Monotherapy With Immune Checkpoint Blockade Improves Survival Outcomes in KRAS-Mutant but Not KRAS Wild-Type Metastatic Lung Adenocarcinoma: Validation From an Extended Swedish Cohort

Abstract

Introduction

Immune checkpoint blockade (ICB) is a standard first-line treatment for stage IV NSCLC without actionable oncogenic alterations. KRAS mutations, prevalent in 30% to 40% lung adenocarcinomas (LUAD) in Western populations, currently lack targeted first-line therapies. This study aimed to assess the predictive value of KRAS mutations for clinical outcomes after distinct ICB regimens, validating our previous findings in a larger cohort with extended follow-up.

Methods

We conducted a retrospective multicenter study including consecutive stage IV LUAD patients (n = 424) treated with either ICB or platinum-doublet chemotherapy between 2016 and 2021 in Western Sweden. Patient demographics, tumor characteristics, treatment details, and survival outcomes were retrospectively collected from patient charts and the Swedish National Lung Cancer Registry. KRAS mutational status was assessed by next-generation sequencing. Primary end points included overall survival (OS) and progression-free survival (PFS), analyzed using Kaplan-Meier curves and multivariate Cox regression.

Results

Among 424 patients diagnosed with metastatic LUAD, 40% harbored KRAS mutations (KRAS^MUT). KRAS^MUT patients exhibited significant improvement in OS (16 versus 8 mo, p < 0.001) and PFS (8 mo versus 5 mo, p < 0.001) with ICB monotherapy. In contrast, KRAS wild-type (KRAS^WT) patients derived no survival advantage from ICB monotherapy (OS, 8 mo versus 8 mo, p = 0.648; PFS 4 mo versus 5 mo, p = 0.871) although they did so with chemoimmunotherapy (OS, 15 mo versus 8 mo, p = 0.032; PFS, 6 mo vs 5 mo, p = 0.033). On multivariate analysis, monotherapy was confirmed as an independent factor improving outcomes in KRAS-mutated patients (hazard ratio [HR] 0.533, 95% confidence interval 0.311-0.912, p = 0.018). Finally, we identified KRAS^G12C (OS: 13.7 mo versus 10.5 mo, p = 0.0046, PFS: 7.7 mo versus 6.2 mo, p = 0.002) and KRAS^G12V (OS: 24.2 mo versus 7.2 mo, p = 0.0204; PFS: 13.7 mo versus 4.5 mo, p = 0.063) but not KRAS^G12D (OS, 5.8 mo versus 6.2 mo, p = 0.777; PFS, 4.6 mo versus 3.2 mo, p = 0.694) as distinctly and independently predictive of improved survival after receiving ICB-containing treatment.

Conclusions

KRAS mutations predict substantial and sustained clinical benefit from first-line ICB monotherapy in metastatic LUAD, whereas KRAS wild-type patients do not. KRAS^G12C and KRAS^G12V mutations confer improved survival, whereas KRAS^G12D does not. Integrating KRAS mutation status into clinical practice could guide personalized treatment strategies, optimizing immunotherapy outcomes in stage IV LUAD.