Clinical Management of Acquired Resistance to Garsorasib (KRAS G12C Inhibitor)

Defining True Disease Progression

During continuous garsorasib therapy, objective radiological progression—defined by target lesion growth or new lesions with or without symptomatic worsening—is required to confirm treatment failure. Isolated tumor marker elevation alone does not warrant a switch in therapy; imaging is typically repeated every six to eight weeks per standard evaluation intervals.

Molecular Profiling at Progression

Acquired resistance commonly stems from secondary KRAS mutations, activation of bypass tracks such as EGFR, MET amplification, or PI3K signaling, and occasionally histological transformation. Circulating tumor DNA (ctDNA) testing offers rapid insight into emerging alterations, while tissue re-biopsy remains the most comprehensive approach when feasible.

Targeted Combination vs. Class Switching

If a co-occurring actionable alteration is identified, rational combination strategies may restore disease control—for instance, adding a MET inhibitor in cases of MET amplification. Conversely, cross-class switching to other commercial KRAS G12C inhibitors often yields limited benefit due to shared on-target resistance, unless progression is driven by non-G12C mechanisms.

Transitioning to Systemic Therapy

In the absence of druggable bypass mutations, platinum-based doublet chemotherapy becomes the standard of care. Fit patients may be evaluated for the addition of immune checkpoint blockade or anti-angiogenic agents, with garsorasib held during cytotoxic treatment cycles.

Leveraging Clinical Trials and Supportive Care

Early discussion regarding next-generation KRAS or pan-RAS clinical programs can preserve therapeutic continuity. Concurrently, proactive palliative management—addressing dyspnea, pain, and nutritional decline—remains an indispensable pillar of care after any line of targeted therapy falters.