Clinical Benefit of PD‐1/PD‐L1 Inhibitors as Standard First‐Line Treatment in Low PD‐L1‐Expressing Advanced Solid Tumors: A Systematic Review and Meta‐Analysis

ABSTRACT This study aimed to assess the benefits of immune checkpoint inhibitors (ICIs) for patients with low or negative PD‐L1 expression in advanced solid tumors. The study included cancers approved by the FDA for first‐line ICI therapy without PD‐L1 restrictions, incorporating phase III randomized clinical trials (RCTs) comparing immunotherapy with conventional care. Individual patient data of PD‐L1 low subgroup were retrieved from Kaplan–Meier (KM) curves using IPDfromKM and KMSubtraction. Pooled analysis employed KM and restricted mean survival time (RMST) analysis to assess ICI benefit. Totally, 40 RCTs with 27,060 patients were enrolled. No survival benefit for low PD‐L1 expression was observed in some cancers. In esophageal squamous cell carcinoma (ESCC), combined positive score (CPS) < 10 had significant OS benefit (HR = 0.82, p = 0.02; RMST‐D = 2.34 months); tumor proportion score (TPS) < 1% showed no OS improvement (HR = 0.87, p = 0.16, RMST‐D = 1.71 months). Human epidermal growth factor receptor 2 (HER2)‐negative gastroesophageal adenocarcinoma (GEA) had no OS benefit with CPS < 5, 1–4, and < 1, but significant benefits with CPS < 10 (HR = 0.87, p = 0.048; RMST‐D = 1.78 months, p = 0.038) and CPS 1–9 (HR = 0.83, p = 0.0085; RMST‐D = 2.21 months, p = 0.007). Patient‐level data indicate that ESCCs with TPS < 1% and HER2‐negative GEAs with CPS < 5 do not benefit from the addition of ICIs to conventional chemotherapy. More nuanced clinical trials and predictive biomarkers are warranted.