Adding programmed death 1/programmed death ligand 1 inhibitors to first-line standard-of-care therapy for metastatic colorectal cancer: A meta-analysis.

Background: In recent years, emerging clinical research has prioritized assessment of combined therapeutic efficacy and safety parameters when programmed death 1 or its ligand (PD-1/L1) inhibitors are incorporated into first-line standard-of-care (SOC) therapy for metastatic colorectal cancer (mCRC). However, data obtained from these trials demonstrated conflicting evidence concerning survival benefits and clinical outcomes.

Aim: To evaluate the therapeutic impact and safety parameters of combining PD-1/L1 inhibitors with SOC protocols as first-line treatment for mCRC.

Methods: Four biomedical databases (PubMed, Embase, Cochrane Library, Web of Science) were systematically interrogated to identify eligible studies published up to October 12, 2024. The analysis focused on evaluating the primary outcome of overall survival (OS) in the mCRC population with secondary outcomes of progression-free survival (PFS), overall response rate (ORR), and incidence rate of grade ≥ 3 adverse events. Additionally, we performed exploratory analyses in the microsatellite stable/mismatch repair-proficient (MSS/pMMR) subpopulation, based on a subset of the included studies. Subgroup analyses according to PD-1/L1 inhibitor use were conducted in both the overall population and the MSS/pMMR subgroup.

Results: This pooled analysis incorporated six randomized controlled trials involving 675 patients with mCRC receiving first-line therapy. The combination of PD-1/L1 inhibitors with SOC regimens demonstrated a significant PFS advantage over SOC monotherapy in intention-to-treat populations [hazard ratio (HR) = 0.8, 95% confidence interval (CI): 0.65-0.98, P = 0.033]. Nevertheless, the MSS/pMMR subgroup showed no PFS benefit (HR = 0.83, 95%CI: 0.67-1.03, P = 0.091), and no cohort exhibited OS improvement (intention-to-treat: HR = 0.84, 95%CI: 0.66-1.05, P = 0.124; MSS/pMMR: HR = 0.79, 95%CI: 0.60-1.03, P = 0.083). Comparable outcomes were observed for ORR (risk ratio = 1.03, 95%CI: 0.90-1.17, P = 0.711) and incidence rate of grade ≥ 3 adverse events (risk ratio = 1.12, 95%CI: 0.93-1.36, P = 0.245) between treatment arms.

Conclusion: The findings indicated that integrating PD-1/L1 blocking agents with SOC regimens for mCRC as first-line treatment failed to demonstrate significant improvements in ORR. Existing clinical data remain inadequate to establish OS advantages, particularly in patients with MSS/pMMR, despite exhibiting manageable toxicity profiles. Subsequent confirmation through rigorously designed phase III clinical trials remains essential to verify these therapeutic outcomes.