Clinicopathologic and Genomic Factors Impacting Efficacy of First-Line Chemoimmunotherapy in Advanced NSCLC

Abstract

Introduction: Although programmed cell death protein 1 and programmed death-ligand 1 (PD-L1) blockade in combination with platinum-doublet chemotherapy has become a mainstay of first-line treatment for advanced NSCLC, factors associated with efficacy of chemoimmunotherapy (CIT) are not well characterized.

Methods: In this multicenter retrospective analysis, clinicopathologic and genomic data were collected from patients with advanced NSCLC (lacking sensitizing genomic alterations in EGFR and ALK) and evaluated with clinical outcomes to first-line CIT.

Results: Among 1285 patients treated with CIT, a worsening performance status and increasing derived neutrophil-to-lymphocyte ratio in the blood were associated with a significantly reduced objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS). With increasing PD-L1 tumor proportion scores of less than 1%, 1% to 49%, 50% to 89%, and greater than or equal to 90%, there was a progressive improvement in ORR (32.7% versus 37.5% versus 51.6% versus 61.7%, p < 0.001), mPFS (5.0 versus 6.1 versus 6.8 versus 13.0 mo, p < 0.001), and generally mOS (12.9 versus 14.6 versus 34.7 versus 23.1 mo, p = 0.009), respectively. Of 789 NSCLCs with comprehensive genomic data, NSCLCs with a tumor mutational burden (TMB) greater than or equal to the 90th percentile had an improved ORR (53.5% versus 36.4%, p = 0.004), mPFS (10.8 versus 5.5 mo, p < 0.001), and mOS (29.2 versus 13.1 mo, p < 0.001), compared with those with a TMB less than the 90th percentile. In all-comers with nonsquamous NSCLC, the presence of an STK11, KEAP1, or SMARCA4 mutation was associated with significantly worse ORR, mPFS, and mOS to CIT (all p < 0.05); this was also observed in the KRAS-mutant subgroup of NSCLCs with co-occurring mutations in STK11, KEAP1, or SMARCA4 (all p < 0.05). In KRAS wild-type NSCLC, KEAP1 and SMARCA4 mutations were associated with a significantly shorter mPFS and mOS to CIT (all p < 0.05), but STK11 mutation status had no significant impact on mPFS (p = 0.16) or mOS (p = 0.38).

Conclusions: In advanced NSCLC, better patient performance status, low derived neutrophil-to-lymphocyte ratio, increasing PD-L1 expression, a very high TMB, and STK11/KEAP1/SMARCA4 wild-type status are associated with improved clinical outcomes to first-line CIT.

Keywords: Chemoimmunotherapy; First-line; KRAS; NSCLC; PD-L1 expression; Tumor mutational burden.

Figure 1.

(A) Objective response rate to chemoimmunotherapy by age, sex, ECOG PS, smoking status, tumor histology (nonsquamous versus squamous), dNLR tertiles (lower [0.10-2.10], middle [2.11-3.33], and upper [3.34-36.8]), and PD-L1 TPS groups: less than 1% versus 1% to 49% versus 50% to 89% versus greater than or equal to 90%. Forest plot for (B) PFS and (C) OS with chemoimmunotherapy according to sex, ECOG PS, smoking status, tumor histology, dNLR tertiles, and PD-L1 expression level groups. CI, confidence interval; dNLR, derived neutrophil-to-lymphocyte ratio; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; NS, not significant; OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival; TPS, tumor proportion score.

Figure 2.

(A) Objective response rate, (B) PFS, and (C) OS to chemoimmunotherapy by KRAS, TP53, STK11, KEAP1, and SMARCA4 mutation status in nonsquamous NSCLC. Outcomes by TP53, STK11, KEAP1, and SMARCA4 mutation status in KRAS^WT and KRAS^MUT nonsquamous NSCLC are illustrated. CI, confidence interval; HR, hazard ratio; NS, not significant; OS, overall survival; PFS, progression-free survival.

Figure 3.

(A) ORR in each TMB decile in the combined TMB cohort. (B) Forest plot for PFS and OS to chemoimmunotherapy according to increasing TMB thresholds in the combined cohort. (C) Forest plot for PFS and OS to chemoimmunotherapy in each TMB decile versus the lowest decile as reference in the combined cohort. (D) ORR, PFS, and OS in NSCLCs with TMB greater than or equal to the 90th percentile versus TMB less than the 90th percentile. CI, confidence interval; HR, hazard ratio; NR, not reached; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; TMB, tumor mutational burden.

Figure 4.

Forest plot for (A) PFS and (B) OS in multivariable Cox regression analysis in the cohort of patients with advanced nonsquamous NSCLC treated with chemoimmunotherapy. CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival; TMB, tumor mutational burden; TPS, tumor proportion score.