KRAS Mutations Impact Clinical Outcome in Metastatic Non-Small Cell Lung Cancer

Abstract

There is an urgent need to identify new predictive biomarkers for treatment response to both platinum doublet chemotherapy (PT) and immune checkpoint blockade (ICB). Here, we evaluated whether treatment outcome could be affected by KRAS mutational status in patients with metastatic (Stage IV) non-small cell lung cancer (NSCLC). All consecutive patients molecularly assessed and diagnosed between 2016−2018 with Stage IV NSCLC in the region of West Sweden were included in this multi-center retrospective study. The primary study outcome was overall survival (OS). Out of 580 Stage IV NSCLC patients, 35.5% harbored an activating mutation in the KRAS gene (KRASMUT). Compared to KRAS wild-type (KRASWT), KRASMUT was a negative factor for OS (p = 0.014). On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.478, 95% CI 1.207−1.709, p < 0.001). When treated with first-line platinum doublet (n = 195), KRASMUT was a negative factor for survival (p = 0.018), with median OS of 9 months vs. KRASWT at 11 months. On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.564, 95% CI 1.124−2.177, p = 0.008). KRASMUT patients with high PD-L1 expression (PD-L1high) had better OS than PD-L1highKRASWT patients (p = 0.036). In response to first-line ICB, KRASMUT patients had a significantly (p = 0.006) better outcome than KRASWT patients, with a median OS of 23 vs. 6 months. On multivariable Cox analysis, KRASMUT status was an independent prognostic factor for better OS (HR 0.349, 95% CI 0.148−0.822, p = 0.016). kRAS mutations are associated with better response to treatment with immune checkpoint blockade and worse response to platinum doublet chemotherapy as well as shorter general OS in Stage IV NSCLC.

Keywords: KRAS; biomarker; chemotherapy; immunotherapy; lung cancer.

Figure 1

KRAS mutations are a negative factor for overall survival. (A) Flow chart showing the patient selection for the study. (B) Kaplan–Meier estimates comparing overall survival and median survival stratified on KRAS^WT vs. KRAS^MUT for the full cohort (n = 580). Pie chart showing patient distribution between KRAS^WT and KRAS^MUT. (C) Kaplan–Meier estimates comparing overall survival for all receiving life-extending treatment (no treatment and only palliative radiotherapy excluded) stratified on KRAS^WT vs. KRAS^MUT. Pie chart showing patient distribution between KRAS^WT and KRAS^MUT.

Figure 2

KRAS^MUT is a negative factor for overall survival when treated with platinum doublet independently of EGFR and ALK mutations. (A) Kaplan–Meier estimates comparing overall survival for all receiving treatment with platinum doublet stratified on KRAS^WT vs. KRAS^MUT. Patients with EGFR and ALK alterations were excluded from KRAS^WT group. Pie chart showing patient distribution between KRAS^WT and KRAS^MUT. (B) Kaplan–Meier estimates comparing overall survival for all KRAS^MUT receiving treatment with platinum doublet stratified on KRAS^G12C vs. KRAS^{non G12C}. Pie chart showing patient distribution between KRAS^G12C and KRAS^{non G12C}.

Figure 2

KRAS^MUT is a negative factor for overall survival when treated with platinum doublet independently of EGFR and ALK mutations. (A) Kaplan–Meier estimates comparing overall survival for all receiving treatment with platinum doublet stratified on KRAS^WT vs. KRAS^MUT. Patients with EGFR and ALK alterations were excluded from KRAS^WT group. Pie chart showing patient distribution between KRAS^WT and KRAS^MUT. (B) Kaplan–Meier estimates comparing overall survival for all KRAS^MUT receiving treatment with platinum doublet stratified on KRAS^G12C vs. KRAS^{non G12C}. Pie chart showing patient distribution between KRAS^G12C and KRAS^{non G12C}.

Figure 3

KRAS^MUT, but not KRAS^WT, had a better outcome with ICB than with platinum doublet treatment. (A) Kaplan–Meier estimates comparing overall survival for all patients, excluding patients with ALK or EGFR alterations, receiving treatment with PT vs. ICB. Pie chart showing patient distribution between PT and ICB. (B) Kaplan–Meier estimates comparing overall survival for all KRAS^MUT receiving treatment with PT vs. ICB. Pie chart showing patient distribution between platinum doublet and ICB. (C) Kaplan–Meier estimates comparing overall survival for KRAS^WT, excluding patients with ALK or EGFR alterations, receiving treatment with platinum doublet vs. ICB. Pie chart showing patient distribution between PT and ICB. ICB: Immune checkpoint blockade; PT: Platinum doublet.

Figure 3

KRAS^MUT, but not KRAS^WT, had a better outcome with ICB than with platinum doublet treatment. (A) Kaplan–Meier estimates comparing overall survival for all patients, excluding patients with ALK or EGFR alterations, receiving treatment with PT vs. ICB. Pie chart showing patient distribution between PT and ICB. (B) Kaplan–Meier estimates comparing overall survival for all KRAS^MUT receiving treatment with PT vs. ICB. Pie chart showing patient distribution between platinum doublet and ICB. (C) Kaplan–Meier estimates comparing overall survival for KRAS^WT, excluding patients with ALK or EGFR alterations, receiving treatment with platinum doublet vs. ICB. Pie chart showing patient distribution between PT and ICB. ICB: Immune checkpoint blockade; PT: Platinum doublet.

Figure 4

PD-L1 status has an impact on overall survival for treated patients with KRAS^MUT. (A) IHC depicting examples of PD-L1 staining used to assess PD-L1 status in both KRAS^WT and KRAS^MUT NSCLC patients. PD-L1 expression is classified as negative, <50% or ≥50% based on tumor proportion score. (B) Kaplan–Meier estimates comparing overall survival for KRAS^MUT treated patients stratified on PD-L1 status. Pie chart showing patient distribution between PD-L1 negative, <50% and ≥50%. (C) Kaplan–Meier estimates comparing overall survival for KRAS^WT treated patients stratified on PD-L1 status. Pie chart showing patient distribution between PD-L1 negative, <50% and ≥50%. IHC: Immunohistochemistry; PD-L1: Programmed death ligand 1. Scale bar: 100 μm.

Figure 4

PD-L1 status has an impact on overall survival for treated patients with KRAS^MUT. (A) IHC depicting examples of PD-L1 staining used to assess PD-L1 status in both KRAS^WT and KRAS^MUT NSCLC patients. PD-L1 expression is classified as negative, <50% or ≥50% based on tumor proportion score. (B) Kaplan–Meier estimates comparing overall survival for KRAS^MUT treated patients stratified on PD-L1 status. Pie chart showing patient distribution between PD-L1 negative, <50% and ≥50%. (C) Kaplan–Meier estimates comparing overall survival for KRAS^WT treated patients stratified on PD-L1 status. Pie chart showing patient distribution between PD-L1 negative, <50% and ≥50%. IHC: Immunohistochemistry; PD-L1: Programmed death ligand 1. Scale bar: 100 μm.

Figure 5

KRAS^MUT patients have a better outcome on ICB treatment than KRAS^WT patients. (A) Kaplan–Meier estimates comparing overall survival for KRAS^MUT PD-L1 ≥ 50% treated patients receiving PD or ICB. Pie chart showing patient distribution receiving PT or ICB treatment. (B) Kaplan–Meier estimates comparing overall survival for KRAS^WT PD-L1 ≥ 50% treated patients receiving PT or ICB. Pie chart showing patient distribution receiving PT or ICB treatment. (C) Kaplan–Meier estimates comparing overall survival for all patients receiving ICB treatment in a first-line setting. Pie chart showing patient distribution between KRAS^WT and KRAS^MUT. (D) Swimmer plot showing survival time for both KRAS^WT and KRAS^MUT ICB-treated patients. Patients with KRAS^G12C mutation are marked with G12C. Status alive at last follow-up is shown. ICB: Immune checkpoint blockade; PT: Platinum doublet; PD-L1: Programmed death ligand 1.