Comparative efficacy of PD-1 versus PD-L1 inhibitors in metastatic colorectal cancer: A real-world propensity score–matched study.

e15599 Background: The treatment of microsatellite instability-high (MSI-H) metastatic colorectal cancers (mCRC) has evolved dramatically in the last decade with the advent of immunotherapy. Despite similar mechanisms, there remains debate regarding the efficacy of PD-L1 vs PD-1 agents in this space. Recent COMMIT results suggest inferior progression-free survival (PFS) with PD-L1 in MSI-H mCRC compared to PD-1 in comparable scenarios (KeyNote-177, CM8HW). Here, we utilize a large national database to demonstrate real-world outcomes for mCRC patients treated with PD-1 vs PD-L1 monotherapy. This highlights a potential difference in the inhibition of the programmed cell death PD-1/PD-L1 axis and contributes to the ongoing debate. Methods: We utilized the TriNetX network, a federated, multicenter, de-identified database. We evaluated adult patients with mCRC who received immunotherapy between 2013 and 2025. Cohorts were defined by first exposure to immune checkpoint inhibitors: anti–PD-1(pembrolizumab/nivolumab) vs anti–PD-L1 (durvalumab/atezolizumab), with a separate comparison vs atezolizumab only. Patients treated with CTLA-4 inhibitors were excluded. Subsequently, propensity score matching was performed for demographics, comorbidities, TNM staging, and dMMR genes. Outcomes were calculated at 3 and 5-year intervals from the index date of initial immunotherapy exposure. Time-to-event outcomes were analyzed using the Kaplan–Meier method, with differences assessed by the log-rank test and Cox proportional hazards. Results: 6235 patients were evaluated for inclusion. After propensity score matching, 1820 patients were included, with 910 patients in each cohort. Over the 5-year follow-up window, Overall survival(OS) favored PD-1 therapy: median OS was 26.4 months in the PD-1 cohort vs 18.3 months in the PD-L1 cohort, HR death = 0.84 (95% CI 0.76 - 0.92, log rank p = 0.003). Landmark survival at 3 years and 5 years also favored PD-1 inhibition over PD-L1 inhibition (41.3 vs 33.9% and 34.2% vs 22.6%, respectively). These findings were confirmed in the secondary analysis with Anti-PD-1 therapy vs Atezolizumab cohort with 547 patients in each cohort. Anti-PD-1 therapy showed improved OS at( HR = 0.73, 95% CI-0.61 - 0.86, log rank P = 0.0002) with 5-year survival probability of 34.5% vs 21.7%, respectively. Conclusions: Treatment with PD-1 monotherapy was associated with improved outcomes compared with PD-L1 monotherapy. Similar differences between PD-1 and PD-L1 blockade have been reported in other tumor types; however, comparative data in mCRC remain limited. In light of recent results from the COMMIT trial, our analysis is timely. One potential explanation is that PD-1 inhibition blocks interactions with both PD-L1 and PD-L2, whereas PD-L1 inhibitors do not disrupt PD-1/PD-L2 signaling. Further prospective studies are needed to confirm and define this difference.