Abstract
The FDA has approved the first KRAS-targeted therapy, sotorasib, for patients with previously treated non-small cell lung cancer with KRASG12C mutations. In a phase II trial, the drug yielded a median progression-free survival of 6.8 months in patients whose disease had advanced despite treatment with standard therapies, namely platinum-based chemotherapy and PD-1–PD-L1 inhibitors.
The FDA has granted accelerated approval to sotorasib (Lumakras; Amgen)—the first KRAS-targeted therapy—for patients with previously treated non–small cell lung cancer (NSCLC). The approval was based on results from the phase II CodeBreaK 100 trial in which the drug yielded a median progression-free survival (PFS) of almost 7 months in patients with locally advanced or metastatic NSCLC with KRASG12C mutations.
“We've come a long way in trying to understand how to identify and develop drugs against particular mutations in NSCLC, but KRAS has long been thought to be undruggable,” says Benjamin Levy, MD, of Johns Hopkins Sidney Kimmel Cancer Center in Baltimore, MD. “This data is particularly exciting because it's looking at a large subset of patients that represents about 13% of all nonsquamous non–small cell lung cancer patients.”
In the phase II trial, sotorasib elicited an objective response in 46 of 124 evaluable patients (37%) who had previously received standard therapies, such as platinum-based chemotherapy and PD-1–PD-L1 inhibitors (NEJM 2021 June 4 [Epub ahead of print]). The median PFS was 6.8 months, and the median overall survival was 12.5 months.
Adverse events were mostly low grade and reversible, noted the trial's lead investigator, Ferdinandos Skoulidis, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston. However, he cautions that clinicians should note two concerns highlighted in the approval: “Labeling includes the potential for hepatotoxicity, with a requirement for regular monitoring of liver function tests, and the risk of pneumonitis/interstitial lung disease,” he says. “Although the latter is rare, it can be life threatening, and patients that experience any new or worsening pulmonary symptoms during treatment with sotorasib should immediately stop treatment and undergo urgent diagnostic evaluation.”
Although de novo resistance to sotorasib is uncommon, most patients will eventually develop acquired resistance to the drug, Skoulidis adds. Based on emerging data, secondary mutations in KRAS or alterations in other components of the MAPK pathway, as well as lineage switching, may play a role.
Researchers are testing combination therapies with the potential to prevent treatment resistance, says Levy, who was not involved in the trial. The three most common strategies under investigation involve combinations of sotorasib or adagrasib (MRTX849; Mirati)—another KRASG12C inhibitor demonstrating effectiveness in ongoing studies—with an EGFR inhibitor, a SHP2 inhibitor, or immunotherapy.
“Additional research is required to delineate the molecular determinants of response to sotorasib and other KRASG12C inhibitors,” said Skoulidis. “We still need to characterize the full spectrum of innate and acquired resistance mechanisms in order to develop precision therapeutic strategies aimed at forestalling or overcoming clinical resistance.”
Sotorasib is getting immediate uptake in the clinic, says Levy. He advises physicians to revisit initial mutational analyses of patients with NSCLC whose disease has progressed to see if they are eligible for the drug.
“Patients with this mutation previously may have had no other treatment options except second-line chemotherapy with its accompanying negative side effects,” he says. “It's important to ensure that all patients with the KRASG12C mutation who are experiencing disease progression on other therapies have access to this new option.” –Janet Colwell
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