Changes in PD-L1 and tumor mutational burden between paired samples and relationship to immune checkpoint inhibitor outcomes in non-small cell lung cancer.
Authors: Di Federico Alessandro , Alden Stephanie Leigh , Smithy James William , Ricciuti Biagio , Alessi Joao Victor Machado , Wang Xinan , Lamberti Giuseppe , Pecci Federica , Gandhi Malini Marion , Spurr Liam Flinn , Awad Mark M. 
Published: June 2023

9127

Background: Programmed cell death receptor ligand 1 (PD-L1) tumor proportion score (TPS) and tumor mutational burden (TMB) are key biomarkers of response to immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC). How often PD-L1 and TMB values change across samples within individual patients (pts) and the impact of this variation on ICI outcomes are limited. Methods: Pts with NSCLC and multiple PD-L1 or TMB assessments at the Dana-Farber Cancer Institute were included. Clinicopathologic and genomic data were analyzed in association with PD-L1 and TMB changes. In patients with > 2 samples, each sample was paired with the subsequent and each pair was analyzed independently. Minor and major changes in PD-L1 were defined as absolute changes of 10-49% and 50-100%, respectively. Results: The PD-L1 cohort included 402 sample pairs (median ΔPD-L1: 0; range: -90,+95%) and the TMB cohort included 413 sample pairs (median ΔTMB: 0 mut/Mb; range: -20.6,+24.5). Concordance between pairs was high for both PD-L1 ( R= 0.53, P < 0.01) and TMB ( R= 0.80, P < 0.01). Samples taken within < 1 year had higher concordance for PD-L1 than samples taken ≥1 year apart (P < 0.01), but length of time between biopsies did not impact TMB concordance. Minor or no changes in PD-L1 were observed in 82.3% of pairs; the frequency of major increases was 9.7% and major decreases was 8%. After dividing TMB into tertiles, 72.6% sample pairs showed no tertile change, 16% increased to a higher tertile, and 11.4% decreased to a lower tertile. PD-L1, but not TMB, decreased with intervening ICI (P = 0.02), but PD-L1 and TMB did not change significantly with other intervening systemic therapies. Acquired copy number losses of the CD274 gene (encoding for PD-L1) were enriched in pairs with a major PD-L1 decrease (Q < 0.05). Similarly, acquired loss of chromosome 9p (which contains the CD274 locus) correlated with a reduction in PD-L1, while 9p gains correlated with an increase in PD-L1 (P = 0.02). A total of 142 pts had multiple PD-L1 scores assessed before ICI initiation. Among pts with at least one PD-L1-positive sample (TPS ≥1%), the presence of another sample that was PD-L1 negative ( < 1%) correlated with worse outcomes to ICI compared to pts with no PD-L1-negative samples: response rate was 11% vs 39% (P < 0.01), median progression-free survival (mPFS) 2.7 vs 8.0 months (P < 0.01), and median overall survival 13.6 vs 21.2 months (P = 0.05), respectively. Among pts with at least one PD-L1 TPS ≥1% and one < 1%, cases where the last PD-L1 TPS before ICI was ≥1% achieved longer mPFS than if the pre-ICI sample was PD-L1 negative (3.6 vs 1.8 months, P = 0.03). Conclusions: Although PD-L1 and TMB generally had high intrapatient concordance across samples, significant changes in values occurred in some patients. Variations in PD-L1 influenced ICI outcomes, warranting an assessment proximal to ICI initiation whenever feasible.