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Amgen, Mirati Report KRAS Inhibitor Activity in Brain Metastases, Tumor Agnostic Cohorts at ASCO

asco 2023

CHICAGO – At the American Society of Clinical Oncology's annual meeting, Amgen and Mirati Therapeutics shared data on the activity of their KRAS inhibitors in new subsets of patients harboring KRAS G12C mutations.

Amgen's Lumakras (sotorasib) and Mirati's Krazati (adagrasib) are both approved in the US as treatments for previously treated KRAS G12C-mutant advanced or metastatic non-small cell lung cancer. Both firms are intent on expanding the indications of their drugs into additional settings and have previously reported therapeutic activity in colorectal and pancreatic tumors.

These first-generation KRAS inhibitors are paving the way in KRAS-mutant cancers. As Amgen and Mirati push their drugs forward into new cancer types and explore their activity in combination with other agents, next-generation treatments entering early-stage studies are trying to address some of the limitations of their predecessors.

"I'm very hopeful for the future because I think this is the decade when we finally crack the KRAS code," Shubham Pant, a professor of gastrointestinal medical oncology and investigational cancer therapeutics at MD Anderson Cancer Center, said at the meeting.

Lumakras' CNS activity

In the Phase III CodeBreaK 200 study, researchers compared Lumakras to docetaxel in pre-treated KRAS G12C-mutated advanced NSCLC patients, including those with previously treated central nervous system (CNS) metastases. At ASCO, they presented data showing that Lumakras improved progression-free survival and time to CNS recurrence versus chemo.

The analysis included 69 patients with CNS metastases at baseline across both study arms with a median follow-up of 20 months. In the Lumakras arm, the median progression-free survival was 6.1 months compared to 4.5 months on chemo. Time to CNS recurrence was 9.6 months with Lumakras versus 5.4 months with chemo.

In reviewing this data, Myung-Ju Ahn, a professor in the department of hematology and oncology at Samsung Medical Center in Seoul, said that it provided initial evidence of Lumakras' activity in patients with CNS metastases. Ahn was not involved with the CodeBreaK 200 study.

"However, this is a post hoc analysis in a small number of patients in each arm and has low statistical power," she added. "Given that only pre-treated and stable patients [with brain metastases] were enrolled in this study, the data on untreated measurable CNS metastases are still limited."

She noted that the incidence of brain metastases in KRAS G12C-mutant NSCLC is around 42 percent, and these patients typically have a poor quality of life and poor survival.

"Surgery and radiotherapy are an option, but recently CNS penetrating drugs are [becoming] more available," Ahn said. "A prospective study [of Lumakras] with serial CNS imaging in patients with active, untreated brain metastases should be explored."

Ahn also pointed out that Lumakras' competitor, Krazati, also has data on intracranial activity. Last year, Mirati reported data from a single-arm study of Krazati in KRAS G12C-mutant advanced NSCLC patients with both previously treated CNS metastases and active, untreated CNS metastases. Among the pre-treated CNS group, one-third had an intracranial response to Krazati, including five patients with a complete response, six with a partial response, and 17 with stable disease.

In previously untreated CNS patients, 32 percent had an intracranial response to Krazati, with three complete responses and three partial responses. The majority of patients, 80 percent, had an intracranial response on Krazati. The median intracranial progression-free survival was 4.2 months.

That data led to the National Comprehensive Cancer Network adding Krazati to its guidelines for KRAS G12C-mutant NSCLC patients with CNS metastases in March. Lumakras has not been added to these guidelines because this is the first intracranial data Amgen has reported on the drug.

Anne-Marie Dingemans, professor of thoracic oncology at Erasmus University Medical Center Cancer Institute in the Netherlands who presented the CodeBreaK 200 data on CNS metastases at ASCO on Sunday, suggested targeted treatments could be used to further delay brain radiotherapy.

"We know radiotherapy does not work immediately, so you always have time to delay it and see whether your targeted treatment has brain efficacy," Dingemans said. "Especially because we cannot predict the patients who will have long-term overall survival [on radiotherapy], it's good to start with systemic treatment, have careful follow-up, and when the patient responds, go on with targeted treatment and delay radiotherapy."

Krazati in a tumor-agnostic cohort

At ASCO, researchers also presented data from a solid tumor cohort of the Phase II KRYSTAL-1 trial of Krazati, which included patients with pancreatic, biliary tract, appendiceal, ovarian, endometrial, breast, and unknown primary cancers.

Krazati demonstrated a response rate of 35 percent and a disease control rate of 85 percent in 64 evaluable patients with various solid tumors. Among 21 patients with pancreatic cancer, the most common tumor type represented in this cohort, the response rate was 33.3 percent. Out of 12 biliary tract cancer patients, 41.7 percent responded to Krazati.

MD Anderson's Pant, who presented the KRYSTAL-1 data at ASCO on Saturday, highlighted Krazati's activity in gynecological cancers in the trial. In this small cohort of seven patients with ovarian and endometrial cancers, more than half, 51.7 percent, responded to Krazati. He added that the KRAS inhibitor's activity across multiple tumor types highlights the need to increase testing for KRAS G12C mutations to identify more patients who would benefit from KRAS inhibitors.

Median progression-free survival for Krazati-treated patients across tumor types was 7.4 months, while it was 5.4 months among pancreatic cancer patients and 8.6 months for those with biliary tract tumors.

Median overall survival was also higher among the patients with biliary tract cancer at 15.1 months. Median overall survival was eight months among pancreatic cancer patients and 14 months in the whole solid tumor cohort.

"Adagrasib demonstrated clinically meaningful activity in a variety of KRAS G12C-mutated solid tumors for which no standard-of-care treatment options are available," Pant said. "Clinical activity of adagrasib in patients with pancreatic cancer and biliary tract cancer is noteworthy, as chemotherapy has limited clinical activity in these patient populations in the second- and further-line setting."

Amgen's Lumakras has also shown activity in pancreatic cancer in previous reports. In data reported last year, Lumakras demonstrated an objective response rate of 21 percent, median progression-free survival of four months, and median overall survival of 6.8 months in this setting.

Based on the activity seen with both Krazati and Lumakras in clinical trials, the NCCN last month added the drugs to its pancreatic cancer treatment guidelines for patients with KRAS G12C mutations, even though these KRAS inhibitors are only approved for NSCLC.

Meanwhile, oncologists are eager to try out these drugs as earlier-line treatments, when patients are healthier and are likely to have better treatment outcomes. "Sometimes, patients enroll on these trials when they have declining performance status, and it's very hard to bring them back from the brink," Pant said. "The utility [of these drugs would be] to move them to post-first-line setting, so we can really see the benefit in these patients and give these patients who have a decent performance status at the time [the] benefit of the drug."