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 RoccoRyo 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)

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
Journal	Nature Medicine
Volume	31
Early online date	28 May 2025
DOIs	https://doi.org/10.1038/s41591-025-03732-5
Publication status	Published - 31 Aug 2025

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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, 2755–2767. Article 110993. https://doi.org/10.1038/s41591-025-03732-5

@article{f4082985476240fd9dcdf0894220e229,

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.",

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",

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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, 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

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.

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

U2 - 10.1038/s41591-025-03732-5

DO - 10.1038/s41591-025-03732-5

M3 - Article

AN - SCOPUS:105006913721

SN - 1078-8956

VL - 31

SP - 2755

EP - 2767

JO - Nature Medicine

JF - Nature Medicine

M1 - 110993

ER -

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

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