Researchers from The College of Texas MD Anderson Most cancers Middle have recognized a brand new biomarker, TTF-1, that was predictive of survival outcomes for sufferers with superior KRAS G12C-mutated non-small cell lung most cancers (NSCLC), following therapy with the KRAS focused remedy sotorasib.
Outcomes from the research, revealed as we speak in Nature Drugs, discovered sufferers with lung tumors that specific low TTF-1 ranges responded poorly to sotorasib – with a median development free survival (PFS) of two.8 months and a median general survival (OS) of 4.5 months – whereas sufferers with tumors expressing excessive TTF-1 ranges had a median PFS of 8.1 months and a median OS of 16 months.
Since TTF-1 testing is routinely carried out in lung most cancers analysis, it offers physicians a right away software to assist determine these sufferers who could profit from sotorasib and people who might have another or intensified therapy method. Our findings help the usage of biomarkers to personalize care and will information the exact utility of mixture methods with KRAS inhibitors.”
Ferdinandos Skoulidis, M.D., Ph.D., lead creator, affiliate professor of Thoracic/Head and Neck Medical Oncology
KRAS is the commonest oncogenic driver in non-squamous NSCLC, discovered to be mutated in 25% to 30% of sufferers. Sotorasib is a focused remedy designed to dam the KRAS G12C mutant protein, which is present in roughly 13% of lung adenocarcinomas, the commonest kind of NSCLC. Sotorasib was accepted by the Meals and Drug Administration in 2021 primarily based on outcomes from the CodeBreaK 100 trial. It was the primary direct KRAS inhibitor to earn regulatory approval.
This research checked out 317 biomarker-evaluable sufferers with beforehand handled superior KRAS G12C-mutated NSCLC who had been concerned within the CodeBreaK 200 scientific trial and 112 biomarker-evaluable sufferers handled within the CodeBreaK 100 scientific trial.
As well as, researchers discovered that the tumor microenvironment – the immune panorama surrounding most cancers cells – can also play a job in how effectively sotorasib works. One subgroup of sufferers had “immune chilly” tumors that lacked expression of the immune checkpoint protein PD-L1, however they responded higher to sotorasib than to chemotherapy. These tumors are usually much less seemingly to reply to immunotherapy.
“This discovering is encouraging as a result of it means that even sufferers who do not reply to immunotherapy may nonetheless profit from sotorasib,” Skoulidis mentioned. “It additionally opens the door to exploring mixture remedies, like pairing sotorasib with chemotherapy to enhance outcomes for much more sufferers.”
Researchers additionally have been capable of display that speedy clearance of circulating tumor DNA (ctDNA) – small fragments of DNA from the tumor discovered within the blood – following initiation of sotorasib was linked with a lot better outcomes. Sufferers with detectable KRAS G12C ctDNA throughout therapy had an elevated danger of development in comparison with these with ctDNA clearance.
In some sufferers, ctDNA ranges dropped as quickly as eight days into therapy, suggesting {that a} easy blood check may assist docs shortly determine who’s benefiting from the remedy.
This work considerably advances precision medication for sufferers with KRAS G12C-mutant NSCLC. Future research will deal with additional refining response prediction to RAS inhibitors for sufferers with TTF-1 expressing tumors and on figuring out probably the most promising mixture methods for these with a poor prognosis who lack TTF-1 expression.
Limitations of the research included incomplete biomarker knowledge for some sufferers, the potential timing of the info evaluation, and the ctDNA panel dimension.
This research was funded by Amgen Inc.
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Journal reference:
Skoulidis, F., et al. (2025). Molecular determinants of sotorasib scientific efficacy in KRASG12C-mutated non-small-cell lung most cancers. Nature Drugs. doi.org/10.1038/s41591-025-03732-5.
