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. 2022 Aug 8;3(9):100390.
doi: 10.1016/j.jtocrr.2022.100390. eCollection 2022 Sep.

Clinicopathologic Characteristics and Outcomes for Patients With KRAS G12D-Mutant NSCLC

Alissa J Cooper  1 , Alona Muzikansky  2 , Jochen Lennerz  3 , Farhaana Narinesingh  3 , Mari Mino-Kenudson  3 , Yin P Hung  3 , Zofia Piotrowska  1 , Ibiayi Dagogo-Jack  1 , Lecia V Sequist  1 , Justin F Gainor  1 , Jessica J Lin  1 , Rebecca S Heist  1
Affiliations

Clinicopathologic Characteristics and Outcomes for Patients With KRAS G12D-Mutant NSCLC

Alissa J Cooper et al. JTO Clin Res Rep. .

Abstract

Introduction: Co-occurring mutations in KRAS-mutant NSCLC are associated with discrete biological properties and modulate therapeutic susceptibilities. As G12D-specific inhibitors are expected to enter the clinic, we sought to investigate the characteristics and outcomes of patients with KRAS G12D-mutant NSCLC.

Methods: This was a retrospective single-institution study. Patients with NSCLC and KRAS G12D mutations detected by the Massachusetts General Hospital SNaPshot next-generation sequencing assay were identified. Clinical and pathologic characteristics were collected by chart review.

Results: A total of 107 patients with KRAS G12D-mutant NSCLC were identified. Most patients were former smokers (80, 74.8%) and had tumors with adenocarcinoma pathologic subtype (93, 86.9%). Among 56 patients evaluated for programmed death-ligand 1 expression, tumor proportion score was less than 50% in 43 (76.8%). Concomitant mutations were identified in STK11 (17 of 107, 15.9%), KEAP1 (10 of 58, 17.2%), TP53 (36 of 107, 33.6%), and SMARCA4 (11 of 107, 10.3%). Among 57 patients treated with first-line therapy, patients with STK11 co-mutations had shorter progression-free survival (1.2 mo, 95% confidence interval [CI]: 0.6-2.9 versus 4.1 mo, 95% CI: 2.5-6.0, p = 0.0235) and overall survival (4.3 mo, 95% CI: 1.2-10.6 versus 17.9 mo, 95% CI: 8.6-31.1, p = 0.0018) compared with wild type. Patients with KEAP1 co-mutations had shorter overall survival (4.6 mo, 95% CI: 1.2-10.6 versus 17.9 mo, 95% CI: 7.1-30.1, p = 0.0125) than those without. TP53 co-mutations exerted no influence on survival.

Conclusions: Co-occurring mutations were common in patients with KRAS G12D-mutant NSCLC. STK11 and KEAP1 co-mutations were associated with worse clinical outcomes, whereas co-occurring TP53 did not affect survival.

Keywords: Co-mutations; KRAS mutation; Non–small cell lung cancer; Targeted therapies.

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Figures

Figure 1
Figure 1
Summary of PD-L1 level and molecular alterations in patients with KRAS G12D-mutated NSCLC. This heatmap summarizes the findings of PD-L1 level (top) and molecular alterations (bottom) for each patient in the cohort, with never smokers (blue), former smokers (green), and current smokers (peach) delineated. Squares populated with gray in the PD-L1 and KEAP1 fields indicate that these tests, respectively, were not available for inclusion. PD-L1, programmed death-ligand 1.
Figure 2
Figure 2
Association of PD-L1 level with molecular alterations. Scatterplot of percent expression of PD-L1 (y axis) is illustrated in relationship to molecular wild-type (blue circles) or mutant (red triangles) status. PD-L1 expression was similar among wild-type and mutant for TP53 and SMARCA4 mutations, but relatively lower in STK11- and KEAP1-mutant samples compared with wild type. PD-L1, programmed death-ligand 1.
Figure 3
Figure 3
Median PFS among patients with metastatic disease treated with first-line therapy. PFS of the overall population is illustrated (A) and stratified by STK11 mutation (B), SMARCA4 mutation (C), KEAP1 mutation (D), and TP53 mutation (E). Plus signs represent data censored at the last time the patient was known to be without progression. CI, confidence interval; PFS, progression-free survival.
Figure 4
Figure 4
Median OS among patients with metastatic disease treated with first-line therapy. OS of the overall population is illustrated (A) and stratified by STK11 mutation (B), SMARCA4 mutation (C), KEAP1 mutation (D), and TP53 mutation (E). Plus signs represent data censored at the last time the patient was known to be alive. CI, confidence interval; OS, overall survival.
Supplementary Figure 2
Supplementary Figure 2
See this image and copyright information in PMC

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