Dr Herzberg on the Distinctions Between Sotorasib and Adagrasib for KRAS G12C+ NSCLC

"Amongst our two commercially available KRAS G12C inhibitors for NSCLC, which are sotorasib and adagrasib there is really more in common than there is different."

Benjamin Herzberg, MD, an assistant professor of medicine at Columbia University Irving Medical Center, discusses the clinical similarities and key distinctions between the two commercially available KRAS G12C inhibitors—sotorasib (Lumakras) and adagrasib (Krazati)—for the treatment of non–small cell lung cancer (NSCLC) harboring a KRAS G12C mutation.

According to Herzberg, sotorasib and adagrasib share many clinical attributes, including comparable toxicity and response profiles. The adverse effect spectra for both agents are consistent with on-target KRAS inhibition and typically include gastrointestinal symptoms, elevated liver enzyme levels, and fatigue. These toxicities are generally manageable and rarely treatment limiting, allowing both drugs to be administered safely in most clinical settings.

Response rates between the 2 agents are also largely similar, with both demonstrating objective response rates in the range of 35% to 45% and a median progression-free survival of approximately 6 months in previously treated patients, Herzberg said. These data support their utility in the second-line or later settings for patients with advanced KRAS G12C–mutant NSCLC.

However, Herzberg highlights 1 notable difference between the two agents: central nervous system (CNS) activity. Although sotorasib has shown potential CNS penetration based on retrospective analyses and small cohorts, the evidence supporting adagrasib’s CNS activity is more robust. Data from clinical studies with adagrasib have demonstrated intracranial responses, offering greater confidence in its ability to control brain metastases. As a result, Herzberg noted that adagrasib may be the preferred option in patients with active brain metastases or in those at higher risk for CNS progression.

The choice between sotorasib and adagrasib in clinical practice is often guided by patient-specific factors, including the presence of brain metastases and the treating physician’s experience with each agent. In the absence of head-to-head comparative data, both inhibitors remain viable and effective treatment options for KRAS G12C–mutant NSCLC, Herzberg explained.

Herzbreg concluded by noting that although sotorasib and adagrasib are largely similar in their systemic activity and toxicity, the emerging intracranial data with adagrasib may offer a clinical advantage in select patient populations. Further studies will be important to clarify the comparative efficacy and CNS penetration of these agents in KRAS G12C–mutant NSCLC.