Role of next generation sequencing-based liquid biopsy in advanced non-small cell lung cancer patients treated with immune checkpoint inhibitors: impact of STK11, KRAS and TP53 mutations and co-mutations on outcome

Alberto Pavan; Andrea Boscolo Bragadin; Lorenzo Calvetti; Alessandra Ferro; Elisabetta Zulato; Ilaria Attili; Giorgia Nardo; Alessandro Dal Maso; Stefano Frega; Andrea Giovanni Menin; Matteo Fassan; Fiorella Calabrese; Giulia Pasello; Valentina Guarneri; Giuseppe Aprile; PierFranco Conte; Rafael Rosell; Stefano Indraccolo; Laura Bonanno

doi:10.21037/tlcr-20-674

Role of next generation sequencing-based liquid biopsy in advanced non-small cell lung cancer patients treated with immune checkpoint inhibitors: impact of STK11, KRAS and TP53 mutations and co-mutations on outcome

Transl Lung Cancer Res. 2021 Jan;10(1):202-220. doi: 10.21037/tlcr-20-674.

Authors

Alberto Pavan¹, Andrea Boscolo Bragadin², Lorenzo Calvetti³, Alessandra Ferro^{1

2}, Elisabetta Zulato⁴, Ilaria Attili^{1

2}, Giorgia Nardo⁴, Alessandro Dal Maso^{1

2}, Stefano Frega¹, Andrea Giovanni Menin⁵, Matteo Fassan⁶, Fiorella Calabrese⁷, Giulia Pasello¹, Valentina Guarneri^{1

2}, Giuseppe Aprile³, PierFranco Conte^{1

2}, Rafael Rosell⁸, Stefano Indraccolo⁴, Laura Bonanno¹

Affiliations

¹ Medical Oncology 2, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy.
² Department of Surgery, Oncology and Gastroenterology, Università degli Studi di Padova, Padova, Italy.
³ Department of Oncology, San Bortolo General Hospital, ULSS8 Berica - East District, Vicenza, Italy.
⁴ Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy.
⁵ Department of Pathology, San Bortolo General Hospital, ULSS8 Berica - East District, Vicenza, Italy.
⁶ Department of Medicine, Surgical Pathology and Cytopathology Unit, Università degli Studi di Padova, Padova, Italy.
⁷ Department of Cardiac, Thoracic, Vascular Sciences and Public Health, Università degli Studi di Padova, Padova, Italy.
⁸ Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Germans Trias I Pujol Health Sciences Institute and Hospital Badalona, Barcelona, Spain.

Abstract

Background: Characterization of tumor-related genetic alterations is promising for the screening of new predictive markers in non-small cell lung cancer (NSCLC). Aim of the study was to evaluate prognostic and predictive role of most frequent tumor-associated genetic alterations detected in plasma before starting immune checkpoint inhibitors (ICIs).

Methods: Between January 2017 and October 2019, advanced NSCLC patients were prospectively screened with plasma next-generation sequencing (NGS) while included in two trials: VISION (NCT02864992), using Guardant360^® test, and MAGIC (Monitoring Advanced NSCLC through plasma Genotyping during Immunotherapy: Clinical feasibility and application), using Myriapod NGS-IL 56G Assay. A control group of patients not receiving ICIs was analyzed.

Results: A total of 103 patients receiving ICIs were analyzed: median overall survival (OS) was 20.8 (95% CI: 16.7-24.9) months and median immune-related progression free disease (irPFS) 4.2 (95% CI: 2.3-6.1) months. TP53 mutations in plasma negatively affected OS both in patients treated with ICIs and in control group (P=0.001 and P=0.009), indicating a prognostic role. STK11 mutated patients (n=9) showed a trend for worse OS only if treated with ICIs. The presence of KRAS/STK11 co-mutation and KRAS/STK11/TP53 co-mutation affected OS only in patients treated with ICIs (HR =10.936, 95% CI: 2.337-51.164, P=0.002; HR =17.609, 95% CI: 3.777-82.089, P<0.001, respectively), indicating a predictive role.

Conclusions: Plasma genotyping demonstrated prognostic value of TP53 mutations and predictive value of KRAS/STK11 and KRAS/STK11/TP53 co-mutations.

Keywords: Immunotherapy; STK11; circulating tumor DNA; lung cancer; predictive biomarkers.