STK11 mutations correlate with poor prognosis for advanced NSCLC treated with first-line immunotherapy or chemo-immunotherapy according to KRAS, TP53, KEAP1, and SMARCA4 status

Andrea De Giglio; Dario De Biase; Valentina Favorito; Thais Maloberti; Alessandro Di Federico; Federico Zacchini; Giulia Venturi; Claudia Parisi; Filippo Gustavo Dall'Olio; Ilaria Ricciotti; Ambrogio Gagliano; Barbara Melotti; Francesca Sperandi; Annalisa Altimari; Elisa Gruppioni; Giovanni Tallini; Francesco Gelsomino; Lorenzo Montanaro; Andrea Ardizzoni

doi:10.1016/j.lungcan.2024.108058

STK11 mutations correlate with poor prognosis for advanced NSCLC treated with first-line immunotherapy or chemo-immunotherapy according to KRAS, TP53, KEAP1, and SMARCA4 status

Lung Cancer. 2024 Dec 20:199:108058. doi: 10.1016/j.lungcan.2024.108058. Online ahead of print.

Authors

Andrea De Giglio¹, Dario De Biase², Valentina Favorito³, Thais Maloberti⁴, Alessandro Di Federico⁵, Federico Zacchini⁶, Giulia Venturi⁷, Claudia Parisi⁸, Filippo Gustavo Dall'Olio⁹, Ilaria Ricciotti⁷, Ambrogio Gagliano⁷, Barbara Melotti³, Francesca Sperandi³, Annalisa Altimari⁴, Elisa Gruppioni⁴, Giovanni Tallini¹⁰, Francesco Gelsomino³, Lorenzo Montanaro¹¹, Andrea Ardizzoni⁵

Affiliations

¹ Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy. Electronic address: [email protected].
² Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
³ Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
⁴ Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
⁵ Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
⁶ Departmental Program in Laboratory Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
⁷ Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
⁸ Department of Medical Oncology, Gustave Roussy, Villejuif, France; Faculty of Medicine, Paris-Saclay University, Paris, France.
⁹ Department of Medical Oncology, Gustave Roussy, Villejuif, France.
¹⁰ Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
¹¹ Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; Departmental Program in Laboratory Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

PMID: 39709652
DOI: 10.1016/j.lungcan.2024.108058

Abstract

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.

Keywords: Immunotherapy; NSCLC; Prognosis; STK11.