ASCO Daily News: In Hot Pursuit of RAS Inhibition

Thomas George, MD
Thomas George, MD, Associate Professor of Medicine, Department of Medicine, Hematology/Oncology

RAS is a common mutation in malignancies yet historically is difficult to inhibit. AMG 510 is a new KRASG12C inhibitor with activity in non‒small cell lung cancer and other cancers.By Dr. Thomas George (pictured), et al.

Article Highlights

  • RAS is a common mutation in malignancies yet historically is difficult to inhibit.
  • AMG 510 is a new KRASG12C inhibitor with activity in non‒small cell lung cancer (NSCLC), colorectal, and appendiceal cancer.
  • A phase I clinical trial of AMG 510 showed partial response or stable disease in the majority of patients with NSCLC and colorectal cancer.

Rat Sarcoma (RAS) is the most commonly mutated gene in human malignancies, estimated to be mutated in 30% of cancer cells, and, therefore, it is a logical target for drug therapies.1,2 Overall, RAS mutations are present in 98% of pancreatic cancers, 52% of colorectal cancers (CRC), 43% of multiple myelomas, 32% of non–small cell lung cancers (NSCLC), and 29% of melanomas.2 RAS exists as a small membrane-bound protein with an active and inactive form and it triggers signaling cascades that are critical for normal cellular function.1,2 However, when mutated, the protein becomes inappropriately and constitutively active, giving rise to unopposed cellular signal transduction and tumorigenesis. The most frequently mutated isoform in cancer is Kirsten Rat Sarcoma (KRAS), seen in 83% of all RAS mutations.1

Clinically, RAS mutations can serve as a negative predictive biomarker for response to certain targeted therapies, namely anti-EGFR therapies (e.g., cetuximab and panitumumab) in CRC.3,4 Extended RAS profiling to determine RAS mutation status is now an established standard of care prior to treatment consideration with these agents in metastatic CRC.5 Although some meta-analyses have shown negative prognostic value of KRAS mutations in terms of overall and disease-free survival, others have shown no statistical association.3

Read the full commentary and review here.