A systematic review in BMC Immunology reported that immune checkpoint inhibitor (ICI)-based combination therapy showed a promising response in patients with proficient mismatch repair (pMMR)/non-microsatellite instability-high (non-MSI-H) metastatic colorectal cancer (mCRC).
Electronic databases were utilized to pool data from 1723 patients with mCRC from 39 cohorts across 35 studies. The primary end points were the pooled objective response rate (ORR) and disease control rate (DCR). The researchers conducted stratified analysis on ICI-based regimens, treatment lines, and RAS mutation status. All studies involved ICIs, either ICI monotherapy, ICIs plus targeted therapy, ICIs plus chemotherapy/radiotherapy, or ICIs plus both targeted therapy and chemotherapy/radiotherapy.
Treatment Response
The pooled ORR was 8.5% (95% CI, 4.4%-13.5%). In first-line regimens, ICIs were associated with an ORR of 74.2% (95% CI, 61.4%-85.4%); in second-line or beyond regimens, the ORR was 6.4% (95% CI, 3.3%-10.4%). The pooled ORR of ICI monotherapy was 2.7% (95% CI, 0.0%-9.4%), and for ICIs plus anti-vascular endothelial growth factor agents (VEGF) and chemotherapy, the ORR was 42.4% (95% CI, 10.0%-78.6%), particularly when used as a first-line therapy. There were no differences in ORRs according to RAS status.
Regarding disease control, the overall pooled DCR was 48.2% (95% CI, 37.8%-58.6%). ICIs in the first-line led to a pooled DCR of 98.7% (95% CI, 92.0%-100%), and in the second-line or beyond regimens, the DCR was 45.1% (95% CI, 34.4%-56.0%). When comparing various regimens, ICIs plus anti-VEGF agent and chemotherapy demonstrated the highest DCR (92.0%; 95% CI, 68.3%-100%), with the greatest effect when used in the first-line. RAS status was not associated with differences in DCRs.
Survival Outcomes
Hazard ratios (HRs) were calculated for overall survival (OS) and progression-free survival (PFS) for ICI-based therapies versus non-ICI-based therapies. Overall, there were no significant differences in survival between ICI-based and non-ICI-based therapies. For OS, the pooled HR was 1.0 (95% CI, 0.9-1.2; P=.51). The 12-month OS rate for ICI-based therapy was 52.3% (95% CI, 46.4%-58.1%), and the regimen of ICIs plus anti-VEGF agent and chemotherapy had the highest 12-month OS rate (71.4%; 95% CI, 50.0%-89.1%).
For PFS, the pooled HR was 1.0 (95% CI, 0.9-1.1; P=.91). Similar to other outcomes, the regimen of ICIs plus anti-VEGF agent plus chemotherapy was associated with a significantly longer PFS (HR, 0.9; 95% CI, 0.8-1.0; P=.02). The pooled 6-month PFS rate was 32.8% (95% CI, 23.5%-42.7%), with the highest rate found with ICI plus anti-VEGF/chemotherapy (55.2%; 95% CI, 24.8%-83.8%).
A total of 21 cohorts were included to calculate the safety of ICI-based therapy in pMMR/non-MSI-H mCRC, and the pooled rate of grade 3 or beyond adverse events (AEs) was 31.8% (95% CI, 20.1%-44.8%). The regimen of ICIs plus anti-VEGF agent and chemotherapy revealed a higher incidence of grade 3 or beyond AEs, but no additional treatment-related adverse events (trAEs) were observed.
Regarding safety, the pooled rate of grade 3 or higher AEs was 31.8%. The regimen of ICIs plus anti-VEGF agent plus chemotherapy was greater than for other regimens, but otherwise there were no additional trAEs.
“The best strategy and biomarkers of ICIs for pMMR/non-MSI-H mCRC remain to be established. On one hand, in order to seek the best strategy of ICI-based therapy for pMMR/non-MSI-H mCRC, we are obliged to optimize which regimen is beneficial in combination with ICIs ([while] maximizing efficacy and minimizing toxicity), facilitate clinical research based on biomarkers, and explore the development of other ICI drugs and cell-based treatment schemes,” the authors concluded.
