NEW YORK – Mirati Therapeutics is hoping to set the bar for intracranial efficacy of KRAS inhibitors based on a positive data readout for Krazati (adagrasib) in KRAS G12C-mutant non-small cell lung cancer patients with untreated central nervous system (CNS) metastases.
Researchers published in the Journal of Clinical Oncology earlier this month prospective efficacy and survival data on 19 evaluable patients with advanced or metastatic KRAS G12C-mutant NSCLC with neurologically stable, asymptomatic, untreated CNS metastases from the Phase I/II KRYSTAL-1 trial.
The findings have bolstered Mirati's confidence in advancing other studies of Krazati including a trial evaluating two dose levels of the drug in NSCLC patents with untreated brain metastases. The company also plans to explore the drug's activity in other tumor types that have spread to the brain, said Mirati Chief Medical Officer Alan Sandler.
"We are the only G12C inhibitor that has shown [activity in untreated CNS metastases] in a prospective manner," Sandler said. "It's a key differentiator between us and Amgen's drug [Lumakras (sotorasib)], and any other future [KRAS inhibitor] drug will have to show that, too."
While Mirati expects to discuss this and upcoming CNS data with the US Food and Drug Administration, it's unclear if a label change or indication expansion is necessary to prescribe Krazati to these NSCLC patients with brain metastases, Sandler said.
In his view, these metastatic NSCLC patients may fall under Krazati's already approved indication. "We'll have to see whether or not it's necessary to [expand the label]," Sandler said. "We want to see if there are patients [in this group] that are not receiving the drug because it's not on the label, but we're not sure that's quite the case."
It's likely that physicians prescribing Krazati have already seen its activity in the brain, he noted, since the National Comprehensive Cancer Network in a March guideline update said Krazati could be an option for KRAS G12C-mutant NSCLC patients with CNS metastases. That update was based on analysis that Mirati previously reported on Krazati's CNS activity, which did not include mature duration of response or overall survival data and included patients with previously treated CNS metastases.
In the latest analysis, among the 19 evaluable NSCLC patients with CNS metastases, 42 percent had an intracranial response on Krazati including three patients who had a complete intracranial response. The intracranial disease control rate was 90 percent. Time to response was 2.1 months and the median intracranial duration of response was about one year.
The median progression-free survival was 5.4 months with a 12-month progression-free survival rate of 33.9 percent. With a follow-up of 13.7 months, the median overall survival was 11.4 months and the 12-month survival rate was 41.1 percent.
Marcelo Negrao, lead author of the study and an assistant professor of thoracic head and neck medical oncology at MD Anderson Cancer Center, noted that these data may reassure clinicians that they can potentially delay standard-of-care stereotactic brain radiotherapy for patients with brain metastases in favor of systemic treatment.
"For this patient population, it is reassuring that you could start off with systemic therapy and assess what the response in the brain would be," Negrao said. "That way, you're not delaying start of systemic therapy, which patients may need urgently, and at the same time, you're giving these patients good and effective treatment for their CNS metastases."
Negrao noted that the treatment failed to reduce CNS tumors in only two patients in the trial but yielded responses in other tumor locations. This, he said, provides another "layer of reassurance" for physicians that Krazati will likely be able to treat both the original tumor site and brain metastases.
"It was a minority of the patients that had failure in the CNS by itself," he said. "That highlights that when you fail [in the brain], you're probably going to fail systemically as well, so that patient will need a new systemic therapy altogether."
While Krazati is the first KRAS inhibitor to report activity in untreated CNS metastases, Amgen earlier reported intracranial activity for Lumakras in KRAS G12C-mutant NSCLC patients with previously treated CNS metastases. Those data showed that among 69 patients who received Lumakras in the CodeBreaK 200 trial, the median progression-free survival was 6.1 months and the time to CNS recurrence was 9.6 months. The study further showed that Lumakras outperformed chemotherapy in both endpoints in this population with previously treated brain metastases.
Previous efficacy data from the KRYSTAL-1 trial in KRAS G12C-mutant NSCLS patients without CNS metastases was similar to the activity in this group. The results that led the FDA to approve Krazati in December showed an overall response rate of 43 percent and an 80 percent disease control rate. A pooled analysis from the Phase I and Phase II portion of the trial at the time demonstrated a median overall survival of 14.1 months on Krazati.
Mirati expects to continue evaluating Krazati's CNS activity in lung cancer and other tumor types. Sandler noted that the concordance between response rates at primary tumor sites and in the brain is encouraging in terms of Krazati's activity in other tumor types that have spread to the brain.
Mirati is studying Krazati in colorectal and pancreatic cancer trials that could include patients with brain metastases. While colorectal cancer does not metastasize to the brain as frequently as NSCLC or pancreatic cancer, the firm will collect data on the drug's CNS activity in both these studies, Sandler said.
The firm also has an ongoing Phase II study, called KRYSTAL-21, in which Mirati is evaluating two dose levels of Krazati in KRAS G12C-mutated NSCLC patients, including those with stable, active brain metastases. That study is evaluating a 600 mg dose, the same dose as in KRYSTAL-1, and a lower 400mg dose.
Mirati is also hoping to evaluate in the KRYSTAL-21 study whether Krazati could be used to prevent new brain lesions, Sandler highlighted.
"With Krazati being able to cross the blood-brain barrier in a non-disruptive way, one could theorize that we might be able to prevent the development of brain metastasis in these groups of patients," he said. "[In KRYSTAL-21], we'll be able to both look at the effectiveness in the untreated patients and also be able to evaluate the development of new brain metastases. And we're looking at the delay in the development of brain metastases in an exploratory fashion in some of our other studies as well."