Chemotherapy plus bevacizumab with or without anti-programmed death 1 immunotherapy as the second-line therapy in colorectal cancer

Abstract

Background: Patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) typically exhibit an immunosuppressive tumor microenvironment and demonstrate a low response rate to immunotherapy. Reports suggest that chemotherapy and anti-angiogenic therapy may have the potential to enhance the response to immunotherapy in these patients. This study aims to evaluate the effectiveness and safety of chemotherapy combined with bevacizumab with or without anti-programmed death 1 (PD-1) immunotherapy as the second-line regimen for MSS mCRC.

Aim: To evaluate the effectiveness and safety of chemotherapy combined with bevacizumab with or without anti-PD-1 immunotherapy as the second-line regimen for MSS mCRC.

Methods: A retrospective analysis was conducted on patients with MSS mCRC diagnosed at Peking University First Hospital and Jilin Cancer Hospital from January 2020 to December 2024. The patients were divided into two groups: The experimental group receiving second-line chemotherapy combined with bevacizumab and anti-PD-1 immunotherapy, and the control group receiving chemotherapy combined with bevacizumab. Propensity score matching was applied to balance potential prognostic factors, including age, gender, Eastern Cooperative Oncology Group score, number of metastases, and primary tumor site. The progression-free survival, overall survival, disease control rate, objective response rate, and treatment-related adverse reactions were compared between the two groups. Kaplan-Meier analysis and log-rank test were used to compare survival outcomes. Inverse probability of treatment weighting was used for sensitivity analysis.

Results: Propensity score matching resulted in 103 matched eligible patients. The median follow-up period was 13.9 months in the matched cohort. The objective response rate was 11.5% and 9% for the experimental and control groups, respectively (P = 0.710), while the disease control rate was 76.9% and 53.2%, respectively (P = 0.058). The median progression-free survival in the experimental group was 8.27 months [95% confidence interval (CI): 6.7-14.7 months], significantly higher than that in the control group, which was 4.63 months (95%CI: 3.9-5.67 months) (hazard ratio = 0.4143, 95%CI: 0.2462-0.6972, P = 0.00066). There was a trend towards the higher median overall survival in the experimental group compared to the control group (hazard ratio = 0.4504, 95%CI: 0.1897-1.07, P = 0.064). The incidences of adverse events were similar between the two groups.

Conclusion: Compared with the standard second-line chemotherapy combined with bevacizumab regimen, second-line therapy that combines chemotherapy with bevacizumab and anti-PD-1 immunotherapy has demonstrated promising efficacy in the treatment of MSS mCRC, while exhibiting a similar safety profile.

Keywords: Immune checkpoint inhibitors; Metastatic colorectal cancer; Microsatellite stable; Programmed death 1; RAS mutation.

Figure 1

Flow chart of patient inclusion. MSS: Microsatellite stable; bev: Bevacizumab; pMMR: Proficient mismatch repair; MSI-H: Microsatellite instability-high.

Figure 2

After propensity score-matching analysis of progression-free survival and overall survival. A: After propensity score-matching analysis of PFS (ratio = 4); B: After propensity score-matching analysis of overall survival (ratio = 4).

Figure 3

Kaplan-Meier curve of original cohort. A: In the original cohort (progression-free survival); B: In the original cohort (overall survival).

Figure 4

Sensitivity analysis of progression-free survival. A: After propensity score-matching analysis in progression-free survival (PFS) (ratio = 1); B: After propensity score-matching analysis in PFS (ratio = 2); C: After propensity score-matching analysis in PFS (ratio = 3); D: After inverse probability of treatment weighting analysis; E: Kaplan-Meier curve after excluding 4 patients who received single-agent chemotherapy combined with bevacizumab and anti- programmed death 1 immunotherapy in PFS; F: Kaplan-Meier curve restricting the cohort to irinotecan-based chemotherapy patients in PFS.

Figure 5

Sensitivity analysis of overall survival. A: After propensity score-matching analysis in overall survival (OS) (ratio = 1); B: After propensity score-matching analysis in OS (ratio = 2); C: After propensity score-matching analysis in OS (ratio = 3); D: After inverse probability of treatment weighting analysis (OS); E: Kaplan-Meier curve after excluding 4 patients who received single-agent chemotherapy combined with bevacizumab and anti-programmed death 1 immunotherapy in OS; F: Kaplan-Meier curve restricting the cohort to irinotecan-based chemotherapy patients in OS.

Figure 6

Forest plots depict the hazard ratios and 95% confidence intervals for progression-free survival by subgroup. CI: Confidence interval; ECOG: Eastern Cooperative Oncology Group.

Figure 7

Lactate dehydrogenase as a predictive biomarker of progression-free survival. A: Receiver operating characteristic curves of lactate dehydrogenase (LDH) at 9 months, 12 months, and 15 months before patients receiving chemotherapy combined with bevacizumab and anti-programmed death 1 immunotherapy; B: Survival curves of LDH before patients receiving chemotherapy combined with bevacizumab and anti-programmed death 1 immunotherapy (high group: LDH ≥ 240 mmol/L and low group LDH < 240 mmol/L). ACU: Area under curve.