Over the course of the last 15 years, the discovery that some lung cancers are driven by gene mutations that can be targeted with drugs has dramatically increased survival time for many patients. However, one identified mutation, to the KRAS gene, has eluded effective drugs.
The reign of this “undruggable” mutation, carried by approximately 13 percent of patients, may be at an end, however, according to newresearch presented at the recent International Association for the Study of Lung Cancer World Conference in Singapore.
Data from a phase 2 trial presented at the conference showed that, of 126 patients with non-small-celllung cancerand a KRAS mutation treated with the experimentalcancer drugsotorasib, 37.1 percent responded.
The average progression-free survival for all patients in the trial (the length of time in which the tumor did not grow) was 6.8 months. For patients who responded to the drug, the duration of the response lasted on average for 10 months.
All of the patients in the trial had advanced cancer and had received several therapies prior to trying sotorasib. The response rate is notable because most patients at this stage of treatment respond poorly to new therapies, with a typical response rate of less than 20 percent and progression free survival of less than four months.
The KRAS Mutations: A Long, Frustrating History
Many times, gene mutations, or errors, are harmless. But sometimes they wreak havoc. That’s the case with this mutation on the KRAS gene, which leads to an alteration in oneamino acidwith disastrous effects — the production of a protein that drives the proliferation of cancer cells.
"All KRAS proteins are smooth and round," saysBob Li, MD, PhD, MPH, anoncologistat Memorial Sloan Kettering Cancer Center in New York City, who led the global clinical trial. That makes it difficult for drugs to find purchase and enter the cell, he says.
“It’s like trying to catch a tennis ball with a key — it bounces off,” says Dr. Li.
A drug capable of glomming onto it has proved elusive for decades. “Despite its discovery in 1982, close to 40 years ago, we have no approved targeted therapy for KRAS. The word ‘undruggable’ is just a reflection of the frustration with that history,” says Li.
KRAS’s Window of Opportunity
Thebreakthrough came in 2013, when scientists at the University of California San Francisco discovered that the KRAS protein harboring the G12C mutation is sometimes active, meaning it sends growth signals, and sometimes inactive, meaning it does not.
During its inactive state, a tiny pocket, big enough for a drug molecule to enter, becomes available on the protein surface. Sotorasib is able to enter the protein during this inactive state and shut the cell down.
“This is a historic milestone in [lung] cancer therapy,” Li said, in a statement issued when the phase 2 results were released. “After four decades of scientific efforts in targeting KRAS, sotorasib has potential to be the first targeted treatment option for this patient population with a high unmet need.”
On February 17, the FDA granted priority review for sotorasib in the treatment of patients with a KRAS mutation and locally advanced or metastatic non-small-cell lung cancer. The U.S. Food and Drug Administration is likely to approve sotorasib as a new treatment for patients with the mutation later this year, according to aFebruary 16 article in Endpoints News.
目前,数据作为一个t sotorasib支持它herapy used alone, after several other treatments have been tried. In the future, it’s possible that sotorasib may be used as a first line therapy for patients with the G12C KRAS mutation, and may be used in combination with other therapies to improve its effectiveness.
*The FDA granted accelerated approval for Lumakras (sotorasib) for some advanced lung cancers on May 28th, 2021.
