Abstract
Background
The third-line treatment options recommended by guidelines for metastatic colorectal cancer (mCRC) are limited with unsatisfactory efficacy. Immune checkpoint inhibitor (ICI)-based strategies have been extensively explored for microsatellite stable (MSS) mCRC at third-line and above settings. This study aimed to evaluate the efficacy and safety of ICI versus non-ICI-based treatments for MSS mCRC patients in third-line setting.
Methods
Electronic medical records of MSS mCRC patients who received at least third-line therapies at Renmin Hospital of Wuhan University between September 2019 and April 2024 were reviewed retrospectively. Propensity score matching (PSM) was used to balance potential confounding factors. The primary outcomes of interest were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR) and adverse events (TRAEs).
Results
Of 243 eligible patients, 93 received third-line ICI therapy and 150 treated with non-ICI therapy. The ORR were 12.9% vs 9.3% and DCR were 80.6% vs 72.0%, respectively. After PSM, an improved median PFS was exhibited in the ICI cohort (5.0 vs 3.6 months; HR = 0.55; 95% CI, 0.39–0.78; P < 0.001), with a directional improvement of OS (13.8 vs 12.4 months; HR = 0.70; 95% CI, 0.47–1.05; P = 0.086). In addition, a more significant survival benefit was found in the triplet regimen of ICI, chemotherapy and target therapy, with a median PFS of 8.2 months and OS of 20.2 months. Patients > 60 years of age, male, with liver metastasis, prior anti-VEGF(R) therapy, and wild-type RAS/BRAF could obtain PFS benefit from third-line ICI over non-ICI treatment. Thirty-six (38.7%) patients developed at least once cross-line immunotherapy in ICI cohort, resulting a directional OS improvement. Grade ≥ 3 AEs occurred in 39.8% and 43.3% of patients in each cohort. Immune-related AEs (irAEs) was 38.7%, and grade ≥ 3 irAEs was 14.0% in ICI cohort.
Conclusion
ICI is a beneficial addition to third-line treatment for some MSS mCRC patients, providing improved survival benefit and controllable safety.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12885-026-15740-w.
Keywords: Metastatic colorectal cancer, Microsatellite stable, Immune checkpoint inhibitor, Third-line treatment
Introduction
Colorectal cancer (CRC) is the third most common malignant cancer diagnosed globally and the second leading cause of cancer-related death, as well as the specific carcinoma with the highest overall lifetime risk of developing and dying from gastrointestinal tumors [1, 2].
Statistics show that 1 in 4 patients are diagnosed with metastatic CRC (mCRC) at initial diagnosis, and about half of patients with localized CRC will eventually develop into mCRC. Patients with mCRC generally have a heavy disease burden and poor prognosis, with a 5-year overall survival (OS) rate of less than 15% [3]. For now, at least, fluorouracil-based doublet or triplet chemotherapy (CT) combined with anti-EGFR or anti-VEGF(R) monoclonal antibody (mAb) is still the standard first- and second-line therapy for mCRC. By comparison, the third-line (3L) treatment options recommended by the current clinical guidelines for mCRC are limited with unsatisfactory efficacy [4]. The median progression-free survival (PFS) of the available 3L drugs such as regorafenib, fruquintinib and TAS-102 is only about 1.9–5.6 months, which obviously cannot meet the urgent needs of the vast number of patients [5–12].
The introduction of immune checkpoint inhibitor (ICI) has remolded the treatment situation and clinical outcomes in most cancer patients. In particular, for CRC patients with mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) phenotype, the application of ICI has shown promising outcomes, including significantly prolonged PFS and long-lasting disease responses [13]. However, more than 95% of mCRC patients have mismatch repair-proficient/microsatellite-stable (pMMR/MSS) genomic status. Due to low tumor mutation burden and the absence of effective lymphocyte infiltration in the immunosuppressive tumor microenvironment (TME), these patients tend to have poor clinical response to ICI monotherapy.
Researchers have conducted a series of studies to explore effective third-line or above treatment strategies for pMMR/MSS mCRC, like ICI in combination with CT, radiotherapy (RT), tyrosine kinase inhibitor (TKI), biotherapy and/or other cytotoxic agents [14–19]. Although these results are mixed, and ICI has not yet been written into the guidelines for patients with pMMR/MSS mCRC, ICI-based combination has already been off-guideline administered as part of routine clinical care after patient-clinician shared decision-making. At present, the relevant data on ICI as 3L treatment for MSS mCRC patients are still relatively lacking. Therefore, this study was designed to evaluate the ICI-based 3L treatment patterns and therapeutic efficacy in pMMR/MSS mCRC patients compared with non-ICI-based therapies to systematically document clinical outcomes and explore potential predictors of benefit.
Patients and methods
Patient selection and treatment
This retrospective observational cohort study was conducted at the Renmin Hospital of Wuhan University, China. The data of mCRC patients between September 2019 and April 2024 were collected. Patients were selected according to the following inclusion and exclusion criteria. Eligible patients were ≥ 18 years of age, had histologically or cytologically confirmed metastatic colorectal adenocarcinoma, had a genetic status of pMMR/MSS phenotype, had received at least one dose of 3L treatment, and had available follow-up data. Patients with other malignancies (except skin basal cell carcinoma and cervical carcinoma in situ), or with incomplete medical data were excluded from the study.
Decisions on patient-specific 3L treatment regimens, drug dosing adjustments, discontinuance or termination were entirely at the discretion of clinician. This study was approved by the ethics committee of Renmin Hospital of Wuhan University (No. 2023 K-K067). The study followed the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. All patients voluntarily participated and provided written informed consent.
Efficacy and safety evaluation
The primary outcomes of interest were median PFS (defined as the time since 3L treatment initiation to disease progression or death from any cause or date of last follow-up), OS (defined as the time from treatment initiation until death or last visit), objective response rate (ORR), disease control rate (DCR), and safety. Subgroup analysis was also conducted.
Patients who received at least one dose of 3L treatment were included in the efficacy and safety analyses. Tumor responses of target lesions were evaluated every 2 treatment cycles according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and classified as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). ORR was determined as the rate of a best response of CR or PR. DCR included CR, PR, and SD. Treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs), including blood routine, liver and kidney function, urine routine, coagulation function, thyroid function, myocardial enzyme profile, and other biochemical indicators were collected through the medical electronic system and/or recorded by telephone visits according to the Medical Dictionary for Regulatory Activities v23.0. The severity of all adverse events (AEs) was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0.
Statistical analysis
Statistical analyses were undertaken using SPSS v26.0. Categorical variables were summarized by percentages and compared by chi-squared test or Fisher’s exact test, as appropriate. Continuous variables were described by median and interquartile range (IQR). Median follow-up time was determined using the reverse Kaplan–Meier estimator. Median PFS and OS were plotted using the Kaplan–Meier method. The survival distributions were compared using the log-rank test. A Cox proportional hazards regression model was performed to calculate the hazard ratio (HR) and bilateral 95% confidence interval (CI). A multivariate Cox regression analysis of PFS was used to evaluate the treatment effect after adjusting important prognostic factors. Forest plot was generated for visual representation of the subgroup analysis. Propensity score matching (PSM) was performed using R v4.2.3 as an exploratory post-hoc analysis with a 1:1 matching ratio and a caliper of 0.02. Treatment patterns were described based on observed distribution of regimens administered. Demographic characteristics, AEs, and other clinical data were summarized descriptively. A P-value of < 0.05 was considered to be statistically significant.
Results
Patient characteristics
Overall, 243 patients with MSS mCRC were included; 93 in the ICI cohort and 150 in the non-ICI cohort received at least one dose of 3L systemic treatment and comprised the efficacy-evaluable population and safety analysis set (Fig. 1). Of the entire cohort, patients were predominantly males (65.4%), with a median age of 59 years (IQR, 51–67) and an ECOG PS score of 0–1 (91.4%). 186 (76.5%) patients had primary tumor located in left-side colon and rectum, 181 (74.5%) had ≥ 2 metastatic organs, and 153 (63.0%) and 122 (50.2%) had liver and lung metastasis, respectively. Almost all patients received prior CT (99.6%), 197 (81.1%) underwent surgery of the primary tumor, 106 (43.6%) received prior RT, 43 (17.7%) had received prior immunotherapy, 193 (79.4%) had previously treated with anti-VEGF(R) targeted therapy. Genetic status was available for 181 (74.5%) patients, among which 82 (33.7%) were RAS mutated type and 13 (5.3%) were BRAF mutant type. Furthermore, in ICI and non-ICI cohort, there was 1 and 2 cases with both RAS and BRAF mutations, respectively. All patients were pMMR and/or MSS phenotypes. Baseline demographic and clinical characteristics were generally similar in two cohorts, although there was a trend to higher prior anti-VEGF(R) therapy involvement in the ICI cohort. Yet, the subsequent PSM analysis adjusted well for the imbalance between the two cohorts, and the variables used for matching included age, sex, primary side, liver metastasis, RAS and BRAF status and prior VEGF(R)i history (Table S1, Fig. S1). The baseline characteristics of all patients and subgroups of patients are presented in Table 1.
Fig. 1.
Flowchart of the study. MMS, microsatellite stable; ICI, immune checkpoint inhibitor
Table 1.
Patient demographics and baseline characteristics
| Characteristics | Patients, No. (%) | ||
|---|---|---|---|
| ICI cohort (n = 93) | Non-ICI cohort (n = 150) | All (n = 243) | |
| Age, median (IQR), year | 57 (50–66) | 59 (52–67) | 59 (51–67) |
| > 60 | 34 (36.6) | 71 (47.3) | 105 (43.2) |
| ≤ 60 | 59 (63.4) | 79 (52.7) | 138 (56.8) |
| Sex | |||
| Male | 62 (66.7) | 97 (64.7) | 159 (65.4) |
| Female | 31 (33.3) | 53 (35.3) | 84 (34.6) |
| ECOG PS score | |||
| 0–1 | 86 (92.5) | 136 (90.7) | 222 (91.4) |
| 2 | 7 (7.5) | 14 (9.3) | 21 (8.6) |
| Primary site | |||
| Left side | 70 (75.3) | 116 (77.3) | 186 (76.5) |
| Right side | 23 (24.7) | 34 (22.7) | 57 (23.5) |
| No. of metastatic organs | |||
| 1 | 27 (29.0) | 35 (23.3) | 61 (25.1) |
| ≥ 2 | 66 (71.0) | 115 (76.7) | 182 (74.9) |
| Type of metastasis | |||
| Liver metastasis | 63 (67.7) | 90 (60.0) | 153 (63.0) |
| Lung metastasis | 50 (53.8) | 72 (48.0) | 122 (50.2) |
| RAS and BRAF status | |||
| RAS MT | 37 (39.8) | 45 (30.0) | 91 (37.4) |
| BRAF MT | 5 (5.4) | 8 (5.3) | 13 (5.3) |
| RAS/BRAF WT | 28 (30.1) | 61 (40.7) | 89 (36.6) |
| Unavailable | 24 (25.8) | 38 (25.3) | 62 (25.5) |
| MMR/MSI status | |||
| pMMR/MSS | 93 (100.0) | 150 (100.0) | 243 (100.0) |
| Prior treatment | |||
| Surgery of primary tumor | 75 (80.6) | 122 (81.3) | 197 (81.1) |
| Chemotherapy | 93 (100.0) | 149 (99.3) | 242 (99.6) |
| Radiotherapy | 38 (40.9) | 68 (45.3) | 106 (43.6) |
| Immunotherapy | 21 (22.6) | 22 (14.7) | 43 (17.7) |
| EGFRia | 12 (12.9) | 31 (20.7) | 43 (17.7) |
| VEGF(R)i b | 80 (86.0) | 113 (75.3) | 193 (79.4) |
ECOG PS Eastern Cooperative Oncology Group performance status, EGFRi epidermal growth factor receptor inhibitor, IQR interquartile range, MMR mismatch repair, MSI microsatellite instability, MSS microsatellite stable, MT mutated type, pMMR mismatch repair proficient, VEGF(R)i vascular endothelial growth factor (receptor) inhibitor, WT wild type
aEGFRi: cetuximab and nimotuzumab
bVEGF(R)i: bevacizumab and tyrosine kinase inhibitors (TKIs) such as regorafenib, fruquintinib, apatinib, anlotinib, dabrafenib, vemurafenib, and trametinib
Treatment patterns
Third-line treatment patterns in two cohorts are described in Table 2. In the ICI cohort, ICI combined with TKI (62 patients, 66.7%) was the most frequently used regimens that led the list. Among them, 45 patients (48.4%) received ICI plus TKI doublet regimens, 9 (9.7%) received ICI in combination with TKI and CT, and 6 (6.5%) treated with ICI in combination with TKI and RT triplet regimens (Fig. 2A). Compared with the main ICI and TKI combination, only thirty-seven (39.8%) patients adopted ICI and CT. Only one patient (1.1%) received ICI alone.
Table 2.
Third-line treatment patterns
| Regimens | Patients, n (%) |
|---|---|
| ICI cohort | 93 (100.0) |
| ICIa | 1 (1.1) |
| ICI + CT | 8 (8.6) |
| ICI + CT + RT | 4 (4.3) |
| ICI + anti-VEGF/EGFR/HER2 mAbb | 2 (2.2) |
| ICI + anti-VEGF/EGFR/HER2 mAb + CT | 8 (8.6) |
| ICI + anti-VEGF/EGFR/HER2 mAb + RT | 1 (1.1) |
| ICI + anti-VEGF/EGFR/HER2 mAb + CT + RT | 7 (7.5) |
| ICI + TKIc | 45 (48.4) |
| ICI + TKI + CT | 9 (9.7) |
| ICI + TKI + RT | 6 (6.5) |
| ICI + TKI + CT + RT | 1 (1.1) |
| ICI + TKI + anti-VEGF/EGFR/HER2 mAb + RT | 1 (1.1) |
| Non-ICI cohort | 150 (100.0) |
| CT | 14 (9.3) |
| CT + RT | 8 (5.3) |
| CT + TKI | 26 (17.3) |
| CT + TKI + RT | 2 (1.3) |
| CT + anti-VEGF/EGFR/HER2 mAb | 43 (28.7) |
| CT + anti-VEGF/EGFR/HER2 mAb + RT | 13 (8.7) |
| CT + anti-VEGF/EGFR/HER2 mAb + TKI | 4 (2.7) |
| anti-VEGF/EGFR/HER2 mAb + RT | 3 (2.0) |
| anti-VEGF/EGFR/HER2 mAb + TKI | 4 (2.7) |
| TKI | 23 (15.3) |
| TKI + RT | 10 (6.7) |
CT chemotherapy, EGFR epidermal growth factor receptor, ICI immune checkpoint inhibitor, mAb monoclonal antibody, RT radiotherapy, TKI tyrosine kinase inhibitor, VEGF vascular endothelial growth factor, HER2 human epidermal growth factor receptor 2
aICI: anti-PD-1 mAb (pembrolizumab, nivolumab, camrelizumab, toripalimab, sintilimab, tislelizumab, penpulimab), anti-PD-L1 mAb (atezolizumab, durvalumab, envafolimab, adebrelimab) and anti-PD-1/CTLA4 mAb (cadonilimab)
bAnti-VEGF mAb (bevacizumab); anti-EGFR mAb (cetuximab and nimotuzumab); anti-HER2 mAb (trastuzumab, pertuzumab, disitamab vedotin and trastuzumab emtansine)
cTKI: VEGFRi (regorafenib, fruquintinib, sulfatinib, apatinib, anlotinib), BRAFi (dabrafenib, vemurafenib), MEKi (trametinib), HER2i (pyrotinib, lapatinib, tucatinib), ALKi (lorlatinib)
Fig. 2.
Major treatment regimens and proportions. A Treatment patterns of patients in ICI cohort. B Treatment patterns of patients in non-ICI cohort. 3L, third-line; CT, chemotherapy; ICI, immune checkpoint inhibitor; RT, radiotherapy; mAb, monoclonal antibody (against VEGF, EGFR or HER2); TKI, tyrosine kinase inhibitor
In non-ICI cohort, CT still dominated the 3L treatment for these patients. The combination of CT and anti-VEGF/EGFR/HER2 mAb (all: 37.4%; CT + mAb: 28.7%; CT + mAb + RT: 8.7%) arranged at first, and CT plus TKI (17.3%) ranked second (Fig. 2B). Compared with 110 (73.3%) patients receiving CT-based treatment, only 40 (26.7%) treated without CT, including 37 (92.5%, 37/40) who received TKI. TKI monotherapy was adopted in 23 (15.3%) patients and only 14 (9.3%) patients were given CT alone.
Treatment response
The ORR was 12.9% (95% CI, 7.5–21.2) and the DCR was 80.6% (95% CI, 71.5–87.4), including 12 (12.9%) confirmed PR and 63 (67.7%) SD in the ICI cohort (Fig. 3A). While, in the non-ICI cohort, the ORR was 9.3% (95% CI, 5.6–15.1) and DCR was 72.0% (95% CI, 64.3–78.6), including 14 (9.3%) cases of PR and 94 (62.70%) cases of SD (Fig. 3A). A reduction in the size of target lesions were achieved in 43 (46.2%) and 66 (44.0%) patients, respectively (Fig. 3B).
Fig. 3.
Tumor response. A Anti-tumor efficacy in each cohort. B Waterfall plot showing the best percent change in the size of target lesions from baseline. The dashed lines at + 20% and −30% indicate thresholds for progressive disease and partial response, respectively, according to RECIST v1.1. 3L, third-line; DCR, disease control rate; ICI, immune checkpoint inhibitor; MT, mutated type; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease
Survival outcomes
As of data cutoff on September 30, 2024, with a median follow-up of 29.0 months (95% CI, 20.5–37.6), the median PFS of the ICI and non-ICI cohort were 4.6 months (95% CI, 3.9–5.3) and 3.8 months (95% CI, 3.3–4.3); median OS were 12.1 months (95% CI, 9.8–14.4) and 12.6 months (95% CI, 10.5–14.7), respectively (Fig. 4A-B). Compared with non-ICI therapy, ICI-based treatment reduced the risk of disease progression by 25% (HR = 0.75; 95% CI, 0.57–0.98; P = 0.038) with an improved PFS of 0.8 months. After PSM, 72 pairs of patients were matched (Table S1, Fig. S1). Significantly improved PFS (5.0 vs 3.6 months; HR = 0.55; 95% CI, 0.39–0.78; P < 0.001) was exhibited in the ICI cohort; the median OS (13.8 vs 12.4 months) also displayed a directional improvement (HR = 0.70; 95% CI, 0.47–1.05; P = 0.086) (Fig. 4C-D). Besides, we observed a directional prolongation in median OS (21.1 vs 12.1 months) in 36 patients who received ICI cross-line therapy at fourth-line and/or above (≥ 4L) settings compared to 23 patients who discontinued ICI therapy at 3L setting, but the difference was not statistically significant (HR = 0.61; 95% CI, 0.32–1.16; P = 0.134) (Fig. 5). Further observation of 56 patients in the non-ICI cohort who started ICI treatment at ≥ 4L showed that the median OS was up to 16.1 months (Fig. 5).
Fig. 4.
Kaplan–Meier curves of PFS and OS. A-B Progression-free survival and overall survival of patients in each cohort before PSM. C-D Progression-free survival and overall survival of patients in each cohort after PSM. CI, confidence interval; HR, hazard ratio; ICI, immune checkpoint inhibitor; OS, overall survival; PFS, progression-free survival; PSM, propensity score matching
Fig. 5.
Comparison of OS in patients with available ≥ 4L treatment data. 3L, third-line; ≥ 4L, fourth-line and/or above; CI, confidence interval; ICI, immune checkpoint inhibitor; OS, overall survival; HR, hazard ratio
The survival curves for specific treatment regimens are presented in Fig. 6 and Table S2. The ICI plus chemotherapy and mAb/TKI showed the longest median PFS of 8.2 months, while the other combinations of ICI plus chemotherapy or ICI plus mAb/TKI or non-ICI regimens of chemotherapy plus mAb/TKI or mAb/TKI alone developed the median PFS of only 3.4–4.4 months (Fig. 6A). Besides, the combination of ICI, chemotherapy and mAb/TKI showed statistically significant improvement in PFS compared with the ICI plus mAb/TKI (P = 0.016), the chemotherapy plus mAb/TKI (P = 0.010), and the mAb/TKI alone regimens (P = 0.002). In terms of OS, the triplet regimen of ICI combined with chemotherapy and mAb/TKI also demonstrated significant survival improvement, especially when compared with the ICI plus mAb/TKI regimen (P = 0.009) and the mAb/TKI alone regimen (P = 0.011) (Fig. 6B).
Fig. 6.
Kaplan–Meier curves of different third-line treatment regimens. A Progression-free survival. B Overall survival. CI, confidence interval; CT, chemotherapy; ICI, immune checkpoint inhibitor; mAb, monoclonal antibody; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase inhibitor; HR, hazard ratio
Prognostic factors for PFS and OS
Univariate and multivariate analyses indicated that ≥ 2 metastatic organs (HR = 2.67; 95% CI, 1.39–5.12; P = 0.003), BRAF mutation (HR = 10.21; 95% CI, 3.26–32.02; P < 0.001), and a history of previous immunotherapy (HR = 2.07; 95% CI, 1.01–4.24; P = 0.047) were independent risk factors for PFS, while the ECOG PS, number of metastatic organs, BRAF mutation and prior surgery history were independent prognostic factors for OS in ICI-cohort (Table 3). The prognostic factors of the non-ICI cohort were shown in Table S3. Liver metastasis and prior VEGF(R)i therapy were two independent risk factors for PFS and OS in this cohort. An ECOG PS score of 0–1 and a history of previous surgery or radiotherapy were independent protective factors for PFS in this cohort of patients.
Table 3.
Univariate and multivariate analyses of prognostic factors for PFS and OS in ICI cohort
| Variables | PFS | OS | ||||||
|---|---|---|---|---|---|---|---|---|
| Univariate analysis | Multivariate analysis | Univariate analysis | Multivariate analysis | |||||
| HR (95% CI) | P | HR (95% CI) | P | HR (95% CI) | P | HR (95% CI) | P | |
| Age (>/≤ 60 years) | 0.75 (0.48 ~ 1.18) | 0.217 | 1.11 (0.66 ~ 1.88) | 0.696 | ||||
| Sex (male/female) | 0.53 (0.33 ~ 0.83) | 0.006 | 0.49 (0.27 ~ 0.89) | 0.020 | 0.93 (0.55 ~ 1.58) | 0.799 | ||
| ECOG PS (0–1/2) | 0.67 (0.31 ~ 1.47) | 0.320 | 0.54 (0.23 ~ 1.27) | 0.157 | 0.26 (0.09 ~ 0.72) | 0.010 | ||
| Primary site (left/right) | 0.75 (0.46 ~ 1.25) | 0.275 | 0.55 (0.30 ~ 0.98) | 0.041 | ||||
| Metastatic organs (≥ 2/1) | 2.56 (1.50 ~ 4.36) | < 0.001 | 2.67 (1.39 ~ 5.12) | 0.003 | 2.79 (1.45 ~ 5.38) | 0.002 | 2.89 (1.34 ~ 6.25) | 0.007 |
| Liver metastasis (yes/no) | 1.76 (1.09 ~ 2.84) | 0.020 | 1.67 (0.99 ~ 2.82) | 0.055 | 1.68 (0.98 ~ 2.88) | 0.060 | ||
| Lung metastasis (yes/no) | 1.26 (0.82 ~ 1.95) | 0.293 | 0.82 (0.49 ~ 1.35) | 0.436 | ||||
| RAS status (MT/WT) | 1.38 (0.83 ~ 2.28) | 0.212 | 1.74 (0.90 ~ 3.36) | 0.100 | 1.32 (0.74 ~ 2.36) | 0.341 | 2.10 (0.94 ~ 4.69) | 0.069 |
| BRAF status (MT/WT) | 4.19 (1.59 ~ 11.04) | 0.004 | 10.21 (3.26 ~ 32.02) | < 0.001 | 8.08 (2.94 ~ 22.10) | < 0.001 | 13.55 (4.39 ~ 41.76) | < 0.001 |
| Prior surgery (yes/no) | 0.63 (0.36 ~ 1.09) | 0.096 | 0.53 (0.28 ~ 1.03) | 0.061 | 0.42 (0.23 ~ 0.77) | 0.005 | 0.44 (0.21 ~ 0.91) | 0.027 |
| Prior RT (yes/no) | 0.86 (0.56 ~ 1.33) | 0.504 | 0.69 (0.42 ~ 1.16) | 0.161 | ||||
| Prior IO (yes/no) | 1.10 (0.64 ~ 1.88) | 0.738 | 2.07 (1.01 ~ 4.24) | 0.047 | 0.58 (0.27 ~ 1.22) | 0.148 | ||
| Prior EGFRi (yes/no) | 0.94 (0.51 ~ 1.75) | 0.850 | 2.05 (0.92 ~ 4.58) | 0.078 | 1.08 (0.55 ~ 2.14) | 0.821 | 2.30 (0.93 ~ 5.69) | 0.071 |
| Prior VEGF(R)i (yes/no) | 1.56 (0.80 ~ 3.04) | 0.186 | 1.61 (0.76 ~ 3.40) | 0.213 | ||||
CI confidence interval, ECOG PS Eastern Cooperative Oncology Group performance status, EGFRi epidermal growth factor receptor inhibitor, HR hazard ratio, ICI immune checkpoint inhibitor, IO immunotherapy, MT mutated type, OS overall survival, PFS progression-free survival, RT radiotherapy, VEGF(R)i vascular endothelial growth factor (receptor) inhibitor, WT wild type
The bold font represents statistical significance at P < 0.05
Subgroup analysis
Variable selection was performed using the backward stepwise regression method. The forest plot of subgroup analysis adjusted for covariates including ECOG PS, metastatic organs, liver metastasis, BRAF status, prior surgery and prior VEGF(R)i therapy showed that most subgroups exhibited a treatment effect for PFS, favoring ICI-based treatment, including patients were > 60 years old (HR = 0.45; 95% CI, 0.28–0.74; P = 0.002), male (HR = 0.54; 95% CI, 0.38–0.78; P < 0.001), had primary tumor at left-side colon and rectum (HR = 0.67; 95% CI, 0.48–0.93; P = 0.016), one metastatic organ (HR = 0.47; 95% CI, 0.26–0.86; P = 0.013), liver metastasis (HR = 0.67; 95% CI, 0.47–0.95; P = 0.025), RAS wild type (HR = 0.52, 95% CI, 0.31–0.88; P = 0.014), BRAF wild type (HR = 0.62, 95% CI, 0.44–0.89; P = 0.009), without previous surgery (HR = 0.25, 95% CI, 0.11–0.58; P = 0.001), radiotherapy (HR = 0.58, 95% CI, 0.39–0.86; P = 0.007) or immunotherapy (HR = 0.69, 95% CI, 0.51–0.95; P = 0.024), and with a history of prior CT (HR = 0.71; 95% CI, 0.54–0.95; P = 0.019), and prior VEGF(R)i (HR = 0.71; 95% CI, 0.52–0.97; P = 0.033) (Fig. 7). As for the subgroup of OS benefits, no significant differences were founded in most subgroups of age, sex, ECOG PS, primary tumor site, visceral metastasis, RAS mutation status and previous treatment history (Fig. S2).
Fig. 7.
Subgroup analysis of progression-free survival. CI, confidence interval; CT, chemotherapy; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFRi, vascular endothelial growth factor receptor inhibitor; HR, hazard ratio; ICI, immune checkpoint inhibitor; IO, immunotherapy; MT, mutated type; NA, not applicable; RT, radiotherapy; VEGF(R)i, vascular endothelial growth factor (receptor) inhibitor; WT, wild type
Safety
Most patients (97.1%) experienced at least one TRAE (Table 4). No unexpected safety concerns were reported, and no treatment-related deaths occurred. In the ICI cohort, the most common TRAEs (all grades) leading to dose reduction and/or treatment interruption were leukopenia (50.5%), thrombocytopenia (46.2%), hand-foot skin reaction (35.5%), anemia (31.2%), thyroid dysfunction (29.0%), and electrolyte disturbance (29.0%). Grade ≥ 3 TRAEs were reported in 37 (39.8%) patients in ICI cohort, mainly including thrombocytopenia (12.9%), leukopenia (7.5%) and neutropenia (5.4%). For patients administrated with non-ICI therapy, TRAEs of any grade occurred in 98.0% (147/150), while grade ≥ 3 TRAEs occurred in 43.3% (65/150) of patients. The most frequently reported grade ≥ 3 TRAE was thrombocytopenia (14.0%). Other TRAEs occurring in more than 5% of patients were leukopenia (12.7%), neutropenia (11.3%), diarrhea (6.0%), and anemia (5.3%).
Table 4.
Safety
| AE, No. (%) | ICI cohort (n = 93) | Non-ICI cohort (n = 150) | ||
|---|---|---|---|---|
| Any | Grade ≥ 3 | Any | Grade ≥ 3 | |
| All AEs | 89 (95.7) | 37 (39.8) | 147 (98.0) | 65 (43.3) |
| irAEs | 36 (38.7) | 13 (14.0) | NA | NA |
| Leukopenia | 47 (50.5) | 7 (7.5) | 74 (49.3) | 19 (12.7) |
| Neutropenia | 25 (26.9) | 5 (5.4) | 51 (34.0) | 17 (11.3) |
| Anemia | 29 (31.2) | 3 (3.2) | 48 (32.0) | 8 (5.3) |
| Thrombocytopenia | 43 (46.2) | 12 (12.9) | 66 (44.0) | 21 (14.0) |
| Nausea and/or vomiting | 15 (16.1) | 0 | 38 (25.3) | 2 (1.3) |
| Diarrhea | 10 (10.8) | 3 (3.2) | 31 (20.7) | 9 (6.0) |
| Electrolyte disturbance | 27 (29.0) | 3 (3.2) | 44 (29.3) | 7 (4.7) |
| Abnormal liver test results | 19 (20.4) | 4 (4.3) | 33 (22.0) | 7 (4.7) |
| Ileus | 9 (9.7) | 2 (2.2) | 10 (6.7) | 3 (2.0) |
| Thromboembolic event | 4 (4.3) | 1 (1.1) | 11 (7.3) | 2 (1.3) |
| Infusion-related reaction | 3 (3.2) | 0 | 6 (4.0) | 1 (0.7) |
| Neurotoxicity | 11 (11.8) | 0 | 18 (12.0) | 0 |
| Proteinuria | 21 (22.6) | 4 (4.3) | 30 (20.0) | 7 (4.7) |
| Fecal occult blood | 10 (10.8) | 1 (1.1) | 23 (15.3) | 5 (3.3) |
| Hypoalbuminemia | 14 (15.1) | 0 | 27 (18.0) | 0 |
| Hypertension | 23 (24.7) | 3 (3.2) | 32 (21.3) | 6 (4.0) |
| Hyperglycemia | 10 (10.8) | 3 (3.2) | 5 (3.3) | 1 (0.7) |
| Mucositis | 11 (11.8) | 2 (2.2) | 19 (12.7) | 2 (1.3) |
| Hoarseness | 19 (20.4) | 0 | 24 (16.0) | 0 |
| Hand-foot skin reaction | 33 (35.5) | 3 (3.2) | 42 (28.0) | 3 (2.0) |
| Rash | 25 (26.9) | 4 (4.3) | 29 (19.3) | 3 (2.0) |
| Myasthenia gravis | 2 (2.2) | 0 | 0 | 0 |
| Immune myositis | 3 (3.2) | 0 | 0 | 0 |
| Abnormal cardiac function | 8 (8.6) | 2 (2.2) | 17 (11.3) | 4 (2.7) |
| Abnormal thyroid function | 27 (29.0) | 3 (3.2) | 37 (24.7) | 2 (1.3) |
| Pneumonitis | 13 (14.0) | 3 (3.2) | 20 (13.3) | 4 (2.7) |
AE(s) adverse event(s), irAE(s) immune-related adverse event(s), NA not applicable
The incidence of irAEs of any grade in the ICI cohort was 38.7%. Most of irAEs were graded 1–2. The incidence of grade ≥ 3 irAEs was 14.0%, mainly including rash, abnormal liver function, hypothyroidism, and hyperglycemia. Moreover, 1 (1.1%) patients developed immune myocarditis, and 2 (2.2%) developed immune pneumonia. All irAEs were manageable after appropriate symptomatic therapy and/or hormonal intervention. The safety profile of two cohorts of patients were comparable. Specific TRAEs by cohort are shown in Table 4.
Discussion
The exploration of high-effect and low-toxicity 3L treatment options for MSS mCRC patients is urgent, and ICI-based combination may be one of the potential strategies. After comprehensive investigation and evaluation of the real-world clinical practice in China, we designed the cohort study to explore the outcomes of 3L treatment with or without ICI for MSS mCRC patients. After screened 243 MSS mCRC patients who visited our cancer center over the past 5 years, we described patient characteristics, treatment regimens, and clinical outcomes in detail, which we hope to provide more real and valuable clinical evidence for the 3L treatment in MSS mCRC patients.
Our preliminary results showed no statistical difference in OS between 3L ICI- and non-ICI-based treatment (12.1 vs 12.6 months, P = 0.727), while the PFS in ICI cohort achieved 4.6 months, significantly superior to the 3.8 months in non-ICI cohort (HR = 0.75; 95% CI, 0.57–0.98; P = 0.038). After PSM, the advantage of ICI-based treatment in PFS was more significant (HR = 0.55; 95% CI, 0.39–0.78; P < 0.001), and the OS also exhibited a directional improvement (HR = 0.70; 95% CI, 0.47–1.05; P = 0.086).
As for the specific combinations, ICI combined with TKI ranks first among various regimens in the ICI cohort. A series of clinical trials of ICI combined with TKI as 3L or above treatment for MSS mCRC have been actively explored with mix outcomes [14–19]. Nivolumab combined with regorafenib showed an ORR of 33% and median PFS of 7.9 month [14]. Pembrolizumab plus lenvatinib provided an ORR of 22% and median PFS of 2.3 months [20]. Durvalumab in combination with cabozantinib reported an ORR of 27.6% and median PFS of 4.4 months [21]. Regorafenib plus sintilimab reported an ORR of 21.4%, median OS of 14.1 months and PFS of 4.1 months [22]. Tislelizumab combined with fruquintinib revealed an ORR of 20% ~ 26% and PFS of 8.5 ~ 9.6 months [17, 18]. Consistent with these previous reports, ICI combined with TKI or mAb in our study showed a median PFS of 4.4 months and OS of 10.8 months. Mettu’s study suggested that patients with MSS/pMMR tumors benefited more from dual inhibition of the vascular endothelial growth factor and PD-1/PD-L1pathways [23]. The synergistic anti-tumor mechanisms of this combination may be as follows: anti-VEGF mAb or TKI, as an anti-angiogenic agent, normalize the vascular system and promote tumor oxygenation, chemokine release and effector T cells infiltration [24]. Meanwhile, ICI-induced immune reprogramming positively regulate anti-angiogenic agent-mediated vascular normalization in TME, ultimately transform the ‘cold tumor’ into ‘hot tumor’, and jointly promote immune-mediated tumor clearance [25]. Besides, a more significant survival benefit was found in the triplet regimen of ICI, chemotherapy and mAb/TKI, with a median PFS of 8.2 months and OS of 20.2 months. Survival benefits of the triplet regimen were also demonstrated in Xu's study, where the combination of tislelizumab, cetuximab, and irinotecan in previously treated MSS and RAS wild-type mCRC revealed an ORR of 33%, median PFS of 7.3 months and OS of 17.4 months [26].
In non-ICI cohort, CT is still the core component of treatment. However, the median OS reported for rechallenging CT at ≥ 3L setting was only about 6–8 months, and the dropout rate for subsequent therapy exceeded half of patients [27, 28]. In this study, less than 10% of patients received CT alone. In terms of CT-based combinations, mAbs row the first, and TKIs are also common alternative options. Specifically, the proportion of patients received TKIs was 29.1% (32/110) of all CT patients and as high as 92.5% (37/40) of those who treated without CT. Overall, TKIs were indeed widely used in the 3L treatment of the whole cohort.
In addition, we specially tracked the ≥ 4L treatment of all patients with disease progression. In the ICI cohort, 84 patients had disease progression and 59 had available data on their later-line therapy, among which 36 (61.0%) continued to receive ICI-based treatment. Survival analysis showed that this group of patients had a directional improvement in OS (HR = 0.61; 95% CI, 0.32–1.16) compared with those without ICI cross-line therapy. This real-world result may provide some records for ICI rechallenge in those heavily pretreated MSS mCRC patients. However, selection bias should be taken into account, and these findings should not be interpreted as support for routine use of ICI re-challenge therapy without further evidence. Among the 150 patients in the non-ICI cohort, 143 had disease progression, and the later-line treatment information was available for 99 patients, among which 56 were treated with ICI-based treatment and obtained a median OS of 16.1 months. This result seems to suggest that ICI-based therapy is still feasible and effective in ≥ 4L settings. Further clinical studies are needed to clarify the effects of later-line and crossline treatment of ICI.
CRC patients with RAS/BRAF mutation are historically characterized by high aggressiveness and inferior survival outcomes [29, 30]. This study demonstrated similar results. BRAF mutation (HR = 13.55; 95% CI, 4.39–41.76; P < 0.001) was an independent risk factor for OS in the ICI cohort. Unlike RAS/BRAF mutations, patients with RAS and/or BRAF wild type appear to be a favorable population for 3L ICI-based treatment. But, it is worth noting that the impact of RAS/BRAF mutations on the therapeutic effect of ICI remains to be further studied. Beyond that, patients with older age, male, left-side colon and rectum, liver metastasis without previous history of surgery, radiotherapy or immunotherapy seemed to be able to obtain a PFS benefit from the 3L ICI-based therapy. Biomarker-defined subpopulation (e.g., POLE/POLD1, TMB, PD-L1, immune infiltration) is a direction worthy of further exploration. And a prospective randomized study designed with pre-specified subgroup analysis, serial biopsies longitudinal immune profiling, and multi-omics molecular analyses is needed for further elucidation.
Safety profiles in both treatment cohorts were similar to the known data of ICI, CT, RT, mAbs and TKIs, and no new safety signals were observed [6, 7, 11, 15, 17, 23, 31]. The incidence of the TRAEs in ICI cohort was slightly lower than that in non-ICI cohort, especially the hematological toxicity of grade ≥ 3 and gastrointestinal reactions. This might be related to the wide difference in the proportion of patients receiving systemic CT in ICI cohort (36/93, 38.7%) and non-ICI cohort (11/150, 73.3%). As part of the combined regimens, ICI did add some additional toxicity associated with immunotherapy, such as immune-related skin reactions, immune pneumonia, immune myocarditis, thyroid dysfunction, and hyperglycemia, etc. But the grade ≥ 3 irAEs in the ICI cohort were similar or even lower than those reported outcomes in several clinical trials, such as interstitial pneumonia. Overall, these irAEs were well-controlled with symptomatic therapies and/or ICI treatment discontinuations with or without subsequent dose reduction. As a retrospective study, there may be considerable bias in the results due to incomplete documentation of AEs, which is one of the common shortcomings of such studies.
The study has several other limitations. First, as an observational study, some selection bias could hardly be evitable. Secondly, recall bias might exist in any retrospective study. Thirdly, limited sample size and insufficient data collection (for instance, nearly 25% of patients have missing data in genetic tests) reduced the statistical power. Fourth, real-world results may be affected by a variety of confounding factors, such as patient comorbidities. Last but not least, due to the highly heterogeneous treatment regimens, the observed outcomes should be interpreted as reflecting the effectiveness of a treatment strategy rather than of any single combination. In brief, the findings of the study need to be interpreted with caution. However, despite these limitations, the present results provide valuable information for ICI-based combinations in MSS mCRC patients at 3L setting, especially that the triplet regimen of ICI, chemotherapy and mAb/TKI may be an option for future prospective trials or off-label use with exhausted standard alternatives and informed consent.
Conclusion
In summary, 3L ICI-based treatment strategy, especially ICI combined with chemotherapy and mAb/TKI, yielded improved outcomes than some non-ICI-based strategies in MSS mCRC, with a manageable safety profile. Further prospective study is warranted to validate these findings.
Supplementary Information
Acknowledgements
The authors thank the patients and their families for participating in this study.
Abbreviations
- CI
Confidence interval
- DCR
Disease control rate
- ECOG PS
Eastern Cooperative Oncology Group performance status
- HR
Hazard ratio
- ICI
Immune checkpoint inhibitor
- IO
Immunotherapy
- irAE
Immune-related adverse event
- mAb
Monoclonal antibody
- mCRC
Metastatic colorectal cancer
- MSI
Microsatellite instability
- MSS
Microsatellite stable
- ORR
Objective response rate
- OS
Overall survival
- PFS
Progression-free survival
- PSM
Propensity score matching
- RECIST
Response Evaluation Criteria in Solid Tumors
- TKI
Tyrosine kinase inhibitor
- TME
Tumor microenvironment
- TRAEs
Treatment-related adverse events
Authors’ contributions
W.S.Z designed the study, review & editing the manuscript; Q.S.Z, K.Z, J.S and W.S.Z collected the patient data and drafted the manuscript; All authors read and approved the final manuscript.
Funding
This work was funded by National Natural Science Foundation of China (No. 82102954).
Data availability
The data that support the findings of this study are available on request from the corresponding author.
Declarations
Ethics approval and consent to participate
This study was approved by the ethics committee of Renmin Hospital of Wuhan University (No. 2023 K-K067) in accordance with the Declaration of Helsinki. All patients voluntarily participated and provided written informed consent.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Qinshuo Zhao, Ke Zhao and Jian Song contributed equally to this work.
References
- 1.Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49. [DOI] [PubMed] [Google Scholar]
- 2.Wang S, Zheng R, Li J, Zeng H, Li L, Chen R, et al. Global, regional, and national lifetime risks of developing and dying from gastrointestinal cancers in 185 countries: a population-based systematic analysis of GLOBOCAN. Lancet Gastroenterol Hepatol. 2024;9(3):229–37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70(3):145–64. [DOI] [PubMed] [Google Scholar]
- 4.Bekaii-Saab T, Kim R, Kim TW, O’Connor JM, Strickler JH, Malka D, et al. Third- or later-line therapy for metastatic colorectal cancer: reviewing best practice. Clin Colorectal Cancer. 2019;18(1):e117–29. [DOI] [PubMed] [Google Scholar]
- 5.Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015;16(6):619–29. [DOI] [PubMed] [Google Scholar]
- 6.Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303–12. [DOI] [PubMed] [Google Scholar]
- 7.Li J, Qin S, Xu RH, Shen L, Xu J, Bai Y, et al. Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial. JAMA. 2018;319(24):2486–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Dasari A, Lonardi S, Garcia-Carbonero R, Elez E, Yoshino T, Sobrero A, et al. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Lancet. 2023;402(10395):41–53. [DOI] [PubMed] [Google Scholar]
- 9.Xu J, Kim TW, Shen L, Sriuranpong V, Pan H, Xu R, et al. Results of a randomized, double-blind, placebo-controlled, phase III trial of trifluridine/tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: the TERRA study. J Clin Oncol. 2018;36(4):350–8. [DOI] [PubMed] [Google Scholar]
- 10.Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909–19. [DOI] [PubMed] [Google Scholar]
- 11.Pfeiffer P, Yilmaz M, Moller S, Zitnjak D, Krogh M, Petersen LN, et al. TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Lancet Oncol. 2020;21(3):412–20. [DOI] [PubMed] [Google Scholar]
- 12.Prager GW, Taieb J, Fakih M, Ciardiello F, Van Cutsem E, Elez E, et al. Trifluridine-tipiracil and bevacizumab in refractory metastatic colorectal cancer. N Engl J Med. 2023;388(18):1657–67. [DOI] [PubMed] [Google Scholar]
- 13.Gryfe R, Kim H, Hsieh ET, Aronson MD, Holowaty EJ, Bull SB, et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med. 2000;342(2):69–77. [DOI] [PubMed] [Google Scholar]
- 14.Fukuoka S, Hara H, Takahashi N, Kojima T, Kawazoe A, Asayama M, et al. Regorafenib plus nivolumab in patients with advanced gastric or colorectal cancer: an open-label, dose-escalation, and dose-expansion phase Ib trial (REGONIVO, EPOC1603). J Clin Oncol. 2020;38(18):2053–61. [DOI] [PubMed] [Google Scholar]
- 15.Cousin S, Cantarel C, Guegan JP, Gomez-Roca C, Metges JP, Adenis A, et al. Regorafenib-avelumab combination in patients with microsatellite stable colorectal cancer (REGOMUNE): a single-arm, open-label, phase II trial. Clin Cancer Res. 2021;27(8):2139–47. [DOI] [PubMed] [Google Scholar]
- 16.Gou M, Yan H, Wang Z, Si H, Chen S, Pan Y, et al. Fruquintinib combination with sintilimab in refractory metastatic colorectal cancer patients in China. J Clin Oncol. 2020;38(15_suppl):4028–4028. [Google Scholar]
- 17.Yuan X, Zhang M, Hou H. Fruquintinib combined with tislelizumab and SBRT as a later-line therapy in microsatellite stability (MSS) metastatic colorectal cancer (mCRC): results from the FRUIT trial. J Clin Oncol. 2023;41(4_suppl):150–150. [Google Scholar]
- 18.Zhao W, Lei J, Ke S, Chen Y, Xiao J, Tang Z, et al. Fecal microbiota transplantation plus tislelizumab and fruquintinib in refractory microsatellite stable metastatic colorectal cancer: an open-label, single-arm, phase II trial (RENMIN-215). EClinicalMedicine. 2023;66:102315. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Wang F, Jin Y, Wang M, Luo HY, Fang WJ, Wang YN, et al. Combined anti-PD-1, HDAC inhibitor and anti-VEGF for MSS/pMMR colorectal cancer: a randomized phase 2 trial. Nat Med. 2024;30(4):1035–43. [DOI] [PubMed] [Google Scholar]
- 20.Gomez-Roca C, Yanez E, Im S-A, Alvarez EC, Senellart H, Doherty M, et al. LEAP-005: A phase II multicohort study of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors—Results from the colorectal cancer cohort. J Clin Oncol. 2021;39(3_suppl):94–94. [Google Scholar]
- 21.Saeed A, Park R, Dai J, Al-Rajabi RMDT, Kasi A, Saeed A, et al. Phase II trial of cabozantinib (Cabo) plus durvalumab (Durva) in chemotherapy refractory patients with advanced mismatch repair proficient/microsatellite stable (pMMR/MSS) colorectal cancer (CRC): CAMILLA CRC cohort results. J Clin Oncol. 2022;40(4_suppl):135–135. [Google Scholar]
- 22.Liu R, Ji Z, Wang X, Zhu L, Xin J, Ma L, et al. Regorafenib plus sintilimab as a salvage treatment for microsatellite stable metastatic colorectal cancer: a single-arm, open-label, phase II clinical trial. Nat Commun. 2025;16(1):1481. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Mettu NB, Ou FS, Zemla TJ, Halfdanarson TR, Lenz HJ, Breakstone RA, et al. Assessment of capecitabine and bevacizumab with or without atezolizumab for the treatment of refractory metastatic colorectal cancer: a randomized clinical trial. JAMA Netw Open. 2022;5(2):e2149040. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Huang Y, Goel S, Duda DG, Fukumura D, Jain RK. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res. 2013;73(10):2943–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Khan KA, Kerbel RS. Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat Rev Clin Oncol. 2018;15(5):310–24. [DOI] [PubMed] [Google Scholar]
- 26.Xu X, Ai L, Hu K, Liang L, Lv M, Wang Y, et al. Tislelizumab plus cetuximab and irinotecan in refractory microsatellite stable and RAS wild-type metastatic colorectal cancer: a single-arm phase 2 study. Nat Commun. 2024;15(1):7255. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Suenaga M, Mizunuma N, Matsusaka S, Shinozaki E, Ozaka M, Ogura M, et al. Phase II study of reintroduction of oxaliplatin for advanced colorectal cancer in patients previously treated with oxaliplatin and irinotecan: RE-OPEN study. Drug Des Devel Ther. 2015;9:3099–108. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Yang Q, Huang Y, Jiang Z, Wang H, Li W, Zhang B, et al. Rechallenge of oxaliplatin-containing regimens in the third- or later-line therapy for patients with heavily treated metastatic colorectal cancer. Onco Targets Ther. 2018;11:2467–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Modest DP, Ricard I, Heinemann V, Hegewisch-Becker S, Schmiegel W, Porschen R, et al. Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group. Ann Oncol. 2016;27(9):1746–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Tran B, Kopetz S, Tie J, Gibbs P, Jiang ZQ, Lieu CH, et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer. 2011;117(20):4623–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Duan J, Zhu L, Shi Y, Wang W, Wang T, Ning T, et al. Chemotherapy re-use versus anti-angiogenic monotherapy as the third-line treatment of patients with metastatic colorectal cancer: a real-world cohort study. BMC Cancer. 2024;24(1):302. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author.