Management of EGFR C797S Mutation in NSCLC
For patients with EGFR C797S mutation detected after osimertinib failure, platinum-based chemotherapy remains the standard of care, though switching to first- or second-generation EGFR TKIs (gefitinib, erlotinib, afatinib) can be considered as these mutations do not confer resistance to earlier generation inhibitors. 1
Understanding C797S Mutation Context
The C797S mutation is a critical on-target resistance mechanism that develops in approximately 15% of patients after first-line osimertinib treatment. 1 This mutation represents one of the most common EGFR on-target alterations causing acquired resistance to third-generation EGFR TKIs, accounting for 10-20% of all resistance mechanisms. 1
Key Clinical Distinction
The treatment approach depends critically on whether C797S develops after first-line osimertinib versus second-line osimertinib (given for T790M resistance):
After first-line osimertinib: C797S mutation does not impart resistance to first- or second-generation EGFR TKIs, and clinical efficacy has been observed when switching to earlier generation inhibitors. 1
After second-line osimertinib (with T790M present): In >95% of cases, C797S occurs in cis with T790M, making first-generation TKIs ineffective. 1 Only when C797S occurs in trans (different allele than T790M) can first-generation EGFR TKIs provide benefit. 1
Treatment Algorithm
First-Line Approach
Platinum-based chemotherapy should be initiated as standard of care. 1 This remains the evidence-based recommendation with established efficacy data.
Alternative Targeted Approaches
Consider first- or second-generation EGFR TKIs (gefitinib, erlotinib, afatinib) in the following scenarios: 1, 2
- C797S developed after first-line osimertinib (without prior T790M)
- Patient preference for oral therapy over chemotherapy
- Clinical trial access is unavailable
A recent case report demonstrated that icotinib (first-generation TKI) provided 8 months of disease control in a patient with EGFR 19del/C797S after almonertinib failure. 2
Investigational Options (Preferred if Available)
Prioritize enrollment in clinical trials with novel agents targeting C797S resistance: 1
- Amivantamab (EGFR/MET bispecific antibody): Phase I/II data show clinical efficacy when administered alone or combined with lazertinib or patritumab deruxtecan 1
- HS-10375: A selective EGFR C797S inhibitor showing objective responses in phase 1 trials, with MTD established at 150 mg daily 3
- Fourth-generation EGFR TKIs designed specifically to overcome C797S resistance 4
Critical Diagnostic Considerations
Mandatory Molecular Testing
Perform comprehensive next-generation sequencing (NGS) at progression, not just targeted T790M testing. 5
Common pitfall: Many laboratories use rapid, low-cost methods specifically targeting T790M that will miss C797S and other resistance mechanisms like PIK3CA mutations. 5 This can lead to inappropriate treatment selection.
Essential testing requirements: 5
- NGS panel covering all EGFR exons (18-21 minimum)
- Assessment for co-occurring alterations (PIK3CA, MET amplification, HER2 amplification)
- Tissue biopsy preferred over liquid biopsy to detect histologic transformation (SCLC conversion occurs in 12-15% and cannot be detected by ctDNA) 1
Allelic Configuration Assessment
Determine whether C797S is in cis or trans configuration with T790M if both mutations are present, as this fundamentally changes treatment options. 1 This requires specialized molecular testing beyond standard NGS.
Management of Oligoprogression
For isolated or slow progression while on osimertinib with C797S detected: 1
- Continue osimertinib with local ablative therapy (surgery, SBRT, RFA)
- Consider dose escalation to osimertinib 160 mg if accessible
- Reserve systemic therapy change for widespread progression
When No Targetable Mechanism Identified
If comprehensive molecular testing reveals C797S without other actionable alterations and chemotherapy/TKI rechallenge have been exhausted, consider EGFR TKI rechallenge after ≥6 months off therapy. 1 The likelihood of benefit increases with longer treatment-free intervals.