Activating mutations in this class of oncogenes, specifically KRAS, have made a big step forward scientifically and clinically just in the last couple of years.
As we continue our transition to biologically and genomically directed cancer
therapies, RAS gene mutations, that represent one of the first discovered, have remained an elusive target.
Activating mutations in this class of oncogenes, specifically KRAS, have made a big step forward scientifically and clinically just in the last couple of years. Previously, KRAS was seen as an “undruggable” mutation, and as such has been one of the major unmet needs in our cancer armamentarium. This mutation not only leads to a more aggressive disease pattern in many cancer types, but also makes patients more resistant to other biological therapies.
Through elegant cellular and molecular studies and innovations drug design, key advancements have been made to bring a new generation of drugs to the clinic.
Early results are showing great promise. One inhibitor, Lumakras (sotorasib), is approved by the Food and Drug Administration (FDA) to treat the KRAS G12C mutation in lung cancer. The approval came quickly following the results demonstrated in the CodeBreaK 100 clinical trial, making Lumakras the first targeted therapy for metastatic KRAS G12C-mutated NSCLC.
One patient featured in this special issue of CURE® benefited from being on the trial. She saw significant improvements in her symptoms within 10 days of being on the drug, and within four weeks had a noticeable decrease in the size of the tumors in her lungs.
She was only able to take the drug for five weeks because tumors in her brain and spine continued to grow — but she attributes stabilization of the lung cancer to Lumakras.
Another promising drug, adagrasib, received FDA breakthrough therapy designation in June 2021. Additionally, a new drug application was accepted this February for patients with previously-treated KRAS G12C-mutated NSCLC.
All these drugs have made great headway; one patient even discusses that she felt she won the lottery after learning she had the KRAS-G12C mutation and was able to be treated with Lumakras.
With more clinical trials underway, even more progress is around the corner for patients with KRAS G12C-mutated NSCLC. Ultimately, we expect to make progress in other cancers — notably in pancreatic cancer that exhibits KRAS mutations in 95% of cases, but predominantly affecting different base pairs in the same gene location: G12D, G12V and G12R. These mutations affect different amino acids on the KRAS protein and are not inhibited by Lumakras or adagrasib.
Success on this front will require additional discovery, but important groundwork has been laid.
DEBU TRIPATHY, M.D.
Professor and Chair
Department of Breast Medical Oncology The University of Texas MD Anderson Cancer Center