What is the management approach for patients with uncommon Epidermal Growth Factor Receptor (EGFR) mutations?

Management of Uncommon EGFR Mutations in NSCLC

For patients with major uncommon sensitizing EGFR mutations (G719X, L861Q, S768I), afatinib or osimertinib should be used as first-line monotherapy, while EGFR exon 20 insertions require platinum-based chemotherapy followed by targeted agents like amivantamab or mobocertinib after progression. 1

Initial Diagnostic Approach

Comprehensive molecular testing is essential:

• Perform broad screening of EGFR exons 18-21 using next-generation sequencing (NGS) rather than single-gene testing 1
• NGS enables identification of all clinically significant mutations including uncommon variants, compound mutations, and co-occurring alterations 1
• Initiate reflex biomarker testing at initial diagnosis for all non-squamous NSCLC patients regardless of stage 1

Classification of Uncommon EGFR Mutations

Uncommon EGFR mutations fall into distinct categories with different treatment sensitivities 1:

TKI-Sensitive Uncommon Mutations (10-15% of EGFR mutations):

• G719X point mutations in exon 18 (~3% of EGFR mutations) 1
• L861Q mutations in exon 21 (~2% of EGFR mutations) 1
• S768I mutations in exon 20 (~2% of EGFR mutations) 1
• Compound mutations containing these variants 1

TKI-Resistant Uncommon Mutations:

• Most EGFR exon 20 insertions (4-10% of all EGFR mutations) 1
• Exon 19 insertions 1
• Specific point mutations: L747S, D761Y, T790M (de novo), T854A 1

Treatment Algorithm for Major Uncommon Sensitizing Mutations

First-Line Treatment for G719X, L861Q, S768I:

Preferred TKI options:

• Afatinib 40 mg daily is FDA-approved specifically for G719X, S768I, and L861Q mutations based on pooled data from Lux-Lung 2,3, and 6 trials showing PFS and response rates comparable to common EGFR mutations 1
• Osimertinib is an alternative option with confirmed activity in these major uncommon alterations, though based on more limited datasets 1

Important caveat: Gefitinib shows significantly shorter PFS in these uncommon mutations compared to afatinib and should be avoided 1

Alternative approach:

• Platinum-pemetrexed chemotherapy can be considered when evidence supporting TKI efficacy is limited or for atypical mutations without established TKI sensitivity 1
• Avoid adding immune checkpoint inhibitors to chemotherapy due to potential toxicity with subsequent targeted therapy and exclusion of EGFR-mutant patients from most ICI trials 1

Compound Mutations:

• Treat compound mutations containing common sensitizing mutations (exon 19 deletions or L858R) with standard EGFR TKIs regardless of the second mutation 2
• For compound mutations with major uncommon variants, use afatinib or osimertinib as for single uncommon mutations 1

Treatment Algorithm for EGFR Exon 20 Insertions

First-Line Treatment:

Platinum-based chemotherapy is the cornerstone of initial therapy 1

• Use platinum-pemetrexed doublet chemotherapy 1
• Avoid checkpoint inhibitor monotherapy - KEYNOTE 024 and 042 excluded all EGFR mutations, and response rates are poor (~4% ORR) 1, 3
• Adding immunotherapy to chemotherapy is controversial with unclear benefit over chemotherapy alone; preferably avoid due to potential toxicity with subsequent targeted agents 1

Second-Line Treatment After Platinum Failure:

FDA-approved targeted agents:

• Amivantamab (bispecific antibody targeting EGFR and MET) 1
• Mobocertinib (selective oral TKI for EGFR/HER2 exon 20 insertions) 1

Note: Standard EGFR TKIs (erlotinib, gefitinib, afatinib, osimertinib) show minimal activity with ORR ~13% and mPFS 3.4 months for most exon 20 insertions 3

Exception - S768I variant: This specific exon 20 mutation (distinct from exon 20 insertions) shows moderate TKI sensitivity with 50% ORR and 18.2 months mPFS, justifying TKI use 3

Management of Very Rare EGFR Mutations

For very rare single point mutations and atypical variants without established TKI sensitivity 2:

• Treatment responses are highly heterogeneous 2
• Consider platinum-pemetrexed chemotherapy as first-line 1
• TKI trial may be reasonable if the mutation contains a known sensitizing component 2
• Comprehensive NGS analysis is critical to identify the dominant oncogenic driver 1

Co-Occurring Alterations

When EGFR mutations coexist with other targetable alterations:

• Perform comprehensive NGS to identify the dominant clone 1
• EGFR TKIs generally show good response rates but inferior outcomes compared to isolated EGFR mutations 1
• If primary resistance occurs, consider targeting the co-alteration pathway 1
• Platinum-based chemotherapy with or without TKIs should be prioritized when multiple confirmed alterations coexist 1

Co-occurring TP53 mutations: Show a non-significant trend toward worse outcomes with EGFR TKI therapy in exon 20 insertions and very rare mutations, but not in major uncommon mutations 2

Monitoring and Resistance Management

At disease progression on any TKI therapy:

• Tissue rebiopsy is recommended when feasible to assess actionable resistance mechanisms and histologic transformation 1
• Characterize on-target resistance (e.g., T790M after first-generation TKIs), off-target bypass pathways, or histologic transformation 1
• Detection of T790M enables use of third-generation TKIs like osimertinib 1

Critical Pitfalls to Avoid

• Do not use gefitinib for uncommon sensitizing mutations - significantly inferior to afatinib 1
• Do not use standard EGFR TKIs for exon 20 insertions (except S768I point mutation) - resistance is inherent 1, 3
• Avoid checkpoint inhibitor monotherapy in any EGFR-mutant NSCLC - poor efficacy and risk of hyperprogressive disease (~20%) 1
• Exercise caution with TKI use after immunotherapy - increased toxicity risk due to long ICI half-life 1
• Do not assume all exon 20 mutations are insertions - S768I point mutation is TKI-sensitive unlike insertions 1, 3