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

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^*

^*Corresponding author for this work

Division of Cancer Sciences (L5)

University of Texas MD Anderson Cancer Center
Cornell University
AstraZeneca
Netherlands Cancer Institute
Centre Hospitalier Universitaire de Rennes
West Virginia University
Roswell Park Cancer Institute
University of Fribourg
Cantonal Hospital of Fribourg
Aix-Marseille University
New York University Langone Medical Center
University Medical Center Groningen
University Hospital Gasthuisberg
Hospital Universitario 12 de Octobre
Henry Dunant Hospital Center
Princess Margaret Hospital
Hospitalet de Llobregat Barcelona
Centre Hospitalier Lyon-Sud
Asan Medical Center
Queensland University of Technology
AORN dei Colli Monaldi
National Hospital Organization (NHO) Kyushu Cancer Center
Medical University of Lublin
Amgen Inc
University Hospital Essen

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	110993
Pages (from-to)	2755–2767
Number of pages	13
Journal	Nature Medicine
Volume	31
Issue number	8
Early online date	28 May 2025
DOIs	https://doi.org/10.1038/s41591-025-03732-5
Publication status	Published - 31 Aug 2025

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Humans
Carcinoma, Non-Small-Cell Lung/genetics
Proto-Oncogene Proteins p21(ras)/genetics
Lung Neoplasms/drug therapy
Mutation
Pyrimidines/therapeutic use
Kelch-Like ECH-Associated Protein 1/genetics
Docetaxel/therapeutic use
NF-E2-Related Factor 2/genetics
DNA-Binding Proteins/genetics
Antineoplastic Agents/therapeutic use
Transcription Factors/genetics
Precision Medicine
Piperazines/therapeutic use
Female
Prognosis
Treatment Outcome
Male
Pyridines

Access to Document

10.1038/s41591-025-03732-5Licence: CC BY-NC-ND

Cite this

Skoulidis, F., Li, B. T., de Langen, A. J., Hong, D. S., Lena, H., Wolf, J., Dy, G. K., Curioni Fontecedro, A., Tomasini, P., Velcheti, V., van der Wekken, A. J., Dooms, C., Paz-Ares Rodriguez, L., Mountzios, G., Sacher, A., Nadal, E., Couraud, S., Kim, S. W., O’Byrne, K., ... Schuler, M. (2025). Molecular determinants of sotorasib clinical efficacy in KRAS^G12C-mutated non-small-cell lung cancer. Nature Medicine, 31(8), 2755–2767. Article 110993. https://doi.org/10.1038/s41591-025-03732-5

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title = "Molecular determinants of sotorasib clinical efficacy in KRASG12C-mutated non-small-cell lung cancer",

abstract = "Molecular determinants of KRAS(G12C)inhibitor efficacy in KRASG12C-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 KRASG12C-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 KRASG12C- circulating tumor DNA may refine clinical response prediction algorithms. Our findings advance precision medicine for patients with KRASG12C-mutated NSCLC and establish a framework for patient stratification and selection for treatment intensification with rationally applied therapeutic combinations.",

keywords = "Humans, Carcinoma, Non-Small-Cell Lung/genetics, Proto-Oncogene Proteins p21(ras)/genetics, Lung Neoplasms/drug therapy, Mutation, Pyrimidines/therapeutic use, Kelch-Like ECH-Associated Protein 1/genetics, Docetaxel/therapeutic use, NF-E2-Related Factor 2/genetics, DNA-Binding Proteins/genetics, Antineoplastic Agents/therapeutic use, Transcription Factors/genetics, Precision Medicine, Piperazines/therapeutic use, Female, Prognosis, Treatment Outcome, Male, Pyridines",

author = "Ferdinandos Skoulidis and Li, \{Bob T.\} and \{de Langen\}, \{Adrianus Johannes\} and Hong, \{David S.\} and Herve Lena and Juergen Wolf and Dy, \{Grace K.\} and \{Curioni Fontecedro\}, Alessandra and Pascale Tomasini and Vamsidhar Velcheti and \{van der Wekken\}, \{Anthonie J.\} and Christophe Dooms and \{Paz-Ares Rodriguez\}, Luis and Giannis Mountzios and Adrian Sacher and Ernest Nadal and Sebastien Couraud and Kim, \{Sang We\} and Kenneth O{\textquoteright}Byrne and Danilo Rocco and Ryo Toyozawa and Izabela Chmielewska and Lindsay, \{Colin R.\} and Antreas Hindoyan and Lata Mukundan and Tomasz Wilmanski and Abraham Anderson and Christine Ardito-Abraham and Amrita Pati and Anita Reddy and Bhakti Mehta and Martin Schuler",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = aug,

day = "31",

doi = "10.1038/s41591-025-03732-5",

language = "English",

volume = "31",

pages = "2755–2767",

journal = "Nature Medicine",

issn = "1078-8956",

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Skoulidis, F, Li, BT, de Langen, AJ, Hong, DS, Lena, H, Wolf, J, Dy, GK, Curioni Fontecedro, A, Tomasini, P, Velcheti, V, van der Wekken, AJ, Dooms, C, Paz-Ares Rodriguez, L, Mountzios, G, Sacher, A, Nadal, E, Couraud, S, Kim, SW, O’Byrne, K, Rocco, D, Toyozawa, R, Chmielewska, I, Lindsay, CR, Hindoyan, A, Mukundan, L, Wilmanski, T, Anderson, A, Ardito-Abraham, C, Pati, A, Reddy, A, Mehta, B & Schuler, M 2025, 'Molecular determinants of sotorasib clinical efficacy in KRAS^G12C-mutated non-small-cell lung cancer', Nature Medicine, vol. 31, no. 8, 110993, pp. 2755–2767. https://doi.org/10.1038/s41591-025-03732-5

TY - JOUR

T1 - Molecular determinants of sotorasib clinical efficacy in KRASG12C-mutated non-small-cell lung cancer

AU - Skoulidis, Ferdinandos

AU - Li, Bob T.

AU - de Langen, Adrianus Johannes

AU - Hong, David S.

AU - Lena, Herve

AU - Wolf, Juergen

AU - Dy, Grace K.

AU - Curioni Fontecedro, Alessandra

AU - Tomasini, Pascale

AU - Velcheti, Vamsidhar

AU - van der Wekken, Anthonie J.

AU - Dooms, Christophe

AU - Paz-Ares Rodriguez, Luis

AU - Mountzios, Giannis

AU - Sacher, Adrian

AU - Nadal, Ernest

AU - Couraud, Sebastien

AU - Kim, Sang We

AU - O’Byrne, Kenneth

AU - Rocco, Danilo

AU - Toyozawa, Ryo

AU - Chmielewska, Izabela

AU - Lindsay, Colin R.

AU - Hindoyan, Antreas

AU - Mukundan, Lata

AU - Wilmanski, Tomasz

AU - Anderson, Abraham

AU - Ardito-Abraham, Christine

AU - Pati, Amrita

AU - Reddy, Anita

AU - Mehta, Bhakti

AU - Schuler, Martin

N1 - Publisher Copyright: © The Author(s) 2025.

PY - 2025/8/31

Y1 - 2025/8/31

N2 - Molecular determinants of KRAS(G12C)inhibitor efficacy in KRASG12C-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 KRASG12C-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 KRASG12C- circulating tumor DNA may refine clinical response prediction algorithms. Our findings advance precision medicine for patients with KRASG12C-mutated NSCLC and establish a framework for patient stratification and selection for treatment intensification with rationally applied therapeutic combinations.

AB - Molecular determinants of KRAS(G12C)inhibitor efficacy in KRASG12C-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 KRASG12C-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 KRASG12C- circulating tumor DNA may refine clinical response prediction algorithms. Our findings advance precision medicine for patients with KRASG12C-mutated NSCLC and establish a framework for patient stratification and selection for treatment intensification with rationally applied therapeutic combinations.

KW - Humans

KW - Carcinoma, Non-Small-Cell Lung/genetics

KW - Proto-Oncogene Proteins p21(ras)/genetics

KW - Lung Neoplasms/drug therapy

KW - Mutation

KW - Pyrimidines/therapeutic use

KW - Kelch-Like ECH-Associated Protein 1/genetics

KW - Docetaxel/therapeutic use

KW - NF-E2-Related Factor 2/genetics

KW - DNA-Binding Proteins/genetics

KW - Antineoplastic Agents/therapeutic use

KW - Transcription Factors/genetics

KW - Precision Medicine

KW - Piperazines/therapeutic use

KW - Female

KW - Prognosis

KW - Treatment Outcome

KW - Male

KW - Pyridines

UR - https://www.scopus.com/pages/publications/105006913721

U2 - 10.1038/s41591-025-03732-5

DO - 10.1038/s41591-025-03732-5

M3 - Article

C2 - 40437272

AN - SCOPUS:105006913721

SN - 1078-8956

VL - 31

SP - 2755

EP - 2767

JO - Nature Medicine

JF - Nature Medicine

IS - 8

M1 - 110993

ER -

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

Abstract

UN SDGs

Keywords

Access to Document

Other files and links

Fingerprint

Seeking improved treatments for patients with advanced non-small-cell lung cancer & KRAS G12C mutation (sotorasib)

Cite this

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

Abstract

UN SDGs

Keywords

Access to Document

Other files and links

Fingerprint

Impacts

Seeking improved treatments for patients with advanced non-small-cell lung cancer & KRAS G12C mutation (sotorasib)

Cite this

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