Why is Gefitinib (Iressa) sensitive in the presence of T790M and C797S mutations?

Gefitinib Sensitivity in T790M and C797S Co-Mutation

Gefitinib regains sensitivity when T790M and C797S mutations are present together because the C797S mutation, which causes resistance to third-generation EGFR inhibitors like osimertinib, does not confer resistance to first-generation reversible EGFR inhibitors—and the critical determining factor is whether these mutations exist in trans (on different alleles) versus cis (on the same allele). 1

Mechanistic Basis for Restored Sensitivity

The allelic configuration determines treatment response:

• Trans configuration (T790M and C797S on different alleles): Tumors retain sensitivity to first-generation EGFR TKIs like gefitinib or erlotinib because the C797S mutation specifically blocks third-generation inhibitors but does not prevent binding of reversible inhibitors to the ATP-binding pocket 1, 2

• Cis configuration (both mutations on same allele): No EGFR TKI—alone or in combination—can effectively suppress EGFR activity, as the compound mutation profile creates pan-resistance 1

• C797S without T790M: When C797S develops in the absence of T790M (such as after first-line osimertinib), tumors remain sensitive to first-generation TKIs because the T790M "gatekeeper" mutation is absent 1, 2

Clinical Evidence and Treatment Approach

Response Patterns

The ESMO 2022 consensus highlights that C797S is the most common on-target resistance mechanism to first-line osimertinib (occurring in ~15% of patients), and because osimertinib is structurally distinct from earlier generation inhibitors, these mutations do not confer resistance to first-generation EGFR TKIs 3

Clinical case reports demonstrate:

• Brief but measurable responses: A patient with T790M and C797S in trans treated with combination gefitinib plus osimertinib showed rapid clinical improvement within 2 weeks, with detectable decline in C797S subclone in plasma, though progression ultimately occurred at 6 weeks 4

• Sequential resistance evolution: A patient with EGFR deletion mutation who developed C797S after osimertinib responded to erlotinib for 4 months, but subsequently acquired T790M in addition to C797S (all in cis), leading to pan-resistance 5

Critical Caveats

The response to gefitinib in this context is typically transient and not durable 5:

• Preclinical mutagenesis screens demonstrate that EGFR-mutant cells with sensitizing mutation plus C797S, when exposed to gefitinib, preferentially develop additional T790M mutation, creating triple-mutant (sensitizing/T790M/C797S) clones that are resistant to all EGFR inhibitors 5, 6

• This represents tumor evolution and adaptability to sequential EGFR inhibition, with cells acquiring the exact mutations needed to escape each successive therapy 5

Current Guideline Recommendations

The 2018 CAP/IASLC/AMP guidelines explicitly state that C797S mutations are "poorly studied and not currently treatable, so testing for C797S is not recommended for routine management at this time" 3

Standard of care after osimertinib failure remains platinum-based chemotherapy 3, though the ESMO 2022 consensus acknowledges that alternative on-target therapies including first-generation TKIs "should be considered as preferred therapeutic options upon development of new EGFR mutations following osimertinib treatment, in the context of clinical trials" 3

Practical Algorithm

When C797S is detected after osimertinib progression:

1. Determine allelic configuration through comprehensive molecular profiling (NGS or droplet digital PCR) to identify whether T790M and C797S are in cis or trans 4, 1

2. Trans configuration: Consider gefitinib or erlotinib monotherapy, or combination gefitinib plus osimertinib in clinical trial setting, with expectation of brief response (weeks to months) 4, 5, 1

3. Cis configuration or C797S alone: First-generation EGFR TKI monotherapy may provide temporary benefit if T790M is absent 1, 2

4. Monitor closely with serial liquid biopsies for emergence of additional resistance mutations, particularly T790M 5

5. Transition to platinum chemotherapy remains the evidence-based standard when progression occurs 3

The fundamental principle is that C797S blocks third-generation inhibitors through steric hindrance at the cysteine 797 residue that these drugs covalently bind, but first-generation reversible inhibitors like gefitinib bind differently and can still access the ATP-binding pocket—though this advantage is rapidly lost as tumors acquire additional mutations under selective pressure 1, 2