KRASG12C/TP53 co-mutations identify long-term responders to first line palliative treatment with pembrolizumab monotherapy in PD-L1 high (≥50%) lung adenocarcinoma

Abstract

Background: Pembrolizumab is a standard of care as first line palliative therapy in PD-L1 overexpressing (≥50%) non-small cell lung cancer (NSCLC). This study aimed at the identification of KRAS and TP53-defined mutational subgroups in the PD-L1 high population to distinguish long-term responders from those with limited benefit.

Methods: In this retrospective, observational study, patients from 4 certified lung cancer centers in Berlin, Germany, having received pembrolizumab monotherapy as first line palliative treatment for lung adenocarcinoma (LuAD) from 2017 to 2018, with PD-L1 expression status and targeted NGS data available, were evaluated.

Results: A total of 119 patients were included. Rates for KRAS, TP53 and combined mutations were 52.1%, 47.1% and 21.9%, respectively, with no association given between KRAS and TP53 mutations (P=0.24). By trend, PD-L1 expression was higher in KRAS-positive patients (75% vs. 65%, P=0.13). Objective response rate (ORR), median progression-free survival (PFS) and overall survival (OS) in the KRAS^G12C group (n=32, 51.6%) were 63.3%, 19.8 months (mo.) and not estimable (NE), respectively. Results in KRAS^other and wild type patients were similar and by far lower (42.7%, P=0.06; 6.2 mo., P<0.001; 23.4 mo., P=0.08). TP53 mutations alone had no impact on response and survival. However, KRAS^G12C/TP53 co-mutations (n=12) defined a subset of long-term responders (ORR 100.0%, PFS 33.3 mo., OS NE). In contrast, patients with KRAS^other/TP53 mutations showed a dismal prognosis (ORR 27.3%, P=0.002; PFS 3.9 mo., P=0.001, OS 9.7 mo., P=0.02).

Conclusions: A comprehensive assessment of KRAS subtypes and TP53 mutations allows a highly relevant prognostic differentiation of patients with metastatic, PD-L1 high LuAD treated upfront with pembrolizumab.

Keywords: KRAS mutations; Non-small cell lung cancer (NSCLC); TP53 mutations; checkpoint inhibitors.

Figure 1

Distribution of KRAS mutations (A), TP53 mutations (B) and mutational pattern according to both mutations (C). KRAS^mut, KRAS mutation; KRAS^wt, KRAS wild type; TP53^mut, TP53 mutation; TP53^wt, TP 53 wild type.

Figure 2

Kaplan-Meier curves for progression-free survival (PFS) depending on KRAS mutational status (A), TP53 mutational status (B), KRAS subgroups (KRAS^G12C vs. KRAS^other (C) and KRAS/TP53 co-mutations (KRAS^G12C/TP53^mut vs. KRAS^G12C/TP53^wt vs. KRAS^other/TP53^mut vs. KRAS^other/TP53^wt (D).

Figure 3

Kaplan-Meier curves for overall survival (OS) depending on KRAS mutational status (A), TP53 mutational status (B), KRAS subgroups (KRAS^G12C vs. KRAS^other mutations (C) and KRAS/TP53 co-mutations (KRAS^G12C/TP53^mut vs. KRAS^G12C/TP53^wt vs. KRAS^other/TP53^mut vs. KRAS^other/TP53^wt (D).