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Deeper Understanding Emerging of KRAS Biology in NSCLC

Danielle Bucco
Published: Friday, Dec 15, 2017

Ferdinandos Skoulidis, MD, PhD
Ferdinandos Skoulidis, MD, PhD
Approximately 25% to 30% of patients with non–small cell lung cancer (NSCLC) have activating mutations in KRAS, creating a challenging unmet treatment need, explained Ferdinandos Skoulidis, MD, PhD.

However, prior studies have shown that, by picking apart the KRAS subtype, there are smaller subsets harboring mutations that could be associated with response to immunotherapy agents. These subgroups include KL (STK11/LKB1 mutations), KP (TP53), and KC (CDKN2A/B). In an analysis further exploring these subtypes, it was found that tumors in the KP subgroup are more likely to respond to checkpoint inhibition.1

Additionally, according to data from the CheckMate-057 trial, immunotherapy might offer a valid treatment option for these patients. This study randomized 582 patients after failure with platinum-based doublet chemotherapy to nivolumab (Opdivo) or docetaxel. In a subgroup analysis of CheckMate-057, patients with KRAS mutation were more like to benefit from nivolumab in terms of an improvement in overall survival (OS).2

“Immunotherapy has emerged as a major treatment option in both metastatic and even earlier stage squamous carcinoma and adenocarcinoma,” said Skoulidis.

In an interview with OncLive® at the 2017 State of the Science SummitTM on Advanced NSCLC, Skoulidis, an assistant professor, Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed potential treatment options for KRAS-mutated lung cancer and highlighted developments in biomarker research in other areas in the field.

OncLive: Please provide an overview of your presentation.

Skoulidis: I discussed the role of biomarkers in the management of NSCLC. This is a very topical theme because lung adenocarcinoma is emerging as the pinnacle of precision cancer medicine among the solid tumors, with the recognition that NSCLC does not constitute a single disease. NSCLC consists of many different molecularly definitive entities, each of which needs to be treated in a unique way.

I discussed the 5 biomarkers that are currently linked to FDA-approved therapies in NSCLC. Those mutations include EGFR, ALK, and ROS1 rearrangements, BRAF V600E, and the expression of PD-L1.

What are the best treatment options for patients with KRAS-mutant lung cancer?

KRAS represents the “elephant in the room” in the field of targeted cancer therapy. Approximately 25% to 30% of patients with lung adenocarcinoma will be found to have an activating mutation in KRAS. We have known about KRAS for a long time. There are no FDA-approved targeted therapies for patients with KRAS-mutant lung adenocarcinoma, so this represents a major unmet clinical need. 

Over the last couple of years, immunotherapy has emerged as a major treatment option in both patients with metastatic and even earlier-stage squamous carcinomas and adenocarcinomas. There is some evidence from the CheckMate-057 trial that immunotherapy might represent a very valid treatment option for patients with KRAS-mutant lung cancer. 

However, what has become clear to us is that KRAS-mutant lung adenocarcinoma is clinically heterogeneous, meaning one patient does not respond in the same way as another due to molecular diversity. We have previously shown that one of the major determinants of the heterogeneity of KRAS-mutant lung adenocarcinoma is common mutations or mutations in genes that happen together with KRAS.

We have identified mutations in 3 key tumor suppressor genes that we believe define 3 major subgroups of KRAS-mutant lung adenocarcinoma. Those are mutations in TP53 in the KP subgroup, STK11 in the KL subgroup, and the p16 gene (CDKN2a/INK4a) in the KC subgroup.

We have previously shown that there are many differences between these subgroups. Potentially, the most clinically relevant difference is in the response of the subgroups to immunotherapy. Through a large collaboration between The University of Texas MD Anderson Cancer Center, Memorial Sloan Kettering Cancer Center, Dana-Farber Cancer Institute, and Massachusetts General Hospital, we collected 174 patients with KRAS-mutant lung adenocarcinoma and assessed their response to immunotherapy based on common mutations. 

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TitleExpiration DateCME Credits
Online Medical Crossfire®: 5th Annual Miami Lung Cancer ConferenceMay 30, 20196.5
Community Practice Connections™: Working Group for Changing Standards in EGFR-Mutated Lung Cancers: Real-World Applications of the Evidence for NursesJun 29, 20191.5
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