Dr Skoulidis on Emerging KRAS Inhibitors in NSCLC

The treatment landscape for KRAS-mutated non–small cell lung cancer (NSCLC) is rapidly evolving, with multiple targeted therapies advancing through clinical development. Although newer KRAS inhibitors are demonstrating promising clinical activity, important questions remain about how these agents will compare and how clinicians will determine the most appropriate treatment for individual patients.

In an interview during the  European Society for Medical Oncology (ESMO) Congress 2026, Ferdinandos Skoulidis, MD, PhD, discusses the expanding range of KRAS-targeted approaches and the need to better understand their differences.

Skoulidis,a professor of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, described divarasib as a best-in-class inactive-state-selective KRAS G12C inhibitor. During the meeting, Skoulidis presented results from the primary analysis of the phase 3 Krascendo 1 trial (NCT06497556), which showed that divarasib significantly improved progression-free survival and overall survival vs sotorasib (Lumakras) or adagrasib (Krazati) in patients with previously treated KRAS G12C–mutated advanced or metastatic NSCLC.

Skoulidis notes that beyond divarasib, several other chemically distinct inhibitors are also being investigated. These include dual-state inhibitors, which target both the active and inactive forms of KRAS, and active-state inhibitors, which target the GTP-bound form of the protein. 

One important unanswered question, according to Skoulidis, is how these different classes of KRAS G12C inhibitors will compare with one another, particularly when combined with immunotherapy in previously untreated patients. Understanding whether a particular inhibitor class offers advantages in efficacy or treatment combinations will be important as additional clinical trial results become available.

Beyond mutation-selective inhibitors, broader approaches targeting RAS signaling are also under investigation. Skoulidis highlights daraxonrasib (Rasonque), a pan-RAS inhibitor being evaluated in patients with previously treated RAS-mutant NSCLC. The phase 3 RASolve-301 trial (NCT06881784) is comparing daraxonrasib with docetaxel, and its results are anticipated to help clarify the role of broader RAS inhibition in this setting.

As both mutant-selective and broad-spectrum RAS inhibitors advance through development, selecting the optimal treatment for an individual patient will become an increasingly important challenge. Skoulidis emphasizes that clinicians will need to understand how the different approaches compare and determine which therapeutic strategy is best suited to each patient's disease.

He notes that his research team is actively investigating these questions through laboratory studies, while pivotal clinical trials will provide important clinical evidence. Together, these efforts may help establish a framework for selecting among the growing number of KRAS- and RAS-directed therapies and determining which approach is most appropriate for individual patients with NSCLC.