Prior immune checkpoint inhibitor exposure, treatment interval, and severe hepatotoxicity with sotorasib in KRAS G12C-mutant non-small-cell lung cancer: a systematic review and meta-analysis
- 1Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
Abstract
BackgroundSevere hepatotoxicity has been reported when sotorasib follows immune checkpoint inhibitor (ICI) therapy, and fixed washout intervals have been proposed. We assessed prior ICI exposure and the ICI-to-sotorasib interval as separate risk factors.
Materials and methodsWe searched PubMed, Europe PMC, Embase, Web of Science, Scopus, CENTRAL, and meeting proceedings for comparative studies of grade 3 or higher hepatotoxicity after KRAS G12C inhibitors. Matched risk ratios (RRs) and unadjusted cohort data were synthesized separately, the latter with an exact conditional odds ratio (OR). Certainty was rated with GRADE.
ResultsOf 530 unique records screened, seven sources were included, all involving sotorasib. In the only matched analysis (meeting abstract, 386 patients per arm), prior ICI exposure was associated with higher risk (13.2% vs 4.4%, RR 3.00, 95% CI 1.76-5.10), whereas matched comparisons at 6 weeks (RR 1.11, 0.61-2.03) and 12 weeks (RR 1.08, 0.52-2.27) detected no difference but could not exclude important effects. All five unadjusted cohorts showed higher risk with shorter intervals, including 21/74 versus 8/75 patients in the earlier versus later interval quartiles of the CodeBreaK 200 trial, although effect sizes were heterogeneous (exact homogeneity P=0.006). Certainty was very low throughout.
ConclusionsPrior ICI exposure was associated with higher risk of severe sotorasib-associated hepatotoxicity, with very low certainty. A shorter interval was associated with higher risk in unadjusted data only, and current evidence does not establish a mandatory washout period. Liver-test monitoring per the prescribing information applies to all patients, whereas additional surveillance after ICI exposure remains an untested precaution.
HIGHLIGHTSO_LIPrior ICI exposure was linked to a threefold higher risk of severe sotorasib hepatotoxicity in a matched analysis. C_LIO_LIShorter ICI-to-sotorasib intervals carried higher risk in all five unadjusted cohorts, including a phase 3 trial. C_LIO_LIMatched comparisons at 6 and 12 weeks showed no interval effect, so a fixed washout is not established. C_LIO_LIExact conditional methods handled zero-event comparator arms without continuity correction. C_LIO_LIAll comparative evidence was of very low certainty, and adjusted prospective data are needed. C_LI
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BibTeX
@misc{cook2026prior,
title = {{Prior immune checkpoint inhibitor exposure, treatment interval, and severe hepatotoxicity with sotorasib in KRAS G12C-mutant non-small-cell lung cancer: a systematic review and meta-analysis}},
author = {S. Cook and H. S. Kim},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.05.26364739},
url = {https://www.medrxiv.org/content/10.64898/2026.10.05.26364739v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Prior immune checkpoint inhibitor exposure, treatment interval, and severe hepatotoxicity with sotorasib in KRAS G12C-mutant non-small-cell lung cancer: a systematic review and meta-analysis
AU - S. Cook
AU - H. S. Kim
PY - 2026
DA - 2026/10/05
PB - medRxiv
DO - 10.64898/2026.10.05.26364739
UR - https://www.medrxiv.org/content/10.64898/2026.10.05.26364739v1
AB - BackgroundSevere hepatotoxicity has been reported when sotorasib follows immune checkpoint inhibitor (ICI) therapy, and fixed washout intervals have been proposed. We assessed prior ICI exposure and the ICI-to-sotorasib interval as separate risk factors. Materials and methodsWe searched PubMed, Europe PMC, Embase, Web of Science, Scopus, CENTRAL, and meeting proceedings for comparative studies of grade 3 or higher hepatotoxicity after KRAS G12C inhibitors. Matched risk ratios (RRs) and unadjusted cohort data were synthesized separately, the latter with an exact conditional odds ratio (OR). Certainty was rated with GRADE. ResultsOf 530 unique records screened, seven sources were included, all involving sotorasib. In the only matched analysis (meeting abstract, 386 patients per arm), prior ICI exposure was associated with higher risk (13.2% vs 4.4%, RR 3.00, 95% CI 1.76-5.10), whereas matched comparisons at 6 weeks (RR 1.11, 0.61-2.03) and 12 weeks (RR 1.08, 0.52-2.27) detected no difference but could not exclude important effects. All five unadjusted cohorts showed higher risk with shorter intervals, including 21/74 versus 8/75 patients in the earlier versus later interval quartiles of the CodeBreaK 200 trial, although effect sizes were heterogeneous (exact homogeneity P=0.006). Certainty was very low throughout. ConclusionsPrior ICI exposure was associated with higher risk of severe sotorasib-associated hepatotoxicity, with very low certainty. A shorter interval was associated with higher risk in unadjusted data only, and current evidence does not establish a mandatory washout period. Liver-test monitoring per the prescribing information applies to all patients, whereas additional surveillance after ICI exposure remains an untested precaution. HIGHLIGHTSO_LIPrior ICI exposure was linked to a threefold higher risk of severe sotorasib hepatotoxicity in a matched analysis. C_LIO_LIShorter ICI-to-sotorasib intervals carried higher risk in all five unadjusted cohorts, including a phase 3 trial. C_LIO_LIMatched comparisons at 6 and 12 weeks showed no interval effect, so a fixed washout is not established. C_LIO_LIExact conditional methods handled zero-event comparator arms without continuity correction. C_LIO_LIAll comparative evidence was of very low certainty, and adjusted prospective data are needed. C_LI
ER -