Krazati’s FDA approval demonstrates a “defining moment” for the treatment of NSCLC with a gene mutation

The Food and Drug Administration (FDA) recent approval of Krazati (adagrasib) represents “a turning point” after 40 years of attempts to treat lung cancers with the KRAS G12C gene mutation, an expert said.

CURE® spoke with Dr. Bob Li, a medical oncologist and physician scientist at Memorial Sloan Kettering Cancer Center in New York City, to learn more about how Krazati can benefit non-small cell lung cancer patients with the KRAS G12C mutation and knowledge gaps that persist in this area.

Trying to target KRAS with therapy

“In targeted therapies, we rely on a lock and key approach,” Li explained. “It’s almost like slipping a key into the lock and turning it. In drug discovery, you have to build the molecular structure that fits in your pocket.”

However, Li described the unique shape of the KRAS gene as a unique challenge for researchers. Of note, the KRAS gene is a gene that creates the K-Ras protein, which is involved in cell signaling pathways that control cell growth, cell maturation, and cell death. “KRAS is like a tennis ball,” Li said. “It’s so round and spherical, you have a key, you try to lock it, it just bounces off and you hold onto it.”

Li added: “KRAS is responsible for almost a quarter of non-small cell lung cancers. It’s a lot of people, a lot of tumors and a lot of suffering. … KRAS has been known… as non-druggable because for four decades, we just haven’t been able to develop a targeted drug that can turn it off.”

The pandemic brings new opportunities

During the COVID-19 pandemic, there were more opportunities for researchers to work together to find a way to treat patients. “During the pandemic, when everything was shut down, because of the scientific collaboration between academic institutions, industry, patients, and their support groups to participate in these trials against non-drug (target) drugs, we have been able to get approval against non-pharmacological (target). ),” Li explained.

As a result, the researchers realized that the KRAS G12C mutation changes shape when it is inactive. “It opens up a little pocket, a little groove, and that provides a window of opportunity to insert a drug that binds to that groove in G12C,” Li said. “(Krazati) takes advantage of this vulnerability of cancer to lock it away and keep it in a dream state.”

Different options for patients

Prior to this FDA approval, the only options for patients with locally advanced or metastatic non-small cell lung cancer with the KRAS G12C mutation were systemic therapies, such as platinum-based chemotherapy and immunotherapy options, which may still be considered. treatment options. Li said. “(Systemic therapy and Krazati) are not mutually exclusive,” Li explained. “We need more and more options for patients so that they can maximize their outcome and their survival.”

Li also noted that Krazati’s approval is for the second-line or higher setting, which means patients must first try standard systemic therapy before moving on to Krazati treatment.

Genetic testing can determine eligibility

Li explained that Krazati is specific only for lung cancer patients who have the KRAS G12C mutation. As a result, Li stressed that it is crucial that patients get the proper tests. “As a first step, everyone with lung cancer needs genetic/genomic testing, next-generation sequencing, or molecular testing. … Knowing that you have a type of lung cancer is not enough,” Li said.

According to Li. simply knowing the type of lung cancer a patient has is no longer enough. “I need to know what the molecular drivers are. Are they mutated in KRAS G12C…along with many other drivers because they may all have a different drug that gives you a magic wand to turn it off?

Management of side effects

While Krazati brings many side effects mainly related to gastrointestinal symptoms, Li believes they are preferable to those faced by patients with other therapies. “Compared to chemotherapy, I think the toxicity profile (of Krazati) is manageable, but it’s certainly not without its side effects,” Li explained.

He mentioned that the data published in the Journal of Clinical Oncology from the KRYSTAL-1 trial indicated that the majority of patients (97.4%) experienced side effects. He mentioned that the most common symptoms experienced by patients were diarrhea (62.9%), nausea (62.1%), vomiting (47.4%), and fatigue (40.5%).

The best way to manage side effects is to maintain proper communication between the patient and the doctor, as well as tailoring the doses to the patients, Li suggested. “I think a dose reduction would be a very safe and appropriate thing to do,” Li said. “Not everyone has to take the same dose as the approved dose; that is not an individualized dose. All the world is different. Everyone’s metabolism is different. Not all patients need a full dose to have therapeutic efficacy. So it’s important to personalize the dosing with the patient and that requires ongoing discussion and follow-up between the patient and the oncologist.”

Looking to the future

Although Krazati can only be used for patients with the G12C mutation, Li hopes that similar drugs will be available for patients with different mutations. “The good news is… we are working on different ways to lock up these bad actors,” Li said.

Li also noted the need to individualize treatments for specific mutations, explaining that “there is no one-size-fits-all approach.”

Another problem, according to Li, is that Krazati does not provide long-term results for many patients. He mentioned that the median progression-free survival (time during and after treatment that a patient is alive without worsening disease) for the trial patients was only six and a half months and that overall survival (time that a patient with cancer is still alive) was 12.6 months.

“Yes, it is progress, but we have to do better, and we have to figure out the resistance mechanisms, which we have (just) scratched the surface of,” Li said.

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