# 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

## TL;DR

This study evaluates whether PD-1/PD-L1 inhibitors benefit patients with low PD-L1 expression in advanced solid tumors, finding mixed results across cancer types.

## Contribution

This is the first meta-analysis to assess clinical benefits of ICIs in low PD-L1-expressing cancers according to FDA guidelines.

## Key findings

- In ESCC with CPS < 10, ICIs showed significant OS benefit (HR = 0.82, p = 0.02).
- HER2-negative GEA with CPS < 5 showed no OS benefit from ICIs.
- RMST analysis provided intuitive survival time gains for some subgroups.

## 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.

This is the first meta‐analysis to focus on the actual clinical benefit of ICIs as standard first‐line therapy for multiple cancers with low PD‐L1 expression, in accordance with current FDA guidelines. The mirror‐based study design enhances precision and accuracy, while ensuring alignment with clinical practice. To our knowledge, our patient‐level analysis provides first evidence that, contrary to FDA guidelines, there is no clinical benefit from the addition of ICIs to conventional chemotherapy as first‐line treatment for HER2‐negative GEAs with CPS <5. Several rigorous algorithms were seamlessly integrated to enhance precision and statistical efficacy in this study. Two well‐known methods, graphical reconstruction and KMSubtraction, were implemented to ensure that individual data more closely approximated the raw data. Additionally, RMST was incorporated as a robust, nonparametric complement to the log‐rank‐based hazard ratio; this metric can be intuitively interpreted as an absolute gain (or loss) of survival time.