Prognostic Value of KRAS/ TP53 Status for Overall Survival in First-Line Monoimmunotherapy and Chemoimmunotherapy Treated Patients With Nonsquamous NSCLC in the Netherlands: A Brief Report

Abstract

Introduction: Programmed death-ligand 1 (PD-L1) is the main predictive biomarker used to identify patients with NSCLC who are eligible for treatment with immune checkpoint inhibitors. Despite its utility, the predictive capacity of PD-L1 is limited, necessitating the exploration of supplementary predictive biomarkers. In this report, we describe the prognostic value of KRAS/TP53 mutation status for overall survival (OS) in patients with NSCLC treated with first-line immunotherapy or combined chemoimmunotherapy.

Methods: Clinical data of all patients diagnosed with metastatic nonsquamous NSCLC in the Netherlands between January 1 and December 31 of 2019 were retrieved from the Netherlands Cancer Registry and linked to pathology reports of the Dutch Nationwide Pathology Databank. A total of 694 patients with available KRAS and TP53 mutation status and treated with first-line pembrolizumab or chemoimmunotherapy were included, with a median follow-up time of 42.5 months. Patients with an EGFR or MET mutation or ALK, ROS1, or RET fusion were excluded from the analysis.

Results: Among patients treated with first-line pembrolizumab or chemoimmunotherapy, mutations in KRAS and TP53 occurred in 48.8% (n = 339) and 58.4% (n = 405), respectively. OS differed significantly between KRAS/TP53 mutational subgroups in patients treated with first-line pembrolizumab or chemoimmunotherapy (log-rank test, p = 0.007). Median OS of pembrolizumab or chemoimmunotherapy treated patients with mutated TP53 was longer in patients with KRAS-wildtype (485 versus 359 d, hazard ratio [HR] = 0.76, p = 0.028) or mutated KRAS (571 versus 447 d, HR = 0.73, p = 0.019). In a separate analysis of treatment subgroups, mutated TP53 was associated with longer median OS in chemoimmunotherapy treated KRAS-wildtype patients (468 versus 341 d, HR = 0.71, p = 0.029) but not in monoimmunotherapy treated patients with KRAS-wildtype (512 versus 371 d, HR = 0.91, p = 0.78). In multivariable Cox regression analysis including age, sex, clinical disease stage, and PD-L1 tumor proportion score, KRAS/TP53 mutation status was no longer associated with OS.

Conclusions: Among patients with metastatic NSCLC who are treated with pembrolizumab or chemoimmunotherapy, the presence of a pathogenic TP53 and KRAS mutation is associated with longer OS. Nevertheless, in multivariable Cox regression analysis including age, sex, clinical disease stage, and PD-L1 tumor proportion score, KRAS/TP53 mutation status was no longer associated with OS.

Keywords: Chemoimmunotherapy; Immunotherapy; KRAS; NSCLC; Real-world data; TP53.

Figure 1

Overall survival of metastatic patients with NSCLC treated with first-line pembrolizumab or chemoimmunotherapy, stratified by KRAS and TP53 mutational status: (A) all mutational subgroups, (B) KRAS-wildtype only, (C) mutated KRAS only. The presence of a mutation in respective genes is indicated by ‘+’ and the absence of a (likely) pathogenic mutation is indicated by ‘−’. Data comprised patients diagnosed in 2019 and were retrieved from the Dutch NCR and the Dutch National Pathology Database (Palga). NCR, National Cancer Registry.