (95%CI: 3.6–5.3) and mOS of 10.5 months (95%CI: 9.6–11.4)[12]. Building on this, the E-BiTS study[13] found that a dose-escalation strategy was safe and effective, with outcomes (mPFS 5.6 months, 95%CI: 2.7–6.5; mOS 17.6 months, 95%CI: 10.1–not reached) appearing superior to those with fixed dosing, suggesting that individualized dose titration may further optimize clinical benefit.
A randomized controlled trial by Kuboki et al[14] compared TAS-102 plus bevacizumab with an irinotecan-containing regimen [folinic acid + fluorouracil + irinotecan (FOLFIRI) or irinotecan plus fluorouracil] plus bevacizumab but failed to demonstrate non-inferiority [mOS 14.8 months vs 18.1 months; hazard ratio (HR) = 1.38, non-inferiority P = 0.592]. The FOLFIRI regimen consists of folinic acid, fluorouracil, and irinotecan. Nonetheless, the TAS-102 arm still achieved an mOS exceeding 14 months, indicating potential benefit in patients intolerant to standard chemotherapy.
Building on the doublet, investigators have further attempted to add irinotecan or oxaliplatin to enhance efficacy. Li et al[15] combined TAS-102 with both irinotecan and bevacizumab in patients who had progressed after first- or second-line therapy. Although OS was not yet mature, the mPFS of 9.2 months (95%CI: 6.285–12.115) and the manageable toxicity profile suggest that this triplet regimen is feasible as a later-line treatment. Subsequently, a study by Yang et al[16] further validated these findings and applied the triplet regimen in the second-line setting. Patients who progressed after first-line oxaliplatin-based therapy were enrolled, and the results showed an mPFS of 6.6 months (95%CI: 4.39–8.81) and an mOS of 17.3 months (95%CI: 13.55–21.05), with a suggestion that patients who underwent primary tumor resection might have a better prognosis.
Attempts to combine TAS-102 with oxaliplatin alone have been less successful. Cecchini et al[17] evaluated TAS-102 plus oxaliplatin in patients with mCRC who had progressed after oxaliplatin-containing therapy and did not achieve a clinically meaningful ORR. However, the addition of bevacizumab changed the scenario. Based on preclinical evidence suggesting that the combination of TAS-102, oxaliplatin, and bevacizumab could improve efficacy, and aiming to explore the activity of immunotherapy in MSS-type mCRC, Bordonaro et al[18] designed a study in which TAS-102 plus oxaliplatin was combined either with bevacizumab or with nivolumab (the latter restricted to patients with MSS tumors) in patients who had progressed after ≥ 1 line of therapy. The results showed that the immunotherapy-combination arm was terminated early because of an ORR below 10%. Notably, the mPFS was comparable between the targeted therapy and immunotherapy arms: 6.3 months (95%CI: 5.5–15.6) and 6.0 months (95%CI: 2.0–8.0), respectively. In the bevacizumab-containing arm, the ORR reached 17.1% (95%CI: 8.1%–32.7%), demonstrating encouraging antitumor activity with manageable toxicity. These findings suggest that in patients with MSS tumors, a targeted strategy with bevacizumab may be superior to an immunotherapy combination, but the limited mPFS in the immunotherapy group also hints at potential benefit in a subset of patients, warranting further biomarker-driven studies.
In patients with RAS wild-type mCRC, the rechallenge strategy with the anti-EGFR antibody panitumumab is a focus of later-line research. A Japanese multicenter phase I/II study[19] evaluated TAS-102 plus panitumumab in heavily pretreated patients with RAS wild-type mCRC, most of whom had failed ≥ 2 lines of therapy. The results indicated that despite increased incidences of stomatitis and neutropenia, this regimen could serve as an alternative treatment for patients intolerant or refractory to fluoropyrimidines, oxaliplatin, and even antiangiogenic agents (such as anti-VEGF drugs). Napolitano et al[20] further confirmed the superiority of this combination in third-line treatment through a randomized controlled design: Compared with TAS-102 monotherapy, the addition of panitumumab significantly prolonged mPFS (4.0 months vs 2.5 months; HR 0.48, 95%CI: 0.28–0.82, P = 0.007), also validating the feasibility of rechallenge with the anti-EGFR monoclonal antibody panitumumab.
Beyond the above combinations, investigators have also explored the combination of TAS-102 with the multikinase inhibitor regorafenib. A phase I dose-escalation study[21] enrolled 12 patients who had received at least 2 prior lines of therapy. With acceptable toxicity, the doublet regimen achieved an mOS of 11.1 months (95%CI: 2.3–18.2), which is higher than historical data for regorafenib or TAS-102 monotherapy, suggesting that this combination warrants further validation in larger cohorts.
On the other hand, based on the rationale that the mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor trametinib can suppress the MEK/extracellular signal-regulated kinase pathway and thereby delay resistance, Chuang et al[22] combined trametinib with TAS-102 in patients who had progressed after standard fluoropyrimidine-based therapy. Unfortunately, in patients with RAS-mutant, PIK3CA and PTEN wild-type mCRC, this combination did not show significant clinical benefit (mPFS 2 months, 95%CI: 1.70–4.82; mOS 7 months, 95%CI: 6.36–11.48), and the incidence of grade ≥ 2 mucositis and diarrhea was increased compared with TAS-102 monotherapy. This negative finding suggests that the strategy of MEK inhibition plus TAS-102 may require more precise biomarkers to identify potential responders; otherwise, it is unlikely to achieve a breakthrough in efficacy (Table 1).
Table 1 Later-line treatment studies of trifluridine/tipiracil hydrochloride mixture.
In summary, multidrug combination therapy with TAS-102 has demonstrated improved efficacy compared with TAS-102 monotherapy. The results suggest that rechallenge with certain drugs may still enhance the efficacy of later-line treatment. However, studies on multidrug combination therapy with TAS-102 still have significant limitations. Most trials remain in the phase I/II clinical trial stage, and complete OS data are not yet available. Screening patients based solely on pathological findings makes it difficult to achieve ideal personalized treatment. Furthermore, the inclusion of patients with favorable Eastern Cooperative Oncology Group scores may have skewed the overall efficacy data toward more favorable results.
NEW ADVANCES IN LATER-LINE TARGETED THERAPY
With a deeper understanding of the molecular mechanisms underlying mCRC, an increasing number of targeted agents and combination strategies have been introduced into later-line treatment, in addition to conventional chemotherapy and antiangiogenic agents (Table 2). Regorafenib, a multikinase inhibitor, has established a role in later-line therapy. The STREAM study[23], a phase II single-arm clinical trial, enrolled patients with RAS-mutant mCRC who had progressed on oxaliplatin-based chemotherapy and received regorafenib as second-line treatment. The results showed an mPFS of 3.6 months (95%CI: 1.9–6.7) and an mOS of 18.9 months (95%CI: 10.3–35.3). Although the primary endpoint was not met, the treatment was well tolerated, suggesting clinical benefit, particularly for patients with oligometastatic or lung-only disease.
Table 2 Targeted therapy involving gene mutations or gene amplifications.
Trial name/Ref.
Type
Sample size
Regimen
Dosage and administration (combination therapy group)
Japan’s RECC study[24] enrolled patients with mCRC who had failed second-line chemotherapy in a dose-escalation study of regorafenib. The study reported an mOS of 8.9 months (95%CI: 7.42–10.38) and an mPFS of 1.9 months (95%CI: 1.69–2.18). Among these patients, those who completed the dose-escalation phase demonstrated superior PFS (2.8 months vs 1.6 months, P = 0.048), even though there was no significant difference in OS (9.4 months vs 7.8 months, P = 0.96). Interestingly, the European REARRANGE study[25] showed that when regorafenib was used as second-line therapy, the 2 dose-reduction groups did not demonstrate a significant difference in efficacy compared with the standard-dose regorafenib group.
Resistance to the EGFR antibody panitumumab is common in RAS wild-type mCRC, and MET amplification is a key driver of resistance. Cabozantinib can delay or reverse panitumumab resistance by inhibiting MET amplification. Based on this rationale, Strickler et al[26] combined panitumumab with cabozantinib in patients with RAS wild-type mCRC. The results demonstrated an mPFS of 3.7 months (90%CI: 2.3–7.1) and an mOS of 12.1 months (90%CI: 7.5–14.3), indicating antitumor activity of the combination. However, the safety profile of cabozantinib after dose adjustment requires further validation.
The study by Jia et al[27] similarly evaluated the combination of cabozantinib and panitumumab in RAS wild-type mCRC, confirming the activity of cabozantinib (with or without panitumumab) and identifying hepatocyte growth factor as a negative prognostic marker. Based on the prior success of combining the MEK inhibitor trametinib with the BRAF inhibitor dabrafenib in BRAF V600E-mutant melanoma, a phase II study[28] evaluated trametinib combined with the EGFR-targeted agent panitumumab. Fourteen patients with RAS/RAF wild-type, previously treated, EGFR inhibitor-naïve mCRC were enrolled. Unfortunately, despite some tumor shrinkage, the combination was not considered promising because of severe skin toxicity, a modest mPFS similar to that of panitumumab monotherapy[29] (4.4 months vs 4.1 months; 95%CI: 2.9–7.1 and 3.2–4.8, respectively), and the early emergence of resistance.
An Australian phase II study[30] suggested that the dual antiangiogenic regimen of bevacizumab plus trebananib (a peptibody targeting the angiopoietin/Tie2 pathway) had manageable toxicity compared with bevacizumab plus chemotherapy. Notably, the study proposed that combination antiangiogenic therapy might promote antitumor immune responses in patients with CRC after immune tolerance, providing a rationale for subsequent combination with immunotherapy.
Gatipotuzumab, a humanized antibody targeting tumor-associated mucin 1, combined with an EGFR-targeted agent may offer clinical benefit in refractory mCRC. Ochsenreither et al[31] enrolled patients with solid tumors, including refractory mCRC, to evaluate the efficacy and safety of gatipotuzumab plus the EGFR antibody tomuzotuximab. All patients with mCRC had progressed after standard chemotherapy, anti-EGFR therapy, and anti-VEGF therapy; in an expansion cohort, some patients received panitumumab as the EGFR-targeted agent. The combination was safe and feasible. Notably, patients receiving panitumumab had better PFS and duration of response than those receiving tomuzotuximab: PFS of 5.5 months (95%CI: 0.5–8.6) vs 1.9 months (95%CI: 1.4–3.7), and duration of response of 7.2 months (95%CI: 6.7–7.6) vs 3.8 months (95%CI: 1.9–5.8). This difference suggests that the properties of different EGFR antibodies may influence the efficacy of combination therapy.
Human epidermal growth factor receptor 2 (HER2) positivity in CRC is more common in patients with RAS/BRAF wild-type tumors. Several studies have explored dual HER2-targeted strategies. A Chinese multicenter phase II study[32] combined pyrotinib (which targets both EGFR and HER2) with trastuzumab in patients with HER2-positive mCRC who had progressed on standard therapy or were intolerant to chemotherapy. Although OS data were not provided, the reported mPFS was 3.4 months (95%CI: 1.8–4.3); among RAS wild-type patients, mPFS was 4.3 months (95%CI: 3.2–8.5), indicating favorable antitumor activity. A study by Yang et al[33] used the same regimen in patients with HER2-positive mCRC who progressed after ≥ 1 line of therapy, reporting not only a promising mPFS of 6.2 months (95%CI: 0.42–11.98) but also an mOS of 21.1 months (95%CI: 15.84–26.36), providing strong support for this regimen.
Another multiregional, multicenter phase II study, MOUNTAINEER[34], combined the HER2-targeted agent tucatinib with trastuzumab in chemotherapy-refractory patients with HER2-positive, RAS wild-type mCRC. The results showed an mPFS of 8.2 months (95%CI: 4.2–10.3) and an mOS of 24.1 months (95%CI: 20.3–36.7). This regimen became the first U.S. Food and Drug Administration–approved treatment for HER2-positive mCRC. At a subsequent follow-up of 32.4 months, the updated data[35] showed sustained efficacy: MPFS 8.1 months (95%CI: 4.2–10.2) and mOS 23.9 months (95%CI: 18.7–28.3).
Pertuzumab is another HER2 monoclonal antibody. Raghav et al[36] compared dual HER2-targeted therapy (pertuzumab plus trastuzumab) with an EGFR-targeted regimen (cetuximab plus irinotecan) in patients with RAS/BRAF wild-type mCRC who progressed after ≥ 1 line of therapy. Unfortunately, although the dual HER2 regimen showed some antitumor activity (as reflected by ORR and PFS), there was no significant difference in PFS between the 2 arms, and the efficacy was strongly influenced by the level of HER2 amplification, suggesting that HER2-targeted therapy requires more precise molecular stratification.
KRAS G12C mutation is an important driver in mCRC, and EGFR has been implicated in resistance mechanisms to KRAS G12C inhibitors. Several studies have explored the combination of KRAS G12C inhibitors with EGFR antibodies. Fakih et al[37] compared sotorasib plus panitumumab vs standard-of-care later-line agents (TAS-102 or regorafenib) in chemotherapy-refractory patients with KRAS G12C-mutant mCRC who had not previously received KRAS G12C-targeted therapy. Although OS data were not yet mature, available data demonstrated an mPFS of 5.6 months (95%CI: 4.2–6.3) for the 960-mg sotorasib group, 3.9 months (95%CI: 3.6–5.7) for the 240-mg sotorasib group, and 2.0 months (95%CI: 1.9–3.9) for the control group, with a favorable safety profile. Subsequently, Pietrantonio et al[38] further evaluated OS for sotorasib plus panitumumab. The HR for the 960-mg group was 0.70 (95%CI: 0.41–1.18, 2-sided P = 0.20). Although mOS was not reached in the 960-mg group, comparison with data from the 240-mg and control arms suggests a favorable OS trend for 960 mg sotorasib. These findings were further validated in a third-line study[39] of patients with KRAS G12C-mutant mCRC using 960 mg sotorasib daily, which achieved an mPFS of 5.7 months (95%CI: 4.2–7.7) and an mOS of 15.2 months (95%CI: 12.5–not estimated), demonstrating robust efficacy and safety.
Another KRAS G12C inhibitor, adagrasib, has been approved by the U.S. Food and Drug Administration for non-small cell lung cancer. The KRYSTAL-1 study[40] evaluated adagrasib plus cetuximab in the later-line treatment of KRAS G12C-mutant mCRC, yielding an mPFS of 6.9 months (95%CI: 5.7–7.4), an mOS of 15.9 months (95%CI: 11.8–18.8), a grade ≥ 3 treatment-related adverse event rate of only 27.7%, and no treatment discontinuations due to adagrasib toxicity.
Glecirasib is a novel KRAS G12C inhibitor. Li et al[41] analyzed data from 2 studies involving patients with KRAS G12C-mutant mCRC who had progressed on prior therapy and received either glecirasib monotherapy or glecirasib in combination with cetuximab. The ORR for glecirasib monotherapy (800 mg daily) was 23% (95%CI: 11–38); only 2 of 44 patients experienced serious treatment-related adverse events, and the grade ≥ 3 event rate was 20%. When combined with cetuximab, the ORR increased to 50%, with acceptable safety. Collectively, these data establish the important role of KRAS G12C inhibitors plus EGFR antibodies in chemotherapy-refractory mCRC.
To investigate whether EGFR antibody rechallenge could confer clinical benefit, Ciardiello et al[42] analyzed 114 patients who had progressed after ≥ 2 lines of therapy, of whom 27.2% had received ≥ 3 lines of antitumor treatment. Rechallenge regimens included cetuximab or panitumumab combined with irinotecan, avelumab, or TAS-102. The results showed an mPFS of 4.0 months (95%CI: 3.2–4.7), an mOS of 13.1 months (95%CI: 9.5–16.7), and a favorable safety profile. Of particular note, patients without liver metastases had better outcomes: MPFS 5.7 months vs 3.6 months (HR 0.56, 95%CI: 0.37–0.83, P = 0.004) and mOS 17.7 months vs 11.5 months (HR 0.63, 95%CI: 0.41–0.97, P = 0.04).
For chemotherapy-refractory patients with RAS/BRAF wild-type mCRC, EGFR antibody rechallenge may still offer meaningful efficacy. The PARERE study[43] enrolled patients with RAS/BRAF wild-type mCRC [by circulating tumor DNA (ctDNA)] who had previously received EGFR antibody therapy and were chemotherapy-refractory, comparing the efficacy of different sequences of panitumumab and regorafenib. The results showed no significant difference in OS between the panitumumab-first and regorafenib-first groups (11.6 months vs 11.7 months, HR 1.13, 85%CI: 0.90–1.41, P = 0.441), but panitumumab-first was associated with numerically better PFS (4.2 months vs 2.4 months, HR 1.26, 95%CI: 0.95–1.66, P = 0.103), significantly higher ORR (16% vs 2%, P = 0.003), and higher DCR (61% vs 36%, P < 0.001). This suggests that for ctDNA-selected wild-type patients, prioritizing EGFR antibody rechallenge may offer better short-term disease control.
Fruquintinib is a tyrosine kinase inhibitor (TKI) targeting VEGF receptors and has been approved for mCRC treatment in China. The phase III multicenter FRESCO-2 study[44] evaluated fruquintinib in refractory mCRC (including patients who had progressed on standard therapy and were intolerant to TAS-102 or regorafenib). Compared with placebo, fruquintinib significantly improved mOS (7.4 months vs 4.8 months, HR 0.66, 95%CI: 0.55–0.80, P < 0.0001), supporting its role as an oral treatment option for refractory mCRC. Because fruquintinib is widely considered for second- and later-line therapy, its multiple adverse effects (including rash with an unclear mechanism) warrant attention, as highlighted in a case report[45].
Anlotinib is another multitarget TKI that includes VEGF receptor among its targets. Chi et al[46] evaluated survival outcomes of anlotinib monotherapy in patients with mCRC who had received ≥ 2 prior lines of therapy. Although mOS was not significantly improved compared with placebo (8.6 months vs 7.2 months, HR 1.02, P = 0.870), the significantly improved mPFS (4.1 months vs 1.5 months, HR 0.34, 95%CI: 0.27–0.43, P < 0.0001) positions anlotinib as a potential third-line option.
It is worth noting that even though some phase III clinical trials have demonstrated the efficacy of drugs such as fruquintinib, a large number of studies remain at the phase II clinical trial stage and lack comprehensive OS data. Drug rechallenge and the modest benefit in PFS have not significantly improved patients’ OS. Furthermore, regarding drug safety, there is still a lack of individualized dose-reduction strategies based on phase III studies.
APPLICATION OF IMMUNE CHECKPOINT INHIBITORS IN THE LATER-LINE SETTING
The advent of immune checkpoint inhibitors (ICIs) has achieved remarkable success in patients with microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) mCRC. However, for the vast majority of patients with pMMR/MSS tumors, the efficacy of immunotherapy as a single agent remains limited. In recent years, research has increasingly focused on dual immunotherapy combinations, immune rechallenge, and novel immune targets.
CheckMate 8HW[47] is the first phase III study to directly compare dual immune checkpoint inhibition (nivolumab plus ipilimumab) with monotherapy (nivolumab) in patients with MSI-H/dMMR mCRC, regardless of prior lines of therapy. The results showed that in both first- and later-line settings, the doublet regimen was superior to nivolumab alone in terms of PFS: MPFS was not reached (95%CI: 53.8–not estimable) in the dual-immunotherapy group vs 39.3 months (95%CI: 22.1–not estimable) in the monotherapy group, with an HR of 0.62 (95%CI: 0.48–0.81), P = 0.0003. This study established the priority of dual immunotherapy in the MSI-H/dMMR population.
A Korean multicenter single-arm study[48] evaluated the anti-programmed death-ligand 1 (anti-PD-L1) monoclonal antibody durvalumab in patients with MSI-H/dMMR or POLE-mutant tumors. The study enrolled 33 patients who had progressed after at least 1 line of chemotherapy (regardless of prior anti-VEGF or anti-EGFR exposure), of whom 14 had failed second-line therapy. Of these patients, 30 had MSI-H/dMMR tumors and 3 had POLE mutations. The results demonstrated that among the 3 patients with POLE-mutant tumors, those with exonuclease domain mutations achieved objective responses; the overall ORR was 42.4%.
Notably, subgroup analysis of this study revealed that the number of prior failed treatment lines was not a major factor influencing survival outcomes. This finding differs from the results of the KEYNOTE-164 study[49] of pembrolizumab monotherapy in MSI-H/dMMR CRC, in which subgroup analysis suggested differences in efficacy according to treatment line. The investigators hypothesized that the absence of a clear line-dependent efficacy difference with durvalumab might be related to the inclusion of patients with poorly differentiated tumors in the present study. This hypothesis provides a new direction for future research: Tumor biological characteristics (such as differentiation grade) may be more predictive of immunotherapy response than treatment history.
For patients with MSI-H/dMMR mCRC who progress after programmed cell death protein 1 (PD-1)/PD-L1 inhibitor therapy, it remains unclear whether subsequent treatment with a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor is effective. Kasi et al[50] summarized 3 cases of disease progression after pembrolizumab monotherapy and found that ipilimumab plus nivolumab was effective in patients who had progressed after PD-1 inhibitor treatment. Although only 3 patients were included, this study provides a potential treatment option for patients progressing after PD-1 inhibitor therapy and further emphasizes the importance of ctDNA in evaluating efficacy and prognosis.
Furthermore, restarting immunotherapy after prior immune treatment may improve patient outcomes. A previous case report[51] described the readministration of the CTLA-4 inhibitor ipilimumab combined with the PD-1 inhibitor nivolumab in a patient with heavily pretreated mCRC, resulting in prolonged disease control. Unfortunately, the authors could not determine whether the extended disease control was due to the CTLA-4 inhibitor or the synergistic effect of the 2 agents. Nevertheless, the report provides evidence that for patients who previously responded to immunotherapy, rechallenge with immune agents may extend survival.
Nivolumab, a PD-1 checkpoint inhibitor, has demonstrated promising efficacy in the treatment of patients with various MSI-H/dMMR solid tumors. Relatlimab, an emerging ICI, targets lymphocyte activation gene 3 protein (an immune checkpoint distinct from PD-1). The CheckMate 142 study[52] evaluated the combination of these 2 ICIs in patients with MSI-H/dMMR mCRC who had failed at least first-line therapy. This dual immunotherapy regimen achieved an mPFS of 27.5 months (95%CI: 5.3–43.7); mOS data are not yet mature (95%CI: 17.2 months–not estimable); and 14% of patients experienced grade ≥ 3 treatment-related adverse events. In summary, this regimen offers sustained clinical benefit and a favorable safety profile.
To address the challenge of immunotherapy resistance in patients with pMMR/MSS tumors, numerous studies are currently underway. A phase I clinical trial conducted by Bullock et al[53] enrolled patients with MSS mCRC who had progressed after standard treatment. The study evaluated the efficacy and safety of a combination of 2 ICIs, the CTLA-4 antibody botensilimab and the anti-PD-1 monoclonal antibody balstilimab, in this patient population. Encouragingly, although some data are still immature, this dual immunotherapy regimen achieved an mPFS of 3.5 months (95%CI: 2.7–4.1) and demonstrated good safety, with no new immune-related adverse events observed.
The combination of nivolumab and ipilimumab has been proven in phase III clinical trials to significantly improve the prognosis of patients with MSI-H/dMMR mCRC. However, patients with MSS/pMMR tumors constitute the majority of patients with CRC. Unfortunately, most clinical trials involving patients with MSS/pMMR tumors have been small-sample, single-arm studies, providing limited evidence. Although some case reports have raised interest in treating the disease, the small sample sizes and low levels of evidence make it difficult to draw persuasive conclusions.
NOVEL MULTI-AGENT COMBINATIONS: CHEMOTHERAPY, TARGETED THERAPY, AND IMMUNOTHERAPY
Chemotherapy combined with targeted therapy
Building on the results of the previous BOND-1 and BOND-2 studies, which demonstrated the efficacy of antibody therapy combined with chemotherapy in second-line treatment, the BOND-3 study[54] further investigated the efficacy and safety of the EGFR-targeted drug cetuximab and the VEGF-targeted drug bevacizumab in combination with irinotecan for the treatment of irinotecan-refractory mCRC. Notably, the enrolled patients had not previously received EGFR-targeted therapy and had RAS wild-type tumors. Compared with the treatment group without bevacizumab, the dual-antibody plus chemotherapy group demonstrated superior OS [19.7 months vs 10.2 months, HR 0.41 (95%CI: 0.15–1.09, P = 0.07)]. Unfortunately, no statistically significant difference in PFS was observed before the study was terminated early due to funding issues.
For patients with fluorouracil resistance or progression, is second-line reuse of the fluorouracil-containing FOLFIRI regimen plus bevacizumab equivalent to irinotecan monotherapy plus bevacizumab? A study by Matsubara et al[55] enrolled 255 patients who progressed after first-line fluorouracil plus oxaliplatin chemotherapy to compare the efficacy of these 2 regimens. Interestingly, data analysis showed no significant differences between the 2 groups in PFS, OS, or relative dose intensity, and the incidence of adverse events such as nausea/vomiting and bone marrow suppression (including neutropenia) was significantly lower with irinotecan plus bevacizumab. This finding suggests that rechallenge with fluorouracil in the second-line setting after prior fluorouracil exposure is not futile and may confer better tolerability.
In clinical practice, most clinicians prefer an oxaliplatin-based regimen as first-line therapy and an irinotecan-based regimen as second-line therapy. Thus, for patients who receive FOLFIRI as first-line treatment, how effective is an oxaliplatin-based regimen in the second-line setting? Giantonio et al[56] administered folinic acid + 5-FU + oxaliplatin (FOLFOX4) plus bevacizumab to patients who progressed after FOLFIRI therapy. The results showed that the combination group, FOLFOX4 monotherapy group, and bevacizumab monotherapy group achieved mOS of 12.9, 10.8, and 10.2 months and mPFS of 7.3, 4.7, and 2.7 months, respectively. Thus, combination therapy plays a critical role in improving patient survival, regardless of the specific chemotherapy regimen chosen.
A study by George et al[57] evaluated the multi-target TKI sorafenib combined with the oral chemotherapy agent capecitabine in a population with a median of 3 prior lines of therapy. The results showed that with manageable toxicity, the combination achieved an mPFS of 6.2 months and an mOS of 8.8 months, compared with 1.8 months and 4.6 months, respectively, for best supportive care, as reported in the article. Although the study was single-arm and provided a low level of evidence, the oral formulation of both agents provides a treatment opportunity for patients unable to receive intravenous infusions.
Combining antiangiogenic agents with chemotherapy is a common therapeutic strategy. A multicenter phase I single-arm study[58] evaluated the combination of the oral antiangiogenic agent valecobulin with irinotecan in patients with mCRC who had failed prior antitumor therapy. The investigators considered the combination highly encouraging: MPFS (4.1 months), mOS (11.6 months), and DCR (79.4%) were all better than historical data for valecobulin monotherapy in refractory solid tumors (mPFS 1.3 months, DCR 32%). Moreover, over 80% of patients in this study had received ≥ 3 prior lines of therapy, suggesting that this regimen could become an important later-line option for mCRC.
Dihydropyrimidine dehydrogenase is the rate-limiting enzyme in 5-FU catabolism, and thymidylate synthase is the target of 5-FU antitumor activity. Studies have shown that upregulation of these 2 enzymes is associated with 5-FU resistance. Based on this, Chen et al[59] at West China Hospital, Sichuan University combined the dihydropyrimidine dehydrogenase inhibitor S-1 and the thymidylate synthase inhibitor raltitrexed with bevacizumab in patients who had failed standard therapy. The results showed that this regimen had a superior ORR (15.9% vs < 5.0%) and mOS (12.2 months vs 5.3–9.3 months) compared with later-line agents such as TAS-102, with manageable toxicity. A 2021 study[60] demonstrated that for second-line treatment of mCRC, regardless of UGT1A1 genotype, modified capecitabine plus irinotecan (mXELIRI) plus bevacizumab was non-inferior to FOLFIRI plus bevacizumab in terms of OS. This result provides clinicians with more flexible dosing options.
Aflibercept, another VEGF-targeting agent, has been approved in the European Union for use in combination with FOLFIRI in patients with oxaliplatin-resistant or progressive mCRC. A Korean multicenter prospective study[61] enrolled 185 patients who progressed after oxaliplatin-containing chemotherapy and treated them with aflibercept plus FOLFIRI. The results showed an mOS of 9.4 months and an mPFS of 7.3 months. Univariate and multivariate analyses identified right-sided colon tumors and prior bevacizumab exposure as predictors of worse prognosis. Patients with prior bevacizumab exposure had shorter PFS than did patients without (6.4 months vs 9.4 months, P = 0.036; HR = 1.96, 95%CI: 1.0–3.7). Therefore, for patients without these 2 unfavorable factors, the aflibercept plus FOLFIRI regimen is worth considering (Table 3).
To explore the efficacy of aflibercept plus FOLFIRI in patients who progressed after first-line oxaliplatin-based chemotherapy plus anti-EGFR therapy, the Japanese phase II study HGCSG1801[62] enrolled 43 patients. The results showed an mPFS of 7.3 months (95%CI: 5.5–11.0), an mOS of 18.8 months (95%CI: 12.9–26.6), and a DCR of 88.4% (95%CI: 74.9%–96.1%). These results indicate that aflibercept plus FOLFIRI is also feasible in patients progressing after anti-EGFR therapy.
A pooled analysis[63] focusing on patients aged ≥ 70 years with mCRC treated with aflibercept plus FOLFIRI reported an mPFS of 6.6 months (95%CI: 5.3-7.9) and an mOS of 15.1 months (95%CI: 12.5-17.8). Interestingly, Martínez-Lago et al[63] found that a history of hypertension might be a favorable prognostic factor, associated with better PFS (7.9 months vs 5.7 months, P = 0.049); moreover, patients who developed grade 3 hypertension during treatment had even better PFS (7.6 months vs 6.6 months, P = 0.024). Another study[64] evaluating this regimen as second-line treatment in patients ≥ 70 years old suggested that after 6 cycles of aflibercept plus FOLFIRI, maintenance therapy with 5FU/LV plus aflibercept alone was non-inferior to continuing FOLFIRI plus aflibercept.
The POLAF study[65], building on the efficacy of aflibercept in patients with oxaliplatin-resistant or progressive disease, further explored biomarkers of efficacy. While confirming the activity of aflibercept plus FOLFIRI, the study found that VEGF-A levels might guide prognosis in mCRC: When VEGF-A levels were < 1941 pg/mL, patients had better mPFS (9 months vs 4 months), mOS (19 months vs 8 months), ORR (26% vs 9%), and DCR (81% vs 55%).
Bevacizumab, a focus of first- and second-line therapy in mCRC, is widely used in combination with fluoropyrimidine-based chemotherapy. A retrospective study by Claramunt García et al[66] enrolled 84 patients who progressed after oxaliplatin-containing therapy to explore the efficacy differences between bevacizumab or aflibercept combined with FOLFIRI as second-line treatment. Results showed that bevacizumab plus FOLFIRI was superior, with better mOS (16.2 months vs 9.3 months; 95%CI: 13.3-19.1 and 5.3-13.4, respectively) and better tolerability.
Another retrospective study[67] based on the treatment landscape of Japanese patients with RAS wild-type mCRC, using database analysis, found that FOLFOX plus anti-EGFR was the most common first-line regimen, and second-line therapy was most often based on irinotecan chemotherapy. Comparison of different antiangiogenic agents (bevacizumab, ramucirumab, and aflibercept) in combination regimens did not yield clear superiority. Additionally, the study found that firstline treatment duration ≥ 6 months, primary tumor resection before first-line therapy, and liver metastasis resection during firstline therapy were all associated with improved second-line prognosis.
S-1 is an oral fluoropyrimidine agent. Based on the established role of irinotecan in second-line treatment of patients progressing after fluorouracil and oxaliplatin, a Japanese phase II study[68] evaluated S-1 plus bevacizumab combined with irinotecan in KRAS wild-type patients who progressed on first-line oxaliplatin- and cetuximab-containing therapy. Results showed a mPFS of 10.1 months (95%CI: 4.11-17.28), an mOS of 21.8 months (95%CI: 9.79-37.91), and 90% of the 17 patients experienced no grade ≥ 3 treatment-related adverse events. This regimen is promising but requires further validation in larger studies.
The mitogen-activated protein kinase (MAPK) pathway, a major driver of resistance in BRAF V600E-mutant mCRC, comprises KRAS, NRAS, MEK, and BRAF. The BEACON study[69] compared a triplet regimen (BRAF inhibitor encorafenib, EGFR inhibitor cetuximab, and MEK1/2 inhibitor binimetinib) with standard chemotherapy (cetuximab plus FOLFIRI or irinotecan monotherapy). Results showed that the triplet group had superior mOS (9.0 months vs 5.4 months; 95%CI: 8.0-11.4 and 4.8-6.6, respectively) and significantly longer mPFS (4.3 months vs 1.5 months; 95%CI: 4.1-5.2 and 1.5-1.7), with no significant difference in safety (grade ≥ 3 adverse event rates 58% vs 61%). These findings were further confirmed in a subsequent Italian multicenter real-world study[70]. Additionally, the “NEW BEACON” study[71], which is ongoing, is investigating a modified cetuximab dosing schedule (every 2 weeks instead of weekly) in combination with encorafenib in chemotherapy-refractory BRAF V600E-mutant mCRC patients.
Trastuzumab is an anti-HER2 monoclonal antibody. Although the proportion of HER2 positivity in CRC is low, given that HER2 positivity is associated with anti-EGFR resistance, treatment of this population remains important. A Chinese phase II clinical trial[72] enrolled HER2-positive, KRAS/BRAF wild-type patients who progressed after ≥ 1 line of therapy to evaluate the efficacy of trastuzumab plus irinotecan. Results showed a mPFS of 4.3 months (95%CI: 2.7-5.9), mOS not yet mature (17.9 months, 95%CI: 11.8-24.1), and most treatment-related adverse events were grade 1-2. Thus, trastuzumab plus chemotherapy is a potentially feasible treatment option.
Suvemcitug is a novel antiangiogenic agent targeting VEGF. In a Chinese phase Ia/Ib study[73], in second-line treatment of mCRC that progressed after ≥ 1 line of oxaliplatin-containing therapy, the agent showed promising antitumor activity and safety, with a mPFS of 7.2 months (95%CI: 5.1-8.7). Although all patients in the Ia phase experienced treatment-related adverse events, the toxicity was manageable overall.
A multicenter study by Yasui et al[74] focused on second-line treatment options for patients with RAS wild-type left-sided mCRC who progressed after first-line anti-EGFR therapy and chemotherapy. Ramucirumab, a monoclonal antibody targeting VEGF, was combined with FOLFIRI as second-line treatment; 95.6% of patients had tumors located in the left colon or rectum. Results showed a mPFS of 7.0 months (95%CI: 5.7-7.6) and an mOS of 23.6 months (95%CI: 16.5-26.3). Currently, no consensus exists on the relative superiority of the 3 antiangiogenic agents, bevacizumab, aflibercept, and ramucirumab, in the second-line setting after anti-EGFR therapy. This study provides evidence for the efficacy of ramucirumab plus FOLFIRI in second-line treatment, offering a strong option for patients with RAS wild-type mCRC.
Based on Onvansertib, a novel PLK1 inhibitor that has demonstrated good antitumor activity against KRAS-mutated CRC cells in preclinical studies, Ahn et al[75] conducted a study evaluating its combination with FOLFIRI and bevacizumab as second-line therapy for patients with KRAS-mutated mCRC[75]. This regimen demonstrated promising preliminary efficacy [mPFS 12.6 months (95%CI: 9.34-not reached), ORR 43.7%], particularly in terms of ORR, which was significantly superior to that of the FOLFIRI plus bevacizumab regimen. A subsequent phase II study[76] further confirmed the efficacy of this regimen in second-line treatment. Notably, patients who had not previously received bevacizumab had superior mPFS [14.9 months (95%CI: 13.5-not reached) vs 6.6 months (95%CI: 5.6-9.8)] and ORR [76.9% (95%CI: 46.2-95.0) vs 10.0% (95%CI: 2.8-23.7)].
The study by Avallone et al[77] innovatively combined bevacizumab with an oxaliplatin-based regimen in a sequential treatment approach for patients with mCRC. Both treatment-naive and patients who had previously received first-line therapy showed significant improvements in quality of life and OS, even though there were no significant differences in PFS and ORR. Therefore, regardless of the treatment regimens we face in the future, we must consider whether combination therapy or sequential therapy can achieve the greatest survival benefit. Survival benefit should take into account both efficacy and quality of life.
Advances in chemotherapy combined with immunotherapy
To address the challenge of low response rates to ICIs in patients with pMMR/MSS mCRC, investigators have attempted to combine ICIs with cytotoxic agents or epigenetic modulators in an effort to reshape the tumor immune microenvironment and enhance immune responses. A case report[78] describing a patient with mCRC who exhibited a strong anticancer immune response following treatment with cytotoxic drugs suggests that cytotoxic drug therapy may lead to the expansion of CD8+ T cells in the body, thereby enhancing the efficacy of immunotherapy. This provides a basis for combining cytotoxic drugs with ICIs.
To overcome the poor efficacy of ICIs in patients with pMMR tumors, Kuang et al[79] combined azacitidine (a DNA methyltransferase inhibitor) with pembrolizumab (a PD-1 inhibitor) in patients with chemotherapy-refractory mCRC. The results showed an mPFS of 1.9 months, an mOS of 6.3 months, and an ORR of 3%, with 96% of treatment-related adverse events being grade < 3. Although the overall clinical efficacy was modest, it is noteworthy that most patients exhibited decreased levels of DNA methylation and increased levels of CD8+ tumor-infiltrating lymphocytes after combination therapy. This finding suggests that azacitidine may influence immune modulation through DNA demethylation.
Temozolomide is an alkylating agent that methylates the MGMT gene promoter and has been approved for the treatment of glioblastoma. Temozolomide can induce hypermutation, a property that offers hope for the use of ICIs in MSS/pMMR CRC by inducing mutations that increase tumor neoantigen burden and thereby enhance immune responses. In the MAYA trial[80], patients who had progressed on prior therapy or were intolerant to standard agents were treated first with temozolomide, followed by combination therapy with ipilimumab and nivolumab. The results showed an mPFS of 7.0 months (95%CI: 5.5–8.3) and an mOS of 18.4 months (95%CI: 14.9–not reached). These efficacy data represent a significant improvement over historical outcomes with ICI monotherapy in the later-line setting for patients with pMMR tumors. However, the dual effects of temozolomide treatment should be considered: On the one hand, temozolomide-induced hypermutation may produce immune sensitization, converting initially “cold” tumors into “hot” tumors; on the other hand, hypermutation may also accelerate the emergence of resistance mutations. Therefore, the balance between sensitization and the risk of resistance must be carefully weighed in clinical practice.
Advances in targeted therapy plus immunotherapy with or without chemotherapy
To address the challenge of poor response to ICIs in patients with pMMR/MSS mCRC, investigators are exploring combination strategies from multiple directions in an effort to convert “cold” tumors into “hot” tumors. The Bruton’s TKI ibrutinib, which has been shown to exert immunomodulatory effects in preclinical studies, has been investigated in combination with pembrolizumab in patients with MSS/pMMR refractory mCRC[81]. Although the antitumor efficacy in this study was limited, efforts to convert “cold” tumors into “hot” tumors continue.
The combination of the VEGF-targeting agent bevacizumab with immunotherapy may be effective in patients with MSS, BRAF V600E-mutant tumors. A recent case report[82] from China described a patient with right-sided colon adenocarcinoma with these characteristics who, after failure of standard therapy, received nivolumab plus bevacizumab and achieved a remarkable clinical response (mPFS 17 months). This case provides a clue for future combination strategies. An observational study[83] from China retrospectively analyzed survival data from 16 patients with MSS/pMMR tumors who received camrelizumab combined with regorafenib or fruquintinib, showing promising therapeutic potential (ORR 25%, DCR 62.5%).
A study by Guo et al[84] similarly suggested that fruquintinib plus ICIs may confer clinical benefit. The investigators combined fruquintinib with the PD-1 antibody sintilimab in patients with advanced solid tumors. Among patients with mCRC who had progressed after ≥ 1 line of therapy, the mPFS was 5.6 months (95%CI: 4.3–7.5) and the mOS was 14.3 months (95%CI: 8.1–23.7). In the dose-expansion cohort, 25 of 37 patients with mCRC had pMMR tumors, indicating that this combination also provides a treatment option for patients with pMMR tumors, who generally respond poorly to immunotherapy.
A study[85] focusing on patients with pMMR/MSS mCRC who had progressed after ≥ 2 lines of therapy and had all received prior bevacizumab showed that treatment with fruquintinib plus sintilimab achieved an mPFS of 4.1 months (95%CI: 3.2–5.8), an mOS of 15.3 months (95%CI: 9.3–19.3), and an ORR of 12.5% (95%CI: 5.9–22.4); patients with liver metastases had significantly shorter mPFS (3.2 months vs 7.6 months, P < 0.001). This study provides additional evidence for the fruquintinib plus sintilimab regimen.
Interestingly, a study by Liu et al[86] in China added electroacupuncture to the combination of fruquintinib and sintilimab. The authors proposed that electroacupuncture could improve the immune microenvironment in patients with MSS tumors, rendering ICI therapy effective (ORR 21.4%, 95%CI: 10.2–39.5; mPFS 6.1 months, 95%CI: 4.8–9.9; mOS 12.4 months, 95%CI: 11.0–not reached). Notably, the addition of electroacupuncture may reduce the incidence of grade ≥ 3 treatment-related adverse events. This innovative combination provides a nonpharmacological approach to improving immunotherapy efficacy.
Regorafenib is an important therapeutic agent for patients with mCRC. To explore the synergistic antiproliferative effect of PD-1 blockade and regorafenib, Wang et al[87] combined toripalimab with regorafenib in patients with MSS/pMMR/MSI-L tumors who had failed at least 2 lines of chemotherapy. The study achieved an ORR of 15.2% (95%CI: 5.7%–32.7%), an mPFS of 2.1 months (95%CI: 2.0–4.3), and an mOS of 15.5 months (95%CI: 10.3–not reached). Subgroup analysis showed that patients with lung-only metastases had substantially longer PFS than those with liver-only metastases (11.4 months vs 2.5 months), although OS was not significantly different between the 2 groups. Notably, the study also analyzed the relationship between gut microbiota and efficacy. The results showed that higher levels of Fusobacterium were associated with worse PFS (2.0 months vs 5.2 months, P = 0.002). This finding provides a potential target for improving immunotherapy efficacy through modulation of the gut microbiota.
A study by Liu et al[88] in China combined regorafenib with another ICI, sintilimab, in patients with MSS mCRC who progressed after ≥ 2 lines of therapy, also achieving encouraging efficacy (mOS 14.1 months, 95%CI: 10.5–17.7; mPFS 4.1 months, 95%CI: 3.4–4.8). Of note, patients with RAS/RAF wild-type tumors had longer mOS than those with mutant tumors (23.3 months vs 12.1 months; 95%CI: 10.0–36.6 and 8.4–15.8, respectively), and the presence of liver metastases predicted shorter PFS and OS. These results are consistent with previous studies, again highlighting the importance of liver metastases as a negative prognostic factor.
LEAP-017[89] is a phase III study that enrolled patients with pMMR or non-MSI-H mCRC who progressed after standard therapy and evaluated the efficacy and safety of the TKI lenvatinib combined with the PD-1 antibody pembrolizumab. Compared with the control arm of regorafenib, the lenvatinib plus pembrolizumab arm did not show a statistically significant improvement in mOS (9.8 months vs 9.3 months; HR 0.83, 95%CI: 0.68–1.02, P = 0.0379, which did not meet the prespecified threshold of P = 0.0214). This negative result suggests that not every TKI-ICI combination will achieve a breakthrough in the pMMR population.
Martinelli et al[90] explored the efficacy and safety of anti-EGFR rechallenge in patients with chemotherapy-refractory, RAS wild-type mCRC who had responded to first-line anti-EGFR therapy but failed second-line treatment. The study enrolled 77 patients, of whom 71 had MSS tumors. The patients received the PD-L1 inhibitor avelumab combined with the anti-EGFR antibody cetuximab. Overall, mOS was 11.6 months (95%CI: 8.4–14.8), mPFS was 3.6 months (95%CI: 3.2–4.1), and no grade 4 or 5 treatment-related adverse events occurred. Notably, the study also performed separate analyses according to RAS/BRAF wild-type and mutant status determined by ctDNA. Among patients with ctDNA RAS/BRAF wild-type tumors, mOS was 17.3 months (95%CI: 12.5–22.0) compared with 10.4 months (95%CI: 7.2–13.6) in patients with mutant tumors (HR 0.49, 95%CI: 0.27–0.90, P = 0.02); mPFS was 4.1 months (95%CI: 2.9–5.2) in patients with wild-type tumors vs 3.0 months (95%CI: 2.6–3.5) in patients with mutant tumors (HR 0.42, 95%CI: 0.23–0.75, P = 0.004). These results not only suggest that the rechallenge regimen of avelumab plus cetuximab is effective and well tolerated but also highlight the important role of ctDNA analysis in prognostic assessment.
To investigate whether inhibiting the EGFR-RAS-MAPK pathway and the PD-1 immune checkpoint could enhance intratumoral T-cell infiltration and thereby achieve tumor killing, a phase Ib/II study[91] combined cetuximab with pembrolizumab in patients with RAS wild-type tumors who had failed at least 1 line of therapy. Although flow cytometry analysis showed a significant increase in cytotoxic T lymphocytes within tumors after combination therapy (47%), the combination of anti-EGFR therapy and an ICI was not recommended because of the lack of a significant difference in efficacy (P = 0.52).
SCT200 is a novel anti-EGFR monoclonal antibody. Zhang et al[92] evaluated it in patients with KRAS/NRAS/BRAF wild-type mCRC who progressed on oxaliplatin-containing chemotherapy. The results showed an mPFS of 5.2 months (95%CI: 3.6–5.5) and an mOS of 20.2 months (95%CI: 12.1–not reached), indicating preliminary efficacy and warranting further investigation.
Bai et al[93] combined the EGFR antibody anituzumab with the anti-PD-1 antibody flinolimab as third-line and subsequent therapy in patients with RAS/BRAF wild-type mCRC. This regimen achieved an mPFS of 4.14 months (95%CI: 2.73–5.45) and an mOS of 12.84 months (95%CI: 6.64–16.06). Although direct comparison between studies is not possible, given that the survival data did not show a clear improvement over historical anituzumab monotherapy, further validation in larger studies is needed.
To further explore efficacy, Bai et al[94] combined anituzumab and flinolimab with different chemotherapy agents as first- or second-line treatment in patients with RAS/BRAF wild-type mCRC. After comprehensive comparison, they concluded that the combination of anituzumab, flinolimab, and the XELOX regimen provided the greatest clinical benefit with tolerable toxicity (mPFS 9.8 months, 95%CI: 3.9–13.8; mOS 20.4 months, 95%CI: 11.6–not reached).
Given the importance of MEK in the MAPK pathway and the ability of MEK inhibitors to improve the tumor immune microenvironment, Johnson et al[95] combined the MEK inhibitor trametinib with the PD-L1 antibody durvalumab in patients with pMMR/MSS tumors progressing after 5-FU-containing chemotherapy. Although the study did not proceed to stage II based on prespecified efficacy criteria, it is noteworthy that patients with lung metastases derived significant benefit, suggesting that the organ-specific tumor microenvironment has an important impact on antitumor activity.
Lentz et al[96] enrolled patients with pMMR/MSS, BRAF wild-type mCRC who progressed after ≥ 2 lines of therapy, combining the MEK inhibitor binimetinib, the anti-VEGF agent bevacizumab, and the PD-1 antibody pembrolizumab to evaluate whether blockade of the MAPK and VEGF pathways could overcome immunotherapy resistance in this population. Although the ORR was not significantly different from historical data for regorafenib and trifluridine/tipiracil (12.0% vs 5.0%, P = 0.038, exceeding the prespecified threshold of 0.025), the regimen showed a high DCR (70.0%, 95%CI: 55.4%–82.1%).
Based on the hypothesis that irinotecan and anti-EGFR agents may sensitize tumor cells to ICIs, Xu et al[97] enrolled 33 patients with MSS, RAS wild-type mCRC who progressed after ≥ 2 lines of therapy, combining irinotecan, cetuximab, and the PD-1 antibody tislelizumab to evaluate the sensitizing potential of these 2 agents. The results showed an mPFS of 7.3 months (95%CI: 5.6–8.6), an mOS of 17.4 months (95%CI: 15.9–not reached), and only 3 patients experienced grade ≥ 3 treatment-related adverse events. This regimen demonstrated promising antitumor activity with a favorable safety profile.
In another phase I nonrandomized controlled trial[98] focusing on later-line treatment of patients with mCRC without liver metastases, 22 patients with MSS tumors received the TKI regorafenib combined with the ICIs ipilimumab and nivolumab. The 3-year PFS rate was 19.3%, the 3-year OS rate was 40.9%, and 3 patients had PFS exceeding 18 months, demonstrating durable clinical benefit.
The synergy between targeted agents and immunotherapies has generated great interest among investigators. For patients with BRAF V600E-mutant, MSS mCRC who progressed after prior therapy, a phase I/II clinical trial[99] evaluated the combination of the BRAF inhibitor encorafenib, the EGFR inhibitor cetuximab, and the PD-1 inhibitor nivolumab. The results showed definite efficacy (mPFS 7.4 months, 95%CI: 5.6–9.6; mOS 22 months, 95%CI: 11.2–25.8).
Inhibition of the RAS-RAF-MEK pathway may be an effective treatment strategy for patients with BRAF V600E-mutant mCRC, and adding ICIs may further enhance efficacy. Wei et al[100] combined the BRAF inhibitor vemurafenib, the EGFR antibody cetuximab, and the PD-1 inhibitor camrelizumab in patients with BRAF V600E-mutant, MSS/pMMR tumors. The results showed an ORR of 33.3%, an mPFS of 3.47 months (95%CI: 1.76–5.18), and an mOS of 7.19 months (95%CI: 4.97–not reached), indicating preliminary efficacy with manageable toxicity.
Improving the efficacy of ICIs in patients with pMMR and MSS tumors remains a research focus. Zanzalintinib is a multitarget TKI inhibiting MET, VEGF receptor 2, AXL, and MER. The STELLAR-303 study[101] combined zanzalintinib with the PD-L1 antibody atezolizumab in patients with non-dMMR/MSS chemotherapy-refractory mCRC. The study was conducted at multiple centers and ultimately enrolled 901 patients. The results showed that the zanzalintinib plus atezolizumab arm had significantly superior OS compared with the regorafenib arm (10.9 months vs 9.4 months, HR 0.80, 95%CI: 0.69–0.93, P = 0.0045). Notably, the presence or absence of liver metastases did not affect the efficacy of this regimen, a feature that gives it a potential advantage in patients with liver metastases.
Exploration of whether PD-1/PD-L1 inhibitors can enhance the efficacy of antiangiogenic therapy has continued. Recently, a phase II randomized controlled study[102] enrolled patients who had failed prior chemotherapy including oxaliplatin and had also failed bevacizumab or cetuximab therapy. They were randomized 2:1 to an experimental arm or a control arm. The control arm received capecitabine plus bevacizumab, while the experimental arm received atezolizumab, a PD-L1 inhibitor, in addition to the control regimen. The results showed similar mOS between the 2 arms (10.3 months vs 10.2 months, HR 0.96, 95%CI: 0.63–1.45), with no statistically significant difference in PFS. However, subgroup analysis found that patients without liver metastases or with MSS/pMMR tumors might derive greater benefit from dual inhibition. This finding suggests that even when overall results are negative, specific subgroups may still benefit from combination therapy, warranting further prospective validation.
Chemotherapy combined with targeted therapy is undoubtedly the most widely accepted foundation for current later-line treatment. To address the issue of suboptimal immunotherapy outcomes in patients with MSS/pMMR tumors, research into multidrug combination therapies is steadily progressing. It must be acknowledged that current multiagent combination therapies for advanced CRC have significant limitations. The uncertainty of efficacy reported in case reports, the early termination of key trials, and the modest benefits observed after limiting the number of metastatic sites all point to the uncertainty surrounding the efficacy of many current regimens. The classification criteria used in subgroup analyses lack support from predictive biomarkers, making it difficult to achieve the goal of personalized precision therapy in the short term. Currently, sequential administration and dose adjustment in multidrug combination regimens are still rarely discussed. We believe these will be particularly important in the design and optimization of future regimens.
APPLICATION OF RADIOTHERAPY IN LATER-LINE TREATMENT
Given that ICIs have shown limited efficacy in patients with pMMR mCRC and that the combination of radiation therapy (RT) and immunotherapy has demonstrated synergistic effects in other cancers, Segal et al[103] conducted a study in which they administered concurrent RT and ICIs (durvalumab plus tremelimumab) to patients with previously treated mCRC. Although no significant clinical benefit was observed, the researchers did identify a distant effect resulting from the combination of RT and immunotherapy.
Regarding the use of RT in combination with ICIs to enhance the efficacy of immunotherapy, West China Hospital, Sichuan University published a related case report[104]. It is worth noting that this is the first reported case of a pathological complete response achieved with the combination of RT and immunotherapy as second-line treatment in a patient with dMMR/MSI-H mCRC, even though the specific contribution of RT to the treatment outcome could not be clearly determined.
Targeted therapy combined with immunotherapy has shown some efficacy in patients with MSS mCRC. One study[105] explored the synergistic effect of RT on immunotherapy by combining it with fruquintinib and sintilimab as third-line treatment. The results showed that patients who received RT had superior mPFS [6.2 months (95%CI: 4.8–7.5) vs 2.7 months (95%CI: 2.2–3.3), P < 0.001], mOS [14.8 months (95%CI: 9.5–20.0) vs 5.9 months (95%CI: 3.6–8.2), P = 0.019], ORR (28.0% vs 6.7%, P = 0.048), and DCR (80.0% vs 36.7%, P = 0.002), indicating that patients derived significant clinical benefit. Interestingly, the study also found that gut microbiota, such as Bifidobacterium, may be associated with a better prognosis.
Building on the established ability of stereotactic body radiotherapy (SBRT) to locally control liver metastases in mCRC, the study by He et al[106] investigated the underlying mechanisms and found that SBRT suppresses SLC7A11 expression; reduced SLC7A11 levels promote ferroptosis, thereby enhancing the sensitivity of CRC cells to SBRT. Sorafenib is a multi-target receptor TKI that can target SLC7A11. This study further investigated the combination of SBRT and sorafenib in patients with mCRC whose disease had progressed after first- or second-line therapy. The results suggest that this regimen overcomes radiation resistance to some extent and has the potential to become a treatment option for patients with liver metastases from mCRC.
Based on the mechanism of synergy between RT and immunotherapy, a multicenter phase II study[107] combined 2 ICIs (durvalumab and tremelimumab) with local tumor ablation therapy (radiofrequency ablation/stereotactic radiotherapy) in patients with mCRC who had liver metastases and whose disease had progressed after first- or second-line treatment. Unfortunately, this combination regimen did not improve patient prognosis.
In summary, small-sample studies and case reports indicate that RT has achieved favorable results in anticancer treatment across multiple clinical centers through mechanisms such as immunosensitization. However, the drawbacks are also apparent: Due to the lack of uniform standards for radiation dose, frequency, and treatment sequencing, there is significant variability in treatment protocols, making it difficult to conduct combined RT studies in multicenter clinical trials. Therefore, we believe that combination therapies involving RT may hold value in comprehensively improving treatment efficacy in the future. However, this requires further standardization and harmonization of global diagnostic and therapeutic practices.
EMERGING AGENTS AND ADJUNCTIVE THERAPIES
New drugs
Based on discoveries regarding the molecular mechanisms of CRC, a variety of new drugs have been developed in recent years, such as antibody–drug conjugates (ADCs) and novel chemotherapy sensitizers. Trastuzumab deruxtecan, a novel ADC, has been evaluated for the treatment of patients with RAS- and BRAF V600E-wild-type tumors who have failed multiple lines of therapy[108]. The results showed that the ORR in HER2-positive patients [IHC 3+/2+, ISH(+)] was 45.3% (95%CI: 31.6%–59.6%). Consistent with previous reports on trastuzumab deruxtecan, the use of this drug is associated with interstitial lung disease and pneumonia, which must be taken seriously.
Another case report[109] on mCRC also described the use of trastuzumab deruxtecan. A patient with HER2-amplified disease harboring a HER2 S310F mutation, who had progressed after multiple lines of therapy, received dual HER2-targeted therapy (trastuzumab deruxtecan plus lapatinib) and showed no disease progression for 10 months. This case also emphasizes the importance of assessing HER2 status before initiating mCRC treatment; particularly in patients who have failed standard therapy, HER2 testing should be part of routine molecular pathology evaluation.
CEACAM5 is a glycoprotein that promotes tumor proliferation and is overexpressed in CRC. Precem-TcT is a novel ADC targeting CEACAM5. In a dose-escalation study by Kopetz et al[110], Precem-TcT was administered to patients with mCRC who had progressed after irinotecan-based therapy. The results showed that doses ≥ 2.4 mg/kg had acceptable safety and antitumor activity. This study is still in the dose-optimization phase, and further results are awaited.
Strickler et al[111] compared the efficacy and safety of dilpacimab, a drug that simultaneously inhibits delta-like ligand 4 and VEGF, in combination with FOLFIRI against the bevacizumab-FOLFIRI regimen. All enrolled patients had previously received oxaliplatin-based chemotherapy and had experienced disease progression. Unfortunately, dilpacimab-FOLFIRI did not demonstrate superior mPFS (3.78 months vs 7.36 months) or mOS (7.95 months vs not reached). The regimen had a poorer safety profile: One death was confirmed to be related to dilpacimab treatment, and 11.8% of patients experienced serious treatment-related adverse events. By contrast, no serious treatment-related adverse events or treatment-related deaths were observed among patients treated with the bevacizumab-FOLFIRI regimen.
Arfolitixorin is a novel folate-based agent that is not affected by folate gene expression, providing more consistent antitumor activity. Carlsson et al[112] substituted arfolitixorin for leucovorin in FOLFOX or FOLFIRI regimens. The results showed that arfolitixorin demonstrated favorable efficacy and safety in first-line, second-line, and later-line settings. This agent offers a new option for patients with low expression of folate metabolism-related genes (e.g., those who responded poorly to prior leucovorin) and has the potential to further optimize the sensitization strategy for fluoropyrimidine-based chemotherapy.
Zabadinostat is a selective HDAC1 inhibitor. Previous studies have shown that zabadinostat can promote T-cell infiltration into the tumor microenvironment. Based on this, Saunders et al[113] combined zabadinostat with nivolumab in patients with MSS mCRC who had progressed after second-line chemotherapy containing both oxaliplatin and irinotecan. The results showed an mPFS of 2.1 months (95%CI: 1.4–3.9) and an mOS of 7.0 months (95%CI: 5.13–10.22). Of note, the frequency of immune-related adverse events was significantly reduced in patients receiving this combination, suggesting that zabadinostat may reduce immune-related toxicity through epigenetic modulation. However, efficacy remains limited, and further optimization is needed.
Vorbipiprant is a novel EP4 receptor inhibitor with demonstrated immunomodulatory effects. To address the low response rate to ICIs in patients with pMMR/MSS tumors, a phase Ib/IIa single-arm study[114] combined vorbipiprant with the PD-1 inhibitor balstilimab in 28 patients with pMMR/MSS mCRC who had progressed after chemotherapy. Statistical analysis showed an mPFS of 2.6 months (95%CI: 1.7–3.6), an mOS of 14.2 months (95%CI: 10.6–not reached), and a DCR of 50%. Regarding safety, only 2 serious treatment-related adverse events occurred, and only 1 of them was considered related to vorbipiprant. Although the improvement in PFS was modest, the mOS of 14.2 months and DCR of 50% in the later-line setting suggest that some patients may benefit from this combination, warranting further efforts to identify the optimal population.
Vilamakitug is a monoclonal antibody targeting interleukin (IL)-1α that neutralizes IL-1α in patients with cancer, thereby inhibiting tumor angiogenesis and resistance and modulating immunity. Thibaudin et al[115] first established the safe dose of vilamakitug combined with TAS-102 and then evaluated this combination with bevacizumab in patients who had failed multiple lines of therapy. The results showed an mPFS of 9.4 months (95%CI: 3.6–not reached). Notably, through monitoring of baseline characteristics and on-treatment cytokine levels, the investigators observed that high pretreatment expression of IL-1α, PD-L1, and CD8, as well as a decrease in IL-6 levels during treatment, were associated with better PFS. This finding provides new biomarkers for identifying potential responders to this combination and offers a new approach to targeting inflammatory pathways in refractory mCRC.
Adjuvant medications
In addition to known anticancer drugs, the anticancer effects of drugs used to treat other diseases or new drugs on CRC have attracted widespread attention in recent years. Maraviroc, a selective CCR5 inhibitor, has previously been used to treat human immunodeficiency virus. It has also been found to upregulate the expression of immune checkpoints, including PD-L1. To explore drug combinations that could make ICIs effective for patients with pMMR tumors, Haag et al[116] combined maraviroc with the PD-1 inhibitor pembrolizumab as a follow-up treatment for patients who had failed standard therapy (including 5-FU, oxaliplatin, EGFR-targeted therapy, VEGF-targeted therapy, and TAS-102). Among the 20 patients enrolled, the ORR was 5.3%, mPFS was 2.10 months (95%CI: 1.68–2.30), and mOS was 9.83 months (95%CI: 5.59–20.02). Apart from 1 patient who experienced grade 4 hyperglycemia, no other treatment-related adverse events of grade ≥ 3 occurred. This combination regimen demonstrated promising antitumor activity.
Metformin has been widely investigated in solid tumor therapy because of its recently recognized immunomodulatory activity, including slowing lymphocyte exhaustion in the tumor microenvironment and potentiating PD-1 blockade. Akce et al[117] combined the anti-PD-1 antibody nivolumab with metformin in patients with chemotherapy-refractory MSS mCRC to explore whether efficacy could be improved. Unfortunately, although metformin showed antitumor activity in patients, the clinical efficacy did not fully materialize. This negative result suggests that the immunomodulatory effects of metformin may be insufficient to reverse primary ICI resistance in mCRC or that more precise biomarkers are needed to identify responding patients.
Based on prior findings that hydroxychloroquine (HCQ) can enhance the antitumor activity of the HDAC inhibitor vorinostat in mCRC through modulation of autophagy, Arora et al[118] compared vorinostat plus HCQ with the second-line agent regorafenib in terms of efficacy and safety. The results showed that the vorinostat plus HCQ arm did not achieve superior mPFS compared with the regorafenib arm (1.9 months vs 4.35 months, P = 0.032), and there was no statistically significant difference in mOS between the 2 groups (P = 0.9). Therefore, although vorinostat plus HCQ demonstrated antitumor activity in preclinical studies, it did not translate into clinical benefit and is not supported as a replacement for regorafenib in later-line mCRC treatment.
Mebendazole, a classic antiparasitic agent, was evaluated in a randomized controlled trial[119] in combination with FOLFOX4 chemotherapy and bevacizumab in patients with mCRC. The results showed striking antitumor activity: Significantly improved PFS (9.25 months vs 3 months, P = 0.000), a marked increase in ORR at 12 weeks (65% vs 10%, P = 0.000), and a decrease in serum VEGF levels. These findings provide strong evidence for drug repurposing and warrant further large-scale validation studies. A 2022 publication[120] noted that celecoxib may serve as an adjunctive sensitizer for patients with mCRC receiving FOLFIRI chemotherapy. The underlying mechanism may involve inhibition of cyclooxygenase-2 and modulation of the inflammatory microenvironment, but prospective studies are needed for confirmation.
Among patients receiving concomitant proton pump inhibitor therapy, those treated with 5-FU had superior OS and PFS compared with those receiving capecitabine, although proton pump inhibitors did not significantly reduce the efficacy of capecitabine[121]. This finding suggests that in patients with mCRC receiving concomitant proton pump inhibitors, the choice of chemotherapy agent may require individualized consideration. Pexastimogene devacirepvec is an oncolytic virus that promotes immune cell infiltration into tumors and has previously been used as monotherapy in only a few patients with CRC. A phase I/II study[122] combined pexastimogene devacirepvec with the PD-L1 antibody durvalumab and the CTLA-4 antibody tremelimumab in patients with MSS mCRC, with regimens stratified into triplet (including tremelimumab) and doublet (without tremelimumab) arms. The results showed that the triplet arm had an mPFS of 2.1 months (95%CI: 1.7–2.8) and the doublet arm had an mPFS of 2.3 months (95%CI: 2.2–3.2); mOS was 5.2 months (95%CI: 4.3–10.2) in the triplet arm and 7.5 months (95%CI: 4.9–10.3) in the doublet arm. No unexpected treatment-related adverse events occurred during the study. Although the PFS and OS data are not striking, given that all enrolled patients had immunotherapy-resistant MSS tumors in the later-line setting and toxicity was manageable, this oncolytic virus–immunotherapy combination is still considered highly promising and warrants further optimization of combination strategies and patient selection.
Napabucasin is an oral reactive oxygen species generator that has been evaluated in multiple solid tumors. Unfortunately, a study[123] combining napabucasin with FOLFIRI as second-line therapy for mCRC did not demonstrate superior OS (mOS 14.3 months vs 13.8 months, HR 0.976, P = 0.74). This negative result does not support the routine use of napabucasin in second-line mCRC treatment.
For the treatment of liver metastases, some investigators have attempted to use an antireflux catheter to improve the efficacy of holmium-166 radioembolization, but no significant difference in outcomes was ultimately observed[124]. Although this attempt was not successful, it provides insight into technical optimization for local treatment of liver metastases.
The development of ADCs and attempts at antitumor therapy using drugs such as metformin have provided more potential treatment options for patients with advanced CRC. However, because of the lack of validation through multicenter trials, the homogeneity of the study populations, and uncertainties regarding efficacy, most of these drugs are unlikely to undergo prospective validation. Therefore, these drugs primarily serve as a reference for enhancing the efficacy of subsequent personalized treatments, and it is highly unlikely that they will be used as first-line treatment regimens.
CONCLUSION
This review focuses on recent clinical progress in later-line treatment for refractory CRC. We synthesize published studies from the past 5 years, with an emphasis on comparing combination strategies across distinct patient populations and critically appraising the strengths and limitations of each regimen. Notably, we have not included several novel, multimechanistic anticancer agents that have shown promising efficacy in recent years. Our team’s primary objective is to highlight, alongside a summary of current evidence, the continued importance of optimizing established drug combinations. Moreover, many of these new agents are still undergoing or awaiting phase III evaluation, with their activity confined to narrow cohorts and their overall benefit remaining uncertain.
Our approach departs from conventional narrative summaries by offering a focused, critical examination of trial design, patient characteristics at enrollment, and primary endpoints. Our analysis suggests that combination therapy in CRC still holds considerable untapped potential. Most investigated combinations remain at phase I/II levels, and robust phase III data are lacking for key subgroups. In addition, the outcomes reported in phase III trials have not consistently translated into real-world practice, underscoring the urgent need for well-designed, multicenter real-world studies. Furthermore, many regimens yield only modest gains in PFS, without meaningful improvements in quality of life or OS. In our view, disease control does not automatically equate to net patient benefit. Such results may apply only to selected patients with specific clinical priorities. Even when a given strategy gains global acceptance, we believe thorough pretreatment communication with patients and families remains essential.
Our review also reveals that predictive biomarkers, such as ctDNA and gut microbiota, have not been systematically incorporated into prospective trial designs. We suspect this reflects a broader issue: The lack of high-level evidence validating these markers has limited their recognition among researchers and sponsors. While we have endeavored to cover the most recently published studies to provide a comprehensive snapshot of the current treatment landscape, our work is constrained by the limited number of available trials, the heterogeneity of study phases, and the absence of head-to-head comparisons. Consequently, this review remains a critical evaluation rather than a direct meta-analytic comparison of effect estimates. In summary, we advocate that future trials should not only integrate potentially valuable predictive biomarkers and clarify the clinical relevance of intermediate endpoints such as PFS vs OS but also adopt rigorous, multilayered eligibility criteria to facilitate personalized therapy, thereby strengthening the level of evidence and enhancing the clinical utility of research findings.
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