FDA’s Approval of Krazati Demonstrates ‘Watershed Moment’ for Treatment of NSCLC With Genetic Mutation

The Food and Drug Administration (FDA)’s recent approval of Krazati (adagrasib) added a second precision drug in what represents “a watershed moment” 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 patients with non-small cell lung cancer 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 sliding a key into the lock and turning it. In drug discovery, you have to build the molecular structure that fits into the pocket.”

However, Li described the unique shape of the KRAS gene is 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 spheric, you have a key, you try to lock it up, it just bounces off you just latch on to 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 undruggable because for four decades, we’ve just not been able to develop a targeted drug that can switch it off.”

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 on clinical trials. “During the pandemic, when everything was shut down, because of scientific collaboration between academic institutions, industry, government regulatory agencies, patients and their support groups getting on these trials against the undruggable (target), we’ve been able to leverage technology and continue multiregional clinical trials to get approval against the undruggable (target),” Li explained.

The clinical trials tested the laboratory discovery made in 2013 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 on G12C,” Li said. “(Krazati) leverages this vulnerability of the cancer to lock it up and keep it in a sleep state.”

Different Options for Patients

Prior to this FDA approval of Krazati and the first KRAS G12C inhibitor Lumakras (sotorasib), the only options for patients with KRAS G12C-mutant locally advanced or metastatic non-small cell lung cancer were systemic therapies such as platinum-based chemotherapy and immunotherapy-options, both of 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 they can maximize their outcome and their survival.”

Li also noted that the approval for Krazati is for the second-line or beyond setting, meaning that patients must first try standard systemic therapy before moving onto treatment with Krazati.

Genetic Testing Can Determine Eligibility

Li explained that Krazati is specific only to patients with lung cancer who have the KRAS G12C mutation. As a result, Li stressed it is crucial for patients to get properly tested. “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 good enough,” Li said.

According to Li. simply knowing the type of lung cancer a patient has isn’t enough anymore. “I need to know what the molecular drivers are. Are they KRAS G12C mutated, … along with many other drivers because they all may have a different drug that gives you a magic bullet to switch it off.”

Managing Side Effects

While Krazati brings many side effects primarily related to GI symptoms, Li believes they are preferable to the ones faced by patients on other therapies. “Compared to chemotherapy, I believe that the (Krazati) toxicity profile is manageable, but it’s certainly not without side effects,” Li explained.

He mentioned that data published in the New England Journal of Medicine from the KRYSTAL-1 trial indicated that most patients (97.4%) experienced side effects. He mentioned that the most common symptoms experienced by patients were diarrhea (70.9%), nausea (69.8%), vomiting (56.9%) and fatigue (59.5%).

The best way to manage side effects is to maintain proper communication between the patient and the doctor, as well as tailoring dosages to patients, Li suggested. “I think a dose reduction would be a very safe thing to do and the appropriate thing to do,” Li said. “Not everyone has to take the same dose as the approved dose; that’s not an individualized dose. Everybody's different. Everyone's metabolism is different. Not every patient needs 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 there will be similar drugs available for patients with different mutations. “The good news is … we’re working on different ways to lock up these bad actors,” Li said.

Li also pointed out the necessity to individualize treatments to specific mutations, explaining “there is no one size fits all (approach).”

Another issue, according to Li, is that Krazati does not give long-term outcomes for many patients. He mentioned that the median progression-free survival (time during and after treatment that a patient is alive without disease worsening) for patients in the trial 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's an advancement, but we need to do better, and we need to find out mechanisms of resistance, which we have (just) scratched the surface (of),” Li said.

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