Intracranial activity of sotorasib vs docetaxel in pretreated KRAS G12C-mutated advanced non-small cell lung cancer from a global, phase 3, randomized controlled trial

Anne-Marie C Dingemans; Konstantinos Syrigos; Lorenzo Livi; Astrid Paulus; Sang-We Kim; Yuanbin Chen; Enriqueta Felip; Frank Griesinger; Kadoaki Ohashi; Gerard Zalcman; Brett G M Hughes; Jens Benn Sørensen; Normand Blais; Carlos G M Ferreira; Colin R Lindsay; Rafal Dziadziuszko; Patrick J Ward; Cynthia Chinedu Obiozor; Yang Wang; Solange Peters

doi:10.1016/j.lungcan.2025.108683

Intracranial activity of sotorasib vs docetaxel in pretreated KRAS G12C-mutated advanced non-small cell lung cancer from a global, phase 3, randomized controlled trial

Anne-Marie C Dingemans^*, Konstantinos Syrigos, Lorenzo Livi, Astrid Paulus, Sang-We Kim, Yuanbin Chen, Enriqueta Felip, Frank Griesinger, Kadoaki Ohashi, Gerard Zalcman, Brett G M Hughes, Jens Benn Sørensen, Normand Blais, Carlos G M Ferreira, Colin R Lindsay, Rafal Dziadziuszko, Patrick J Ward, Cynthia Chinedu Obiozor, Yang Wang, Solange Peters

^*Corresponding author for this work

Department of Oncology

4 Citations (Scopus)

Abstract

OBJECTIVES: To assess the efficacy and safety of sotorasib in patients with brain metastases using data from the phase 3 CodeBreaK 200 study, which evaluated sotorasib in adults with pretreated advanced or metastatic KRAS G12C-mutated non-small cell lung cancer (NSCLC).

MATERIALS AND METHODS: Patients with KRAS G12C-mutated NSCLC who progressed after platinum-based chemotherapy and checkpoint inhibitor therapy were randomized 1:1 to sotorasib or docetaxel. An exploratory post-hoc analysis evaluated central nervous system (CNS) progression-free survival (PFS) and time to CNS progression in patients with treated and stable brain metastases at baseline. Measures were assessed by blinded independent central review per study-modified Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria.

RESULTS: Of the patients randomly assigned to receive sotorasib (n=171) or docetaxel (n=174), baseline CNS metastases were present in 40 (23%) and 29 (17%) patients, respectively. With a median follow-up of 20.0 months for this patient subgroup, median CNS PFS was longer with sotorasib compared with docetaxel (9.6 vs 4.5 months; hazard ratio, 0.43 [95% CI, 0.20-0.92]; P=0.02). Among patients with baseline treated CNS lesions of ≥10 mm, the percentage of patients who achieved CNS tumor shrinkage of ≥30% was two-fold higher with sotorasib than docetaxel (33.3% vs 15.4%). Treatment-related adverse events among patients with CNS lesions at baseline were consistent with those of the overall study population.

CONCLUSIONS: These results suggest intracranial activity with sotorasib complements the overall PFS benefit observed with sotorasib vs docetaxel, with safety outcomes similar to those in the general CodeBreaK 200 population.

CLINICAL TRIALS REGISTRATION NUMBER: NCT04303780.

Original language	English
Article number	108683
Journal	Lung Cancer
Volume	207
ISSN	0169-5002
DOIs	https://doi.org/10.1016/j.lungcan.2025.108683
Publication status	Published - 2025

Keywords

Brain metastases
KRAS G12C-mutated
NSCLC
Non-small cell lung cancer
Randomized controlled trial
Sotorasib
Survival

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Dingemans, A.-M. C., Syrigos, K., Livi, L., Paulus, A., Kim, S.-W., Chen, Y., Felip, E., Griesinger, F., Ohashi, K., Zalcman, G., Hughes, B. G. M., Sørensen, J. B., Blais, N., Ferreira, C. G. M., Lindsay, C. R., Dziadziuszko, R., Ward, P. J., Obiozor, C. C., Wang, Y., & Peters, S. (2025). Intracranial activity of sotorasib vs docetaxel in pretreated KRAS G12C-mutated advanced non-small cell lung cancer from a global, phase 3, randomized controlled trial. Lung Cancer, 207, Article 108683. https://doi.org/10.1016/j.lungcan.2025.108683

Dingemans, A-MC, Syrigos, K, Livi, L, Paulus, A, Kim, S-W, Chen, Y, Felip, E, Griesinger, F, Ohashi, K, Zalcman, G, Hughes, BGM, Sørensen, JB, Blais, N, Ferreira, CGM, Lindsay, CR, Dziadziuszko, R, Ward, PJ, Obiozor, CC, Wang, Y & Peters, S 2025, 'Intracranial activity of sotorasib vs docetaxel in pretreated KRAS G12C-mutated advanced non-small cell lung cancer from a global, phase 3, randomized controlled trial', Lung Cancer, vol. 207, 108683. https://doi.org/10.1016/j.lungcan.2025.108683

@article{49ebab5ec6f14d49a0be5f3bcc7cd536,

title = "Intracranial activity of sotorasib vs docetaxel in pretreated KRAS G12C-mutated advanced non-small cell lung cancer from a global, phase 3, randomized controlled trial",

abstract = "OBJECTIVES: To assess the efficacy and safety of sotorasib in patients with brain metastases using data from the phase 3 CodeBreaK 200 study, which evaluated sotorasib in adults with pretreated advanced or metastatic KRAS G12C-mutated non-small cell lung cancer (NSCLC).MATERIALS AND METHODS: Patients with KRAS G12C-mutated NSCLC who progressed after platinum-based chemotherapy and checkpoint inhibitor therapy were randomized 1:1 to sotorasib or docetaxel. An exploratory post-hoc analysis evaluated central nervous system (CNS) progression-free survival (PFS) and time to CNS progression in patients with treated and stable brain metastases at baseline. Measures were assessed by blinded independent central review per study-modified Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria.RESULTS: Of the patients randomly assigned to receive sotorasib (n=171) or docetaxel (n=174), baseline CNS metastases were present in 40 (23\%) and 29 (17\%) patients, respectively. With a median follow-up of 20.0 months for this patient subgroup, median CNS PFS was longer with sotorasib compared with docetaxel (9.6 vs 4.5 months; hazard ratio, 0.43 [95\% CI, 0.20-0.92]; P=0.02). Among patients with baseline treated CNS lesions of ≥10 mm, the percentage of patients who achieved CNS tumor shrinkage of ≥30\% was two-fold higher with sotorasib than docetaxel (33.3\% vs 15.4\%). Treatment-related adverse events among patients with CNS lesions at baseline were consistent with those of the overall study population.CONCLUSIONS: These results suggest intracranial activity with sotorasib complements the overall PFS benefit observed with sotorasib vs docetaxel, with safety outcomes similar to those in the general CodeBreaK 200 population.CLINICAL TRIALS REGISTRATION NUMBER: NCT04303780.",

keywords = "Brain metastases, KRAS G12C-mutated, NSCLC, Non-small cell lung cancer, Randomized controlled trial, Sotorasib, Survival",

author = "Dingemans, \{Anne-Marie C\} and Konstantinos Syrigos and Lorenzo Livi and Astrid Paulus and Sang-We Kim and Yuanbin Chen and Enriqueta Felip and Frank Griesinger and Kadoaki Ohashi and Gerard Zalcman and Hughes, \{Brett G M\} and S{\o}rensen, \{Jens Benn\} and Normand Blais and Ferreira, \{Carlos G M\} and Lindsay, \{Colin R\} and Rafal Dziadziuszko and Ward, \{Patrick J\} and Obiozor, \{Cynthia Chinedu\} and Yang Wang and Solange Peters",

year = "2025",

doi = "10.1016/j.lungcan.2025.108683",

language = "English",

volume = "207",

journal = "Lung Cancer",

issn = "0169-5002",

publisher = "Elsevier Ireland Ltd",

}

TY - JOUR

T1 - Intracranial activity of sotorasib vs docetaxel in pretreated KRAS G12C-mutated advanced non-small cell lung cancer from a global, phase 3, randomized controlled trial

AU - Dingemans, Anne-Marie C

AU - Syrigos, Konstantinos

AU - Livi, Lorenzo

AU - Paulus, Astrid

AU - Kim, Sang-We

AU - Chen, Yuanbin

AU - Felip, Enriqueta

AU - Griesinger, Frank

AU - Ohashi, Kadoaki

AU - Zalcman, Gerard

AU - Hughes, Brett G M

AU - Sørensen, Jens Benn

AU - Blais, Normand

AU - Ferreira, Carlos G M

AU - Lindsay, Colin R

AU - Dziadziuszko, Rafal

AU - Ward, Patrick J

AU - Obiozor, Cynthia Chinedu

AU - Wang, Yang

AU - Peters, Solange

PY - 2025

Y1 - 2025

N2 - OBJECTIVES: To assess the efficacy and safety of sotorasib in patients with brain metastases using data from the phase 3 CodeBreaK 200 study, which evaluated sotorasib in adults with pretreated advanced or metastatic KRAS G12C-mutated non-small cell lung cancer (NSCLC).MATERIALS AND METHODS: Patients with KRAS G12C-mutated NSCLC who progressed after platinum-based chemotherapy and checkpoint inhibitor therapy were randomized 1:1 to sotorasib or docetaxel. An exploratory post-hoc analysis evaluated central nervous system (CNS) progression-free survival (PFS) and time to CNS progression in patients with treated and stable brain metastases at baseline. Measures were assessed by blinded independent central review per study-modified Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria.RESULTS: Of the patients randomly assigned to receive sotorasib (n=171) or docetaxel (n=174), baseline CNS metastases were present in 40 (23%) and 29 (17%) patients, respectively. With a median follow-up of 20.0 months for this patient subgroup, median CNS PFS was longer with sotorasib compared with docetaxel (9.6 vs 4.5 months; hazard ratio, 0.43 [95% CI, 0.20-0.92]; P=0.02). Among patients with baseline treated CNS lesions of ≥10 mm, the percentage of patients who achieved CNS tumor shrinkage of ≥30% was two-fold higher with sotorasib than docetaxel (33.3% vs 15.4%). Treatment-related adverse events among patients with CNS lesions at baseline were consistent with those of the overall study population.CONCLUSIONS: These results suggest intracranial activity with sotorasib complements the overall PFS benefit observed with sotorasib vs docetaxel, with safety outcomes similar to those in the general CodeBreaK 200 population.CLINICAL TRIALS REGISTRATION NUMBER: NCT04303780.

AB - OBJECTIVES: To assess the efficacy and safety of sotorasib in patients with brain metastases using data from the phase 3 CodeBreaK 200 study, which evaluated sotorasib in adults with pretreated advanced or metastatic KRAS G12C-mutated non-small cell lung cancer (NSCLC).MATERIALS AND METHODS: Patients with KRAS G12C-mutated NSCLC who progressed after platinum-based chemotherapy and checkpoint inhibitor therapy were randomized 1:1 to sotorasib or docetaxel. An exploratory post-hoc analysis evaluated central nervous system (CNS) progression-free survival (PFS) and time to CNS progression in patients with treated and stable brain metastases at baseline. Measures were assessed by blinded independent central review per study-modified Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria.RESULTS: Of the patients randomly assigned to receive sotorasib (n=171) or docetaxel (n=174), baseline CNS metastases were present in 40 (23%) and 29 (17%) patients, respectively. With a median follow-up of 20.0 months for this patient subgroup, median CNS PFS was longer with sotorasib compared with docetaxel (9.6 vs 4.5 months; hazard ratio, 0.43 [95% CI, 0.20-0.92]; P=0.02). Among patients with baseline treated CNS lesions of ≥10 mm, the percentage of patients who achieved CNS tumor shrinkage of ≥30% was two-fold higher with sotorasib than docetaxel (33.3% vs 15.4%). Treatment-related adverse events among patients with CNS lesions at baseline were consistent with those of the overall study population.CONCLUSIONS: These results suggest intracranial activity with sotorasib complements the overall PFS benefit observed with sotorasib vs docetaxel, with safety outcomes similar to those in the general CodeBreaK 200 population.CLINICAL TRIALS REGISTRATION NUMBER: NCT04303780.

KW - Brain metastases

KW - KRAS G12C-mutated

KW - NSCLC

KW - Non-small cell lung cancer

KW - Randomized controlled trial

KW - Sotorasib

KW - Survival

UR - https://www.scopus.com/pages/publications/105012518745

U2 - 10.1016/j.lungcan.2025.108683

DO - 10.1016/j.lungcan.2025.108683

M3 - Journal article

C2 - 40774040

SN - 0169-5002

VL - 207

JO - Lung Cancer

JF - Lung Cancer

M1 - 108683

ER -

Intracranial activity of sotorasib vs docetaxel in pretreated KRAS G12C-mutated advanced non-small cell lung cancer from a global, phase 3, randomized controlled trial

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Keywords

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