Thoracic Oncology

 2nd line NSCLC EGFR Exon 18 inframe deletion tx options

Kate Fox's profile image
Kate Fox posted 08-28-2025 03:36 PM

Hello. I've never done this before, but I was hoping to get some help with a difficult case of ours. 

I have a 52 YO male with metastatic (bone and lymph) NSCLC. ECOG 1. PDL1 1%.  EGFR Exon 18 inframe deletion p.E709_T710delinsD. 

Treatment history:

  • 1st line: Carboplatin/pemetrexed/osimertinib x 4 cycles starting April 2025, then pemetrexed/osimertinib x 4 cyles. Had good initial response, now with pulmonary progression

Repeat NGS pending although I don't expect to see any big changes. 

This mutation isn't called out in the NCCN guidelines that I can find. I was able to find some data that 2nd EGFR TKI is better than 1st generation TKI in 1st line, but that doesn't help here. The Tempus NGS report recommends afatinib likely due to this study.  

Options as I see from looking through guidelines of other EGFR mutations in NSCLC and lit search are afatinib monotherapy, afatinib + cetuximab, amivantamab, or datopotamab deruxtecan? No data that I can find of any of these agents/options in 2nd line with this specific exon 18 mutation, but I'd rather not go for monotherapy IV chemo or IO unless there is data showing this mutation doesn't infer IO resistance.  

Any thoughts or perspectives appreciated. 

Lauren Yeager's profile image
Lauren Yeager posted 08-29-2025 10:32 AM

Kate,

We recently had a patient with both EGFR L858R and EGFR Exon 18 E709. She progressed on Osimertinib monotherapy after just under 2 years. We also debated next steps for her and ended up going with afatinib monotherapy based on https://pubmed.ncbi.nlm.nih.gov/38578683/ and other articles suggesting E709 conferring resistance to 3rd gen TKI. It was also appealing from an ease of administration perspective compared to the other options. I'm assuming your patient likely progressed quicker due to not having a co-19/21 mutation and just having the exon 18 E709 mutation. Our patient unfortunately progressed after a little under 2 months of therapy with afatinib. We planned to transition to Ami/chemo after this, but she ended up not making it out of a hospitalization and going hospice. Where your patient already had Carbo/Peme recently, your listed options sound very reasonable for next steps pending NGS results and insurance approval. Best of luck to your patient!

-Lauren

Kevin Chen's profile image
Kevin Chen SIG Leader posted 09-03-2025 05:56 AM

Hi Kate, 

Sounds like a tricky situation. Agree with Lauren that these exon18 mutations may respond better to second-generation EGFR TKIs. There's some in-vitro data suggesting that the E709_T710delinsD may actually be more afatinib sensitive than the other more exon18 mutations seen such as G719X (https://pubmed.ncbi.nlm.nih.gov/26206867; FYI - AZD9291 is osimertinib). Durability may be difficult to predict given the scarcity of this mutation and most of the available evidence being case reports, but it may be worth a shot given his short duration of chemo-osi treatment. Other options such as amivantamab and dato-dxd also seem reasonable to me, but convenience of oral vs IV treatments are an important factor to consider when discussing with patient & their goals. Wishing your patient the best. 

-Kevin

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