How is Lung Cancer With a KRAS Mutation Treated?

"RAS" is a protein in cells that trigger a series of chemical reactions that tell cells when to divide and when to die. If a RAS gene is mutated, the protein is abnormal, causing the cell to be continuously "on," growing and dividing in an uncontrolled way. KRAS mutations are seen in about 25% of lung adenocarcinomas (a type of lung cancer), and are more commonly present in people who smoke. Tumors with KRAS mutations have a worse prognosis. This type of mutation does not typically overlap with other driver mutations such as EGFR.

Genetics are becoming more important when it comes to treating lung cancer, Dr. Geoffrey Oxnard, a thoracic oncologist at Boston Medical Center, explained to SurvivorNet in a previous conversation on the topic.

“We want to know the genetics of a cancer,” he explained. “We want to know what makes that cancer tick. How does it think? What drives it? And so certainly in lung adenocarcinoma, there's an additional step that is standard beyond histology, beyond the pathologist looking at the specimen, which is getting the tumor DNA out and sequencing it to figure out what genetic changes are running that cancer, so that we can try to target those genetic changes.”

He added: “We are looking for mutations in genes like KRAS, EGFR, ALK, etc., and by finding these, we can get a better flavor for what makes this cancer tick and how to plan treatments down the line.”

A KRAS-Targeted Agent

For decades, KRAS-mutated lung cancer did not have a targeted therapy available. Chemotherapy was the only option for patients with locally advanced disease or disease that had spread (metastatic). This was not for lack of trying; many drugs were tested in clinical trials, but the lack of efficacy was thought to be from the unique molecular shape and structure of the KRAS protein.

However, in May 2021, the first KRAS-targeted agent called sotorasib received approval for patients who have received at least one prior systemic therapy such as chemotherapy. Approval was based on the clinical trial, aptly named "CodeBreak," which studied sotorasib vs. standard chemotherapy in non-small cell lung cancer patients with the KRAS G12C mutation.  (It’s important to note that sotorasib only targets the KRAS G12C mutation and not other KRAS mutations.  KRAS G12C makes up about 40% of mutations in NSCLC.)

The latest results of the CodeBreak trial were presented at the American Association for Cancer Research (AACR) annual 2022 meeting.

The CodeBreak Trial:

• The efficacy of sotorasib was evaluated in 174 patients whose disease had progressed on or after at least one prior systemic therapy.
• These patients were evaluated for two years.
• Overall, the response rate in patients receiving sotorasib was superior to chemotherapy.  The objective response rate (ORR) was 40.7% with a median response duration of 12.3 months. (ORR measures how tumors are responding based on radiological tests.)
• 32.5% of patients still alive at two years.

Currently, a trial is underway studying the use of sotorasib as the first treatment for patients with locally-advanced or disease that had spread (metastatic). The primary results are expected in 2023.

“Eventually KRAS therapy is going to move to first line, but it’s the whole process,” Dr. Narjust Duma, a thoracic medical oncologist at the Dana-Farber Brigham Cancer Center, tells SurvivorNet. “We start in third line, second line and then eventually get to first line.”

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Sotorasib Side Effects

Patients with brain metastases were not studied in the CodeBreak trial. This medication is given indefinitely until cancer progression or other reason to switch therapy. The most common side effects seen in patients are:

• Diarrhea
• Muscle aches and pains
• Nausea
• Fatigue
• Liver dysfunction
• Cough

Patients prescribed sotorasib should not take certain antacid medications like proton pump inhibitors (Prilosec, Prevacid) or H2 receptor blockers (Zantac, Pepcid).

The Significance of Sotorasib

Having an approved targeted agent for KRAS mutations is providing a lot of hope in the lung cancer community. Even those who study the disease admit that such a development would have been unheard of just a few years ago.

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“Fifty percent of all patients with lung cancer have a target mutation now,” Dr. Duma tells SurvivorNet. “It’s 50% of stage four, and (cancer is) becoming a chronic disease for some of these mutations. So, the EGFR, the ALK, ROS1, those patients have very prolonged responses. Those are the survivors that … when I was a fellow, I never thought we’d see a patient live that long with stage four cancer.

“The other mutations, we end up 50%, BRAF, KRAS, MET and RET. They do have target pills, but their response is not that long,” she added, noting that with the newer mutations, the drug development has a long way to go.

Questions to Ask Your Doctor

• Has my cancer been tested for the KRAS gene?
• If positive for the KRAS gene, how will this affect my cancer treatment?
• Is there a specific medication I can use to target the KRAS gene?
• How will I know if that is working to treat my cancer?

 

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