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Updated: Jun 4, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
STK11 mutations correlate with poor prognosis for advanced NSCLC treated with first-line immunotherapy or
Andrea De Giglio1, Dario De Biase2, Valentina Favorito3
1Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Background:
The upfront treatment of non-oncogene-addicted NSCLC relies on immunotherapy alone (ICI) or in combination with chemotherapy (CT-ICI). Genomic aberrations such as KRAS, TP53, KEAP1, SMARCA4, or STK11 may impact survival outcomes.
Methods:
We performed an observational study of 145 patients treated with first-line IO or CT-ICI for advanced non-squamous (nsq) NSCLC at our institution tested with an extensive lab-developed NGS panel. The primary objective was to assess the clinical outcomes of STK11-mutated patients. Then, we performed an external validation through the public OAK/POPLAR dataset, including nsq NSCLC patients treated with single-agent ICI or CT.
Results:
Most patients were male (59.7 %), former smokers (61.1 %), with ECOG PS 0-1 (84 %), and received first-line CT-IO (58.6 %). 44.8 % had a mutation in KRAS, 21.4 % in KEAP1, 50.3 % in TP53, 13.1 % in SMARCA4, and 14.4 % in the STK11 gene. The mOS was 8 mo. (95 % CI, 5-16.7) for STK11 mutated pts and 17.3 mo. for STK11 wild-type patients (95 % CI, 8.9-24.4) (p = 0.038). TP53 (8.3 vs 17.3), KRAS (9.2 vs 15.9), and KEAP1 (8.9 vs 15.9) mutated patients evidenced a trend for dismal mOS. SMARCA4 status had no impact on mOS. STK11 mutations were detrimental to OS in the univariate (HR 1.74, p = 0.041) and multivariate model (HR 1.97, p = 0.025) after adjusting for sex, age, ECOG PS, treatment (ICI vs CT-ICI), KRAS, KEAP1, TP53, and SMARCA4 status. Genomic alterations did not impact the mPFS in our cohort. Within the OAK/POPLAR dataset, STK11 mutations (60/818 pts) were significantly associated with increased death risk in the univariate (HR 2.01, p < 0.001) and multivariate model (HR 1.66, p = 0.001) after adjusting for age, sex, treatment (ICI vs CT), KRAS, KEAP1, TP53, and SMARCA4 status.
Conclusion:
STK11 aberrations hampered the mOS of nsq NSCLC patients treated with first-line ICI or CT-ICI. The negative prognostic impact seems to be unrelated to ICI administration.
Insights
STK11 mutations significantly worsen overall survival in non-squamous non-small cell lung cancer (NSCLC) patients receiving initial immunotherapy or chemo-immunotherapy. This negative prognostic impact appears independent of the specific treatment received.
Area of Science:
- Oncology
- Genomics
- Thoracic Surgery
Background:
- Upfront treatment for non-oncogene-addicted non-small cell lung cancer (NSCLC) involves immunotherapy alone (ICI) or combined with chemotherapy (CT-ICI).
- Genomic alterations in KRAS, TP53, KEAP1, SMARCA4, and STK11 may influence survival outcomes in NSCLC patients.
Purpose of the Study:
- To assess the clinical outcomes of STK11-mutated patients with advanced non-squamous NSCLC treated with first-line ICI or CT-ICI.
- To validate findings on an external dataset (OAK/POPLAR) for STK11 mutations in NSCLC.
Main Methods:
- An observational study of 145 advanced non-squamous NSCLC patients treated with first-line ICI or CT-ICI, utilizing a comprehensive NGS panel.
- External validation performed on the OAK/POPLAR dataset including NSCLC patients treated with single-agent ICI or CT.
Main Results:
- STK11 mutations were associated with significantly poorer median overall survival (mOS) (8 months vs. 17.3 months, p=0.038) in the primary cohort.
- TP53, KRAS, and KEAP1 mutations showed a trend towards dismal mOS, while SMARCA4 had no impact.
- External validation confirmed STK11 mutations significantly increased death risk (HR 1.66, p=0.001) in NSCLC patients.
Conclusions:
- STK11 aberrations negatively impact the mOS of non-squamous NSCLC patients receiving first-line ICI or CT-ICI.
- The detrimental prognostic effect of STK11 mutations appears independent of immunotherapy administration.
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