Do trials help after Osimertinib resistance develops in men?

Question

Hi doctor,

I am 34 years old, and my younger brother, who is just 29, was diagnosed with EGFR-positive non-small cell lung cancer six months ago. He started on Osimertinib and initially responded well, but his latest CT scan showed the tumor has slightly increased in size, and the oncologist is saying there might be resistance developing. His T790M mutation was negative on the liquid biopsy. We are desperately trying to find clinical trials that might help him because standard second-line options like Docetaxel or Ramucirumab feel so aggressive for someone his age.

His performance status is still good, ECOG 1, and his lung function test shows FEV1 at 72 %. I have been trying to look on the internet, but I do not know how to filter properly for EGFR-positive non-small cell lung cancer trials that he would actually qualify for. His bilirubin and creatinine are normal.

Are there any specific phase 2 or phase 3 trials for Osimertinib resistance we should be looking at, and which type of doctor or center should we approach to get him enrolled?

Please help.

Thank you.

Answer 1

Hi,

Welcome to icliniq.com.

I am really sorry you and your brother are going through this.

What you are describing is, unfortunately, a well-known and very challenging phase in EGFR (estimated glomerular filtration rate)-mutated non-small cell lung cancer, especially when resistance to Osimertinib begins to develop despite an initially good response. The good news is that your brother’s relatively young age, good performance status ECOG 1 (Eastern Cooperative Oncology Group), and preserved organ function actually make him a strong candidate for clinical trials, and this is exactly the stage where trials are often most beneficial.

Right now, the most important concept is that “Osimertinib resistance” is not one single thing. There are multiple biological mechanisms, such as MET (mesenchymal-epithelial transition) amplification, HER2 (human epidermal growth factor receptor 2) changes, small-cell transformation, etc., and many modern trials are designed to target these specific resistance pathways. For example, one of the most promising and actively studied strategies is combining Osimertinib with MET inhibitors, especially when MET-driven resistance is suspected.

The SAVANNAH (phase II) and SACHI (phase III) trials are particularly important here, using Savolitinib and Osimertinib, and they have shown meaningful improvements in progression-free survival compared to chemotherapy. Even if your brother has not yet been tested for MET amplification, this is something his oncologist should strongly consider via tissue biopsy or advanced NGS panel (next-generation sequencing panel), because it directly opens eligibility for these trials.

Another major development you should know about is the newer EGFR/MET bispecific antibody approach, especially with drugs like Amivantamab. The MARIPOSA-2 trial (phase III) showed that combining amivantamab with chemotherapy (and sometimes Lazertinib) improved outcomes after Osimertinib progression, and this regimen is now becoming a new standard option in some regions. Importantly, there are still ongoing trials exploring Amivantamab combinations without heavy chemotherapy, which may be more suitable for someone young like your brother who you feel may not tolerate aggressive regimens well.

There are also trials exploring continuing Osimertinib with added chemotherapy (like Pemetrexed platinum), based on studies such as FLAURA2, which showed improved disease control when chemotherapy is layered onto targeted therapy. While this still involves chemo, it is often better tolerated than Docetaxel-based second-line regimens and is sometimes used in trial settings in a more controlled, personalized way.

I hope this information helps you.

Revert in case of queries.

Regards.