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. 2025 Jun 1;131(11):e35917.
doi: 10.1002/cncr.35917.

Circulating tumor DNA dynamic variation predicts sotorasib efficacy in KRASp.G12C-mutated advanced non-small cell lung cancer

Francesco Passiglia  1 , Francesco Pepe  2 , Gianluca Russo  2 , Edoardo Garbo  1 , Angela Listì  1 , Federica Benso  1 , Claudia Scimone  2 , Lucia Palumbo  2 , Monica Pluchino  3 , Roberta Minari  4 , Paola Bordi  4 , Massimiliano Cani  1 , Antonio Ungaro  5 , Chiara Ambrogio  6 , Riccardo Taulli  1 , Enrica Capelletto  1 , Maurizio Balbi  1 , Luisella Righi  1 , Marcello Tiseo  3   4 , Diana Giannarelli  7 , Giancarlo Troncone  2 , Silvia Novello  1 , Umberto Malapelle  2
Affiliations

Circulating tumor DNA dynamic variation predicts sotorasib efficacy in KRASp.G12C-mutated advanced non-small cell lung cancer

Francesco Passiglia et al. Cancer. .

Abstract

Background: The objective of this study was to investigate the correlation between circulating tumor DNA (ctDNA) KRAS G12C-mutation dynamic variations and treatment outcomes in patients with advanced non-small cell lung cancer (NSCLC) receiving sotorasib therapy in a real-world setting.

Methods: Peripheral blood samples were prospectively collected from 32 patients at baseline, at cycle 3, and then at each radiologic assessment during sotorasib treatment. Both tissue and plasma samples were analyzed by using ultra-deep, customized next-generation sequencing (NGS) assays. Plasma samples from 27 of 32 patients also were analyzed by digital polymerase chain reaction analysis, and ctDNA dynamic variations were correlated with radiologic responses and patients' clinical outcomes.

Results: A significant correlation between NGS and digital polymerase chain reaction-detected KRAS G12C variant allelic fractions (p < .001) was observed. Patients who achieved clearance of KRAS G12C-mutant ctDNA levels had a significant improvement in the objective response rate (80% vs. 8%; p < .001), median progression-free survival (7.9 vs. 2.8 months; p < .001), and median overall survival (16.8 vs. 6.4 months; p < .001) compared with those who did not achieve clearance. The clearance of ctDNA was the only prognostic factor significantly associated with both median progression-free survival (hazard ratio, 0.15; 95% confidence interval, 0.04-0.48) and median overall survival (hazard ratio, 0.09; 95% confidence interval, 0.02-0.45) in multivariable analysis. Moreover, a dynamic increase in the KRAS G12C median variant allele fraction anticipated radiologic disease progression in 70% of patients who were evaluable at the resistance time point.

Conclusions: This study demonstrated that early clearance of KRAS G12C-mutant ctDNA predicted the clinical benefit of sotorasib in patients with advanced NSCLC, suggesting that dynamic monitoring of ctDNA levels also may anticipate sotorasib resistance.

Keywords: KRASp.G12C; circulating tumor DNA; liquid biopsy; non‐small cell lung cancer (NSCLC); sotorasib.

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Conflict of interest statement

Francesco Passiglia reports personal/consulting and/or advisory fees from Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Janssen, Merck Sharp and Dohme, Novartis, Pfizer, PharmaMar, Roche, and ThermoFisher Scientific outside the submitted work. Francesco Pepe reports personal/consulting and/or speakers' bureau fees from Menarini International and Roche outside the submitted work. Massimiliano Cani reports travel support from Amgen and AstraZeneca outside the submitted work. Chiara Ambrogio reports grants/contracts from Boehringer Ingelheim and Verastem Inc. outside the submitted work. Luisella Righi reports consulting/advisory fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Novartis, and Roche outside the submitted work. Marcello Tiseo reports institutional research grants from AstraZeneca, Boehringer Ingelheim, and Roche; personal/consulting and/or speakers' fees from Amgen, AstraZeneca, BeiGene USA Inc., Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly & Company, F. Hoffmann‐La Riche, Johnson & Johnson Health Care Systems Inc., Merck, Merck Sharp and Dohme, Novartis, Pfizer, Pierre Fabre Pharmaceuticals, and Takeda Oncology; and travel support from Amgen and Takeda Oncology outside the submitted work. Diana Giannarelli reports personal/consulting and/or advisory fees from AstraZeneca, Amgen, and Sanofi outside the submitted work. and Amgen. Giancarlo Troncone reports personal advisory or speakers' fees from Bayer, Merck Sharp & Dohme, Roche, and Pfizer outside the submitted work. Silvia Novello reports grants/contracts from Amgen, AstraZeneca, BeiGene Switzerland GmbH, Boehringer Ingelheim, Eli Lilly and Company, F. Hoffman La‐Roche, Merck Sharp and Dohme, Novartis, Pfizer Canada Inc., and Takeda Oncology; and support for professional activities from AstraZeneca, BeiGene Switzerland GmbH, Bristol Myers Squibb, Novartis, Takeda Oncology, and ThermoFisher Scientific outside the submitted work. Umberto Malapelle reports personal/consulting or speakers' bureau fees from AstraZeneca, Amgen, Boehringer Ingelheim, Diaceutics, Diatech, Eli Lilly & Company, GlaxoSmithKline, Hedra, Janssen Biotech, Merck, Merck Sharp & Dohme, Novartis, Roche Health Solutions Inc., and ThermoFisher Scientific outside the submitted work. The remaining authors disclosed no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Overall correlation between (A) batch 1 and 2 NGS‐detected KRAS G12C VAFs, (B) batch 1 NGS and dPCR‐detected KRAS G12C VAFs, and (C) batch 2 NGS and dPCR‐detected KRAS G12C VAFs. dPCR indicates digital polymerase chain reaction analysis; NGS, next‐generation sequencing; VAFs, variant allele fractions.
FIGURE 2
FIGURE 2
(A) Dynamic variations in KRAS G12C–mutant ctDNA (VAF) with the receipt of sotorasib therapy across 32 patients who had advanced NSCLC and were included in the study. An asterisk indicates patients who had ctDNA clearance. (B) A clinical case of paired molecular and radiologic evolution of disease during sotorasib therapy. The patient was affected by intrathoracic metastatic disease with detectable KRAS G12C–mutant ctDNA levels at baseline [T0]. After 1 month of sotorasib [T1], rapid clearance of KRAS G12C–mutant ctDNA was observed in correlation with a radiologic partial response of both mediastinal lymphadenopathy and left perihilar lesions (arrow and arrowheads, respectively). Subsequently, stable disease was noted with a relatively consistent level of KRAS G12C–mutant ctDNA. Finally, a rapid increase in the concentration of mutated ctDNA was registered before noticeable radiologic disease progression (mediastinal lymphadenopathy is indicated by the red circle). AMG, analysis mutated gene; ctDNA indicates circulating tumor DNA; T0‐6, Timepoints 0‐5; TR, timepoint resistance; VAF, variant allele fraction.
FIGURE 3
FIGURE 3
Median (A) progression‐free survival and (B) overall survival in patients who had clearance versus no clearance of KRAS G12C–mutant ctDNA under sotorasib therapy. ctDNA indicates circulating tumor DNA.
FIGURE 4
FIGURE 4
Paired molecular, radiologic, and morphologic evolution of disease during sotorasib therapy. (A) A patient who had an initial response to sotorasib in multiple left pulmonary nodules (yellow circle), followed by stable disease according to RECIST criteria, with a parallel low concentration of the mutant ctDNA at baseline (T0) and during the course of treatment. At the time of disease progression, a rapid increase in KRAS G12C–mutant ctDNA levels was recorded. Tissue‐core biopsy of the progressive right paravertebral lesion (red circle) confirmed the original adenocarcinoma histology of the resected specimen with KRAS G12C mutation. (B) A patient who had an initial, subtle, dimensional increase in the primary right pulmonary lesion (arrowheads) followed by RECIST disease progression characterized by the occurrence of new, bilateral, large adrenal masses (circles). At the ctDNA level, the progression corresponded to a rapid increase in mutant ctDNA levels. Histologic examination of the progressed ileal mass (see text) revealed a poorly differentiated sarcomatoid carcinoma rather than the original TTF1‐positive adenocarcinoma, resulting in a histologic shift of the tumor during sotorasib therapy. AMG, analysis mutated gene; ctDNA indicates circulating tumor DNA; EE, hematoxylin‐eosin; RECIST, Response Evaluation Criteria in Solid Tumors; T0‐6, timepoint 0‐6; TR, timepoint resistance.
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References

    1. Hendriks L, Remon J, Faivre‐Finn C, et al. Non‐small cell lung cancer. Nat Rev Dis Primers. 2024;10(1):71. doi:10.1038/s41572-024-00551-9 - DOI - PubMed
    1. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K‐Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503(7477):548‐551. doi:10.1038/nature12796 - DOI - PMC - PubMed
    1. Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti‐tumour immunity. Nature. 2019;575(7781):217‐223. doi:10.1038/s41586-019-1694-1 - DOI - PubMed
    1. Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med. 2021;384(25):2371‐2381. doi:10.1056/nejmoa2103695 - DOI - PMC - PubMed
    1. De Langen AJ, Johnson ML, Mazieres J, et al. Sotorasib versus docetaxel for previously treated non‐small‐cell lung cancer with KRASG12C mutation: a randomised, open‐label, phase 3 trial. Lancet. 2023;401(10378):733‐746. doi:10.1016/s0140-6736(23)00221-0 - DOI - PubMed

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