What is the first-line treatment for non-small cell lung cancer (NSCLC) patients with HER2 exon 20 insertion?

First-Line Treatment for NSCLC with HER2 Exon 20 Insertion

For patients with non-small cell lung cancer (NSCLC) harboring HER2 exon 20 insertion mutations, platinum-based chemotherapy should be offered as first-line therapy, preferably without immune checkpoint inhibitors (ICIs). 1

Treatment Algorithm

First-Line Treatment

1. Platinum-based chemotherapy

   • Standard platinum doublet chemotherapy regimens as recommended in NCCN guidelines 1
   • Preferably without immune checkpoint inhibitors due to:
     • Potential risk of toxicity with later lines of targeted therapy 1
     • Limited efficacy of ICIs in driver-mutated NSCLC 1
     • Data indicating ICI monotherapy may be less effective in NSCLC with HER2 mutations 1

2. Important considerations:

   • Complete molecular testing before initiating therapy to confirm HER2 exon 20 insertion status 1
   • Avoid single-agent immunotherapy regardless of PD-L1 expression levels 1
   • While chemotherapy plus immunotherapy combinations (like KEYNOTE-189 or IMpower-150 regimens) are feasible, it remains unclear if this approach is superior to chemotherapy alone 1

Second-Line Treatment Options

After disease progression on platinum-based chemotherapy:

1. Preferred option: Fam-trastuzumab deruxtecan-nxki (T-DXd) 1

   • Demonstrated 55% objective response rate in the DESTINY-Lung01 trial 1
   • Median overall survival of 17.8 months 1
   • Most patients (86%) in the trial had HER2 exon 20 insertion mutations 1

2. Alternative options:

   • Ado-trastuzumab emtansine (T-DM1) - categorized as "other recommended" option 1
   • Amivantamab or mobocertinib (if available) 1
   • Poziotinib - demonstrated 27.8% response rate in previously treated patients 2

Clinical Pearls and Caveats

• HER2 exon 20 insertions occur in approximately 2-5% of NSCLC cases (primarily adenocarcinomas) 1

• Molecular testing is crucial - NCCN recommends biomarker testing with tissue and/or blood-based broad multi-gene panel 1

• Standard EGFR TKIs are ineffective against HER2 exon 20 insertions due to structural changes that lower binding affinity 1

• Monitor for treatment-related toxicities:

  • T-DXd can cause interstitial lung disease (ILD) - 2 fatal cases reported in DESTINY-Lung01 1
  • Grade 3+ adverse events with T-DXd include neutropenia (19%) and anemia (10%) 1
  • Poziotinib has high toxicity rates including rash (48.9%), diarrhea (25.6%), and stomatitis (24.4%) 2

• Switching between agents with similar mechanisms of action at disease progression is not recommended 1

This treatment approach is based on the most recent NCCN (2024) and ESMO (2022) guidelines, which represent the highest level of evidence currently available for this specific molecular subtype of NSCLC.