New Biomarker May Guide Best Use of KRAS Inhibitors in Lung Cancer

• Lung cancer patients with high TTF-1 expression had improved survival outcomes following treatment with the KRAS inhibitor sotorasib
• This biomarker may help physicians determine those most likely to benefit from sotorasib and those who may need alternative or combination therapies
• TTF-1 is a readily available biomarker commonly used for lung cancer diagnostics

Researchers from The University of Texas MD Anderson Cancer Center have identified a new biomarker, TTF-1, that was predictive of survival outcomes for patients with advanced KRAS G12C-mutated non-small cell lung cancer (NSCLC), following treatment with the KRAS targeted therapy sotorasib.

Results from the study, published today in Nature Medicine, found patients with lung tumors that express low TTF-1 levels responded poorly to sotorasib – with a median progression free survival (PFS) of 2.8 months and a median overall survival (OS) of 4.5 months – whereas patients with tumors expressing high TTF-1 levels had a median PFS of 8.1 months and a median OS of 16 months.

Title: Molecular determinants of sotorasib clinical efficacy in KRASG12C-mutated non-small-cell lung cancer

Authors: 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

“Since TTF-1 testing is routinely performed in lung cancer diagnosis, it gives physicians an immediate tool to help identify those patients who may benefit from sotorasib and those who may need an alternative or intensified treatment approach. Our findings support the use of biomarkers to personalize care and could guide the precise application of combination strategies with KRAS inhibitors.” – said lead author Ferdinandos Skoulidis, M.D., Ph.D., associate professor of Thoracic/Head and Neck Medical Oncology.

Ferdinandos Skoulidis

KRAS is the most common oncogenic driver in non-squamous NSCLC, found to be mutated in 25% to 30% of patients. Sotorasib is a targeted therapy designed to block mutant  the KRAS G12Cprotein, which is found in roughly 13% of lung adenocarcinomas, the most common type of NSCLC.

Sotorasib was approved by the Food and Drug Administration in 2021 based on results from the CodeBreaK 100 trial. It was the first direct KRAS inhibitor to earn regulatory approval.

This study looked at 317 biomarker-evaluable patients with previously treated advanced KRAS G12C-mutated NSCLC who had been involved in the CodeBreaK 200 clinical trial and 112 biomarker-evaluable patients treated in the CodeBreaK 100 clinical trial.

In addition, researchers found that the tumor microenvironment – the immune landscape surrounding cancer cells – may also play a role in how well sotorasib works. One subgroup of patients had “immune cold” tumors that lacked expression of the immune checkpoint protein PD-L1, but they responded better to sotorasib than to chemotherapy. These tumors are typically less likely to respond to immunotherapy.

“This finding is encouraging because it suggests that even patients who don’t respond to immunotherapy might still benefit from sotorasib. It also opens the door to exploring combination treatments, like pairing sotorasib with chemotherapy to improve outcomes for even more patients.” – Skoulidis said.

Researchers also were able to demonstrate that rapid clearance of circulating tumor DNA (ctDNA) – small fragments of DNA from the tumor found in the blood – following initiation of sotorasib was linked with much better outcomes. Patients with detectable KRAS G12C ctDNA during treatment had an increased risk of progression compared to those with ctDNA clearance.

In some patients, ctDNA levels dropped as soon as eight days into treatment, suggesting that a simple blood test could help doctors quickly identify who is benefiting from the therapy.

This work significantly advances precision medicine for patients with KRAS G12C-mutant NSCLC. Future studies will focus on further refining response prediction to RAS inhibitors for patients with TTF-1 expressing tumors and on identifying the most promising combination strategies for those with a poor prognosis who lack TTF-1 expression.

Limitations of the study included incomplete biomarker data for some patients, the potential timing of the data analysis, and the ctDNA panel size.

This study was funded by Amgen Inc. A full list of collaborating authors and their disclosures can be found here.

More posts featuring MD Anderson Cancer Center in OncoDaily.