Investigation of Acquired Resistance Biomarkers to Anti–PD-(L)1 Therapy in Patients with Advanced NSCLC

Although immune checkpoint inhibitors (ICIs) have advanced the treatment of patients with non–small-cell lung cancer (NSCLC), most patients develop resistance to ICIs following an initial response. The mechanisms of resistance remain largely unknown.1

This retrospective study included patients with advanced NSCLC treated with ICIs at the Dana-Farber Cancer Institute and whose tumors underwent genomic analysis before and after treatment. Mutations, tumor mutational burden (TMB), copy number variations, and PD-L1 tumor proportion scores (TPS) were analyzed in pre- and post-ICI samples. Acquired resistance was defined as the development of disease progression after an initial objective response or stable disease ≥3 months with PD-(L)1 blockade.2

A total of 45 patients with advanced NSCLC who received ICI had matched pre- and post-ICI tissue samples available for genomic profiling. Several putative resistance mechanisms were identified in 55% of cases (n = 25), including an acquired STK11 mutation (20%), an acquired KEAP1 mutation (4%), and development of concurrent KEAP1 and SMARCA4 mutations (4%). In addition, 1 (4%) patient with KRAS G12C–mutant NSCLC developed concurrent STK11 and KEAP1 mutations that led to resistance to ICI therapy. In 3 (12%) cases with preexisting STK11 or KEAP1 mutations before ICI administration, acquired copy losses of STK1 and KEAP1, respectively, were identified, resulting in bi-allelic inactivation of these genes. In addition, acquired beta-2-microglobulin (B2M) mutations were detected in 3 (12%) patients, 1 of whom developed concurrent B2M copy loss, indicating bi-allelic inactivation. Eight (32%) additional patients developed B2M gene deletions.2

Other acquired alterations that were implicated in ICI resistance included CDKN2A/B loss (n = 10; 40%), including 5 with bi-allelic deletion, acquired PTEN deletions (n = 5; 20%), and MDM2 amplification (n = 2; 8%).

Furthermore, alterations in immune checkpoint genes were identified, including acquired CD274 (PD-L1) and PDCD1LG2 (PD-L2) loss in 8% of cases (n = 2), and bi-allelic deletion in 1 case (4%). ICI treatment did not affect TMB (median TMB: 8.7 [pre-ICI] vs 9.1 [post-ICI] mut/Mb; P = .6), PD-L1 expression (median PD-L1 TPS: 3% [pre-ICI] vs 5% [post-ICI] mut/Mb; P = .5), or aneuploidy levels (as fraction of the genome altered [FGA]) (median FGA: 18.4% [pre-ICI] vs 21.1% [post-ICI]; P = .2). These findings suggest that acquired gene level copy number variations were not a reflection of increased cancer aneuploidy.2

In a control cohort of 30 patients with pre- and post-chemotherapy matched samples that underwent genomic analysis, no acquired mutations in STK11, KEAP1, SMARCA4, or B2M were detected.2

The investigators concluded that mechanisms of acquired resistance to PD-(L)1 blockade are heterogeneous, and novel therapeutic approaches are required to delay and overcome ICI resistance in patients with NSCLC.


  1. Onoi K, Chihara Y, Uchino J, et al. Immune checkpoint inhibitors for lung cancer treatment: a review. J Clin Med. 2020;9:1362.
  2. Ricciuti B, Alessi JVM, Li YY, et al. Genomic correlates of acquired resistance to PD-(L)1 blockade in patients with advanced non-small cell lung cancer (NSCLC). Presented at: 2022 American Society of Clinical Oncology Annual Meeting; June 3-7, 2022. Chicago, IL. Abstract 9021.

Related Items

Conference Correspondent Coverage is Brought to You by the Publishers of:
Oncology Practice Management
Personalized Medicine in Oncology

Learn more about our family of publications.

View Our Publications