Skip to main content
Premium Trial:

Request an Annual Quote

ASCO Study Details Activity of Amgen's Lumakras, First Approved KRAS-Targeted Drug, in NSCLC

NEW YORK – Amgen further detailed the activity of its US Food and Drug Administration-approved KRAS G12C inhibitor sotorasib (Lumakras) in non-small cell lung cancer patients at the American Society of Clinical Oncology's virtual annual meeting on Friday, showing the drug's efficacy across various subgroups with co-occurring tumor mutations.

At the meeting, researchers presented mature survival data from the single-arm Phase II CodeBreak 100 trial. The presentation comes a week after the FDA granted accelerated approval to sotorasib for patients with pretreated KRAS G12C-mutated, advanced or metastatic NSCLC, making it the first KRAS inhibitor to hit the market. The agency made its decision based on data from the same study showing an objective response rate of 36 percent and a disease control rate of 81 percent.

At the meeting, researchers reported additional results on 126 KRAS G12C-mutated, advanced NSCLC patients with a median follow-up of 15 months. Patients on sotorasib had a median overall survival of 12.5 months, a median progression-free survival of 6.8 months, and a response rate of 37 percent. Of the patients who responded, four had a complete response, 42 had a partial response, and 54 had stable disease. The median duration of response was 11 months.

Researchers screened patients' blood and tissue samples for KRAS G12C mutations using next-generation sequencing tests. In approving sotorasib, the FDA also approved two companion diagnostics to identify patients with this mutation: Qiagen's tissue-based Therascreen KRAS RGQ PCR kit and Guardant Health's blood-based Guardant360 CDx.

At ASCO, researchers led by Ferdinandos Skoulidis, an assistant professor in the department of thoracic/head and neck medical oncology at MD Anderson Cancer Center, also presented exploratory subgroup analysis from CodeBreak 100.

They looked at responses based on patients' treatment regimen prior to sotorasib. Patients who had received a checkpoint inhibitor but not platinum-based chemotherapy saw a higher response rate on sotorasib, 69 percent, compared to the 37 percent response rate seen in the entire study population. This subgroup also had longer median overall survival, 17.7 months versus 12.5 months for all participants, though the small number of patients may have skewed these results, cautioned Skoulidis. A majority of patients in the study (81 percent) had been previously treated with both platinum-based chemotherapy and immunotherapy.

Skoulidis and colleagues also considered sotorasib's efficacy according to patients' tumor mutational burden. Among patients with high and low tumor mutational burden, based on a cutoff of 10 mutations per megabase, the overall response rate was 40 percent and 43 percent, respectively.

Researchers also evaluated response rates among patients who had co-occurring mutations in genes such as TP53, STK11, and KEAP1. They reported that patients with STK11-mutant but KEAP1-wild type NSCLC had response rates of 50 percent, a median overall survival of 15.3 months, and a median progression-free survival of 11 months — better outcomes than in the overall study population. Skoulidis noted that STK11 was "previously associated with worse clinical outcomes" in NSCLC patients.

Meanwhile, KEAP1 mutations appeared to reduce sotorasib's efficacy compared to the overall population, with only 20 percent of patients in this subset experiencing tumor shrinkage. These lower response rates in patients with KEAP1-mutant tumors were seen regardless of whether they had STK11 mutations. Median progression-free survival was also lower, 5.5 months for those with KEAP1-mutant and STK11-wild-type tumors, and 2.6 months for those with mutations in both genes.

"These results suggest that STK11 mutations, when present alone, without co-occurring KEAP1 mutations, may be associated with improved sotorasib efficacy," Skoulidis said. "On the other hand, patients with KEAP1-mutant tumors appeared to derive less benefit from sotorasib."

While CodeBreak 100 was a single-arm study, Skoulidis said the median overall survival is better than what has been observed for advanced lung cancer patients with KRAS mutations who have been treated with docetaxel in other studies, including the Phase III SELECT-1 trial and the Phase III OAK trial. In these studies, lung cancer patients on docetaxel, which is being compared to sotorasib in the Phase III CodeBreak 200, have a median overall survival range of 7.9 months to 10.3 months, Skoulidis noted.

"Median overall survival of 12.5 months [in CodeBreak 100] in a more heavily pretreated population, with 81 percent having failed both immune checkpoint inhibitors and chemotherapy, and with favorable safety profile, I think represents a step forward," he said.

Amgen is conducting the Phase III CodeBreak 200 trial comparing sotorasib against docetaxel in a larger patient population to confirm the Phase II results. Skoulidis added that the drugmaker will explore in this trial whether a lower dose of sotorasib, 240mg versus 960mg, will impact efficacy.

"We look forward to results of CodeBreak 200," he said. "If the same magnitude of benefit of 12.5 months [median] overall survival is confirmed [in that trial], as a clinician I would consider that a benefit for patients compared to the standard of care."

Finally, Amgen is evaluating sotorasib in patients with solid tumors and untreated brain metastases in the CodeBreak 101 study. The CodeBreak 100 trial did include some NSCLC patients with brain metastases, Skoulidis said, but they had to have been previously treated and stable to be included in the trial.

Following the approval of Amgen's drug, more KRAS inhibitors will likely follow, as this is a highly active area for drug development. Mirati Therapeutics, for example, is also advancing a registration-enabling study for adagrasib in KRAS G12C-mutated NSCLC and is expecting to complete a new drug application submission to the FDA later this year.