Association of PD-L1 Expression and Other Variables With Benefit From Immune Checkpoint Inhibition in Advanced Gastroesophageal Cancer: Systematic Review and Meta-analysis of 17 Phase 3 Randomized Clinical Trials
Menée à partir d'une revue systématique de la littérature publiée entre 2000 et 2022 (17 essais cliniques de phase III), cette méta-analyse évalue, par rapport à plusieurs biomarqueurs ou facteurs clinico-pathologiques, l'association entre l'expression tumorale de PD-L1 et l'efficacité des inhibiteurs de point de contrôle immunitaire pour traiter un cancer oesogastrique de stade avancé
Importance : Approval by the US Food and Drug Administration of immune checkpoint inhibition (ICI) for advanced gastroesophageal cancer (aGEC) irrespective of PD-L1 status has generated controversy. Exploratory analyses from individual trials indicate a lack of meaningful benefit from ICI in patients with absent or low PD-L1 expression; however, analysis of a single variable while ignoring others may not consider the instability inherent in exploratory analyses.
Objective : To systematically examine the predictive value of tissue-based PD-L1 status compared with that of other variables for ICI benefit in aGEC to assess its stability.
Data Sources : MEDLINE, Embase, Scopus, Web of Science, Cochrane Central Register (2000-2022).
Study Selection : Data Extraction, and Synthesis Randomized clinical trials (RCTs) were included of adults with aGEC (adenocarcinoma [AC] or squamous cell carcinoma [SCC]) randomized to anti
−
PD-1 or PD-L1
−
containing treatment vs standard of care (SOC). Study screening, data abstraction, and bias assessment were completed independently by 2 reviewers. Of 5752 records screened, 26 were assessed for eligibility; 17 trials were included in the analysis.
Main Outcomes and Measures : The prespecified primary end point was overall survival. The mean hazard ratio (HR) for ICI vs SOC was calculated (random-effects model). Predictive values were quantified by calculating the ratio of mean HRs between 2 levels of each variable.
Results : In all, 17 RCTs (9 first line, 8 after first line) at low risk of bias and 14 predictive variables were included, totaling 11 166 participants (5067 with SCC, 6099 with ACC; 77.6% were male and 22.4% were female; 59.5% of patients were younger than 65 years, 40.5% were 65 years or older). Among patients with SCCs, PD-L1 tumor proportion score (TPS) was the strongest predictor of ICI benefit (HR, 0.60 [95% CI, 0.53-0.68] for high TPS; and HR, 0.84 [95% CI, 0.75-0.95] for low TPS), yielding a predictive value of 41.0% favoring high TPS (vs
≤
16.0% for other variables). Among patients with AC, PD-L1 combined positive score (CPS) was the strongest predictor (after microsatellite instability high status) of ICI benefit (HR, 0.73 [95% CI, 0.66-0.81] for high CPS; and HR, 0.95 [95% CI, 0.84-1.07] for low CPS), yielding a predictive value of 29.4% favoring CPS-high (vs
≤
12.9% for other variables). Head-to-head analyses of trials containing both levels of a variable and/or having similar design generally yielded consistent results.
Conclusions and Relevance : Tissue-based PD-L1 expression, more than any variable other than microsatellite instability-high, identified varying degrees of benefit from ICI-containing therapy vs SOC among patients with aGEC in 17 RCTs.
JAMA Oncology , résumé, 2021