Mechanisms of Acquired Resistance to Savolitinib, a Selective MET Inhibitor in MET-Amplified Gastric Cancer.

Abstract

PURPOSE:

Some gastric cancers harbor MET gene amplifications that can be targeted by selective MET inhibitors to achieve tumor responses, but resistance eventually develops. Savolitinib, a selective MET inhibitor, is beneficial for treating patients with MET-driven gastric cancer. Understanding the resistance mechanisms is important for optimizing postfailure treatment options.

PATIENTS AND METHODS:

Here, we identified the mechanisms of acquired resistance to savolitinib in 3 patients with gastric cancer and MET-amplified tumors who showed a clinical response and then cancer progression. Longitudinal circulating tumor DNA (ctDNA) is useful for monitoring resistance during treatment and progression when rebiopsy cannot be performed.

RESULTS:

Using a next-generation sequencing 100-gene panel, we identified the target mechanisms of resistance MET D1228V/N/H and Y1230C mutations or high copy number MET gene amplifications that emerge when resistance to savolitinib develops in patients with MET-amplified gastric cancer.

CONCLUSION:

We demonstrated the utility of ctDNA in gastric cancer and confirmed this approach using baseline tumor tissue or rebiopsy.

• Authors: Melanie M Frigault, Aleksandra Markovets, Barrett Nuttall, Kyoung-Mee Kim, Se Hoon Park, Esha A Gangolli, Peter G S Mortimer, Simon J Hollingsworth, Jung Yong Hong, Kyung Kim, Seung Tae Kim, J Carl Barrett, Jeeyun Lee
• Journal: JCO precision oncology (JCO Precis Oncol) Vol. 4 ( 2020) ISSN: 2473-4284 [Electronic] United States
• PMID: 32923890 (Publication Type: Journal Article)
• Copyright: © 2020 by American Society of Clinical Oncology.