CAMBRIDGE, Mass.--(BUSINESS WIRE)--Foundation Medicine, Inc. and its collaborators today announced results from a Dana-Farber Cancer Institute-led study that used genomic testing, including Foundation Medicine’s liquid-based comprehensive genomic profiling (CGP) test, FoundationOne®Liquid CDx, among several assays, to investigate resistance mechanisms in 38 patients with cancer treated with a KRAS G12C inhibitor. The study found a complex landscape of acquired resistance mechanisms, with putative resistance mechanisms identified in 45% of patients. These mechanisms were diverse, and some patients (18%) had multiple resistance alterations. Study findings support the need for development of additional KRAS inhibitors and combination treatment strategies and reinforce the utility of liquid biopsy assays in evaluating resistance. The study, “Acquired Resistance to KRAS G12C Inhibition in Cancer,” was published yesterday in The New England Journal of Medicine.
The KRAS oncogene encodes a protein frequently altered in cancer, and mutations typically occur at hotspots in the protein, increasing the activity of KRAS and driving pro-tumorigenic signaling. Although KRAS mutations are among the most common cancer drivers, only recently have investigational KRAS inhibitors entered clinical development, with the first KRAS inhibitor just approved for certain patients with lung cancer. In this study of patients receiving an investigational therapy, researchers identified multiple resistance pathways – in some cases even within a single sample – through the use of genomic testing from several labs. These findings help researchers better understand the landscape of acquired resistance to KRAS inhibitors to inform the development of additional therapeutics targeting KRAS alterations or combination therapies designed to block oncogenic signaling and result in clinical responses.
“Resistance mechanisms to cancer treatment are often complex, which is challenging for oncologists and researchers to describe and effectively counter. That’s why we were excited to help incorporate genomic testing though Foundation Medicine’s comprehensive liquid biopsy assay into this study – one of the first analyzing resistance mechanisms to KRAS inhibitors,” said Alexa Schrock, Ph.D., Director, Clinical Development at Foundation Medicine. “Comprehensive liquid biopsy assays not only enable widespread access to genomic testing, which is particularly appealing to patients with treatment resistance, but they also provide insights to help drive the development of new therapeutic approaches for these patients.”
The study included a total of 38 patients, 27 with non-small cell lung cancer (NSCLC), 10 with colorectal cancer and one with appendiceal cancer. Using multiple genomic tests, mechanisms of putative resistance to adagrasib monotherapy were detected in 17 patients (45% of the cohort), eight of whom had multiple resistance mechanisms. In one patient with NSCLC (tested with FoundationOne Liquid CDx), testing revealed acquired KRAS alterations including H95D, R68S, G12W and G12V, as well as acquired RTK and MAPK pathway alterations.
This clinical analysis was aided by a deep mutational scanning screen of a library of KRAS G12C variants that systematically defined potential secondary alterations conferring resistance to KRAS G12C inhibition. The findings suggest a diverse landscape of KRAS G12C inhibitor resistance mechanisms, which can help inform novel therapeutic strategies to effectively overcome this drug resistance in patients with cancer.
About FoundationOne®Liquid CDx
FoundationOne Liquid CDx is a qualitative next generation sequencing based in vitro diagnostic test for prescription use only that uses targeted high throughput hybridization-based capture technology to analyze 324 genes utilizing circulating cell-free DNA (cfDNA) isolated from plasma derived from anti-coagulated peripheral whole blood of advanced cancer patients. The test is FDA-approved to report short variants in over 300 genes and is a companion diagnostic to identify patients who may benefit from treatment with specific therapies (listed in Table 1 of the Intended Use) in accordance with the approved therapeutic product labeling. Additional genomic findings may be reported and are not prescriptive or conclusive for labeled use of any specific therapeutic product. Use of the test does not guarantee a patient will be matched to a treatment. A negative result does not rule out the presence of an alteration. Patients who are negative for companion diagnostic mutations should be reflexed to tumor tissue testing and mutation status confirmed using an FDA-approved tumor tissue test, if feasible. For the complete label, including companion diagnostic indications and complete risk information, please visit www.F1LCDxLabel.com.
About Foundation Medicine
Foundation Medicine is a molecular information company dedicated to a transformation in cancer care in which treatment is informed by a deep understanding of the genomic changes that contribute to each patient's unique cancer. The company offers a full suite of comprehensive genomic profiling assays to identify the molecular alterations in a patient’s cancer and match them with relevant targeted therapies, immunotherapies and clinical trials. Foundation Medicine’s molecular information platform aims to improve day-to-day care for patients by serving the needs of clinicians, academic researchers and drug developers to help advance the science of molecular medicine in cancer. For more information, please visit www.FoundationMedicine.com or follow Foundation Medicine on Twitter (@FoundationATCG).
Foundation Medicine® and FoundationOne® are registered trademarks of Foundation Medicine, Inc.
Source: Foundation Medicine