Molecular determinants of sotorasib clinical efficacy in KRASG12C-mutated non-small-cell lung cancer

Ferdinandos Skoulidis; Bob T Li; Adrianus Johannes de Langen; David S Hong; Herve Lena; Juergen Wolf; Grace K Dy; Alessandra Curioni Fontecedro; Pascale Tomasini; Vamsidhar Velcheti; Anthonie J van der Wekken; Christophe Dooms; Luis Paz-Ares Rodriguez; Giannis Mountzios; Adrian Sacher; Ernest Nadal; Sebastien Couraud; Sang-We Kim; Kenneth O'Byrne; Danilo Rocco; Ryo Toyozawa; Izabela Chmielewska; Colin R Lindsay; Antreas Hindoyan; Lata Mukundan; Tomasz Wilmanski; Abraham Anderson; Christine Ardito-Abraham; Amrita Pati; Anita Reddy; Bhakti Mehta; Martin Schuler

doi:10.1038/s41591-025-03732-5

Molecular determinants of sotorasib clinical efficacy in KRAS^G12C-mutated non-small-cell lung cancer

Nat Med. 2025 May 28. doi: 10.1038/s41591-025-03732-5. Online ahead of print.

Authors

Ferdinandos Skoulidis¹, Bob T Li^{2

3}, Adrianus Johannes de Langen⁴, David S Hong⁵, Herve Lena⁶, Juergen Wolf⁷, Grace K Dy⁸, Alessandra Curioni Fontecedro^{9

10}, Pascale Tomasini¹¹, Vamsidhar Velcheti¹², Anthonie J van der Wekken¹³, Christophe Dooms¹⁴, Luis Paz-Ares Rodriguez¹⁵, Giannis Mountzios¹⁶, Adrian Sacher¹⁷, Ernest Nadal¹⁸, Sebastien Couraud¹⁹, Sang-We Kim²⁰, Kenneth O'Byrne²¹, Danilo Rocco²², Ryo Toyozawa²³, Izabela Chmielewska²⁴, Colin R Lindsay^{25

26}, Antreas Hindoyan²⁷, Lata Mukundan²⁷, Tomasz Wilmanski²⁷, Abraham Anderson²⁷, Christine Ardito-Abraham²⁷, Amrita Pati²⁷, Anita Reddy²⁷, Bhakti Mehta²⁷, Martin Schuler²⁸

Affiliations

¹ University of Texas MD Anderson Cancer Center, Houston, TX, USA. fskoulidis@mdanderson.org.
² Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, New York, NY, USA.
³ AstraZeneca, Gaithersburg, MD, USA.
⁴ Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
⁵ University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁶ Centre Hospitalier Universitaire de Rennes-Hôpital Pontchaillou, Rennes, France.
⁷ Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany.
⁸ Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
⁹ Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland.
¹⁰ Cantonal Hospital of Fribourg, Fribourg, Switzerland.
¹¹ Aix Marseille University, APHM, INSERM, NCRS, CRCM, Hôpital Nord, Multidisciplinary Oncology and Therapeutic Innovations Department, Marseille, France.
¹² Perlmutter Cancer Center, New York University Langone, New York, NY, USA.
¹³ Department of Pulmonology and Tuberculosis, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
¹⁴ Department of Respiratory Diseases, University Hospitals KU Leuven, Leuven, Belgium.
¹⁵ Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain.
¹⁶ Fourth Department of Medical Oncology and Clinical Trials Unit, Henry Dunant Hospital Center, Athens, Greece.
¹⁷ Princess Margaret Cancer Centre, Toronto, ON, Canada.
¹⁸ Catalan Institute of Oncology (ICO), IDIBELL, L'Hospitalet, Barcelona, Spain.
¹⁹ Cancer Institute of Hospices Civils de Lyon, Lyon Sud Hospital, Pierre Bénite, France.
²⁰ Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
²¹ Princess Alexandra Hospital and Queensland University of Technology, Brisbane, Queensland, Australia.
²² Department of Pulmonary Oncology, AORN dei Colli Monaldi, Naples, Italy.
²³ Department of Thoracic Oncology, NHO Kyushu Cancer Center, Fukuoka, Japan.
²⁴ Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland.
²⁵ The Christie NHS Foundation Trust, Manchester, UK.
²⁶ Division of Cancer Sciences, University of Manchester, Manchester, UK.
²⁷ Amgen, Inc., Thousand Oaks, CA, USA.
²⁸ Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. martin.schuler@ume.de.

PMID: 40437272
DOI: 10.1038/s41591-025-03732-5

Abstract

Molecular determinants of KRAS(G12C)inhibitor efficacy in KRAS^G12C-mutated non-small-cell lung cancer (NSCLC) remain poorly characterized. Here we report one of the largest integrated analyses to date of sotorasib clinical efficacy biomarkers from the phase 2 CodeBreaK 100 and phase 3 CodeBreaK 200 studies. We reveal differential sotorasib activity and relative benefit compared to docetaxel across KRAS^G12C-mutated NSCLC co-mutational subsets and transcriptional subtypes. We also identify low expression of TTF1 and KEAP1 co-mutations/NRF2 activation as major determinants of sotorasib anti-tumor efficacy and adverse prognostic features. Exploratory analyses highlight potential tumor cell-extrinsic contributors to sotorasib anti-tumor activity and suggest that early on-treatment clearance of KRAS^G12C- circulating tumor DNA may refine clinical response prediction algorithms. Our findings advance precision medicine for patients with KRAS^G12C-mutated NSCLC and establish a framework for patient stratification and selection for treatment intensification with rationally applied therapeutic combinations.