What adjuvant therapy is recommended for a patient with completely resected non‑small‑cell lung cancer harboring an EGFR exon 20 insertion?

Adjuvant Treatment for Completely Resected NSCLC with EGFR Exon 20 Insertion

For patients with completely resected non-small-cell lung cancer harboring an EGFR exon 20 insertion, platinum-based adjuvant chemotherapy should be offered, as there are currently no approved targeted therapies for this specific mutation in the adjuvant setting. 1

Treatment Approach

Standard Adjuvant Chemotherapy

• Platinum-doublet chemotherapy remains the cornerstone of adjuvant treatment for completely resected stage II-IIIA NSCLC with EGFR exon 20 insertions 1
• Cisplatin-based regimens (such as cisplatin plus vinorelbine) are preferred based on the LACE meta-analysis demonstrating a 5.4% 5-year overall survival improvement, with the most pronounced benefit in stage III patients (HR 0.83; 95% CI 0.72-0.94) 1
• Carboplatin-based chemotherapy is a reasonable alternative for patients with contraindications to cisplatin, as demonstrated by improved overall survival (33 months vs 24 months, P=0.037) in resected stage III NSCLC 1

Why Targeted Therapy Is Not Recommended

Critical distinction: EGFR exon 20 insertions are fundamentally different from classical EGFR mutations (exon 19 deletions and L858R). 1

• Osimertinib, the only FDA-approved adjuvant targeted therapy for EGFR-mutant NSCLC, is specifically indicated only for exon 19 deletions and exon 21 L858R mutations—not for exon 20 insertions 1
• EGFR exon 20 insertions are resistant to first-, second-, and third-generation EGFR TKIs due to disruption of the α-C helix protein structure, which lowers affinity for these agents 1, 2
• The ADAURA trial, which established osimertinib's role in the adjuvant setting, specifically enrolled only patients with exon 19 deletions or L858R mutations 1

Molecular Testing Considerations

• Comprehensive molecular profiling should be performed on all resected non-squamous NSCLC to identify the specific EGFR mutation subtype 1
• Distinguishing exon 20 insertions from classical EGFR mutations is essential, as this fundamentally changes treatment recommendations 1
• EGFR exon 20 insertions represent approximately 12% of all EGFR mutations and have prevalence similar to BRAF, ROS1, and ALK alterations 1

Emerging Therapies (Not Yet Approved for Adjuvant Use)

While targeted agents exist for metastatic EGFR exon 20 insertion-positive NSCLC, none are currently approved or studied in the adjuvant setting:

• Amivantamab (bispecific antibody targeting EGFR and MET) is FDA-approved only for second-line therapy in metastatic disease after platinum-based chemotherapy 1, 3
• Mobocertinib (selective oral TKI) has shown activity in the metastatic setting but has no adjuvant data 4
• These agents should not be used off-label in the adjuvant setting outside of clinical trials 1

Immunotherapy Considerations

Checkpoint inhibitors should not be routinely added to adjuvant chemotherapy for EGFR exon 20 insertions:

• EGFR-mutant tumors (including exon 20 insertions) typically have low tumor mutational burden and show limited benefit from immune checkpoint inhibitors 1
• The combination of immunotherapy with chemotherapy in this population lacks comparative data demonstrating superiority over chemotherapy alone 1
• There is potential risk of increased toxicity with subsequent targeted therapy if immunotherapy is used first, due to the long half-life of checkpoint inhibitors 1

Surveillance and Recurrence Management

• If recurrence occurs after adjuvant chemotherapy, platinum-based chemotherapy with or without bevacizumab should be considered as first-line therapy for metastatic disease 1
• After platinum failure in the metastatic setting, targeted agents such as amivantamab should be considered as second-line therapy 1, 3
• Repeat molecular profiling at recurrence is essential to identify any new targetable alterations 1

Common Pitfalls to Avoid

• Do not assume all EGFR mutations are the same—exon 20 insertions require different management than classical mutations 1
• Do not use osimertinib off-label for exon 20 insertions in the adjuvant setting, as it lacks efficacy for this mutation subtype 1, 2
• Do not delay adjuvant chemotherapy while waiting for investigational targeted therapies, as chemotherapy has proven survival benefit 1
• Do not prioritize single-agent immunotherapy, as KEYNOTE 024 and KEYNOTE 042 intentionally excluded patients with EGFR mutations 1