Updates in the Treatment of EGFR Mutant Advanced-Stage NSCLC

Tony S.K. Mok, MD: Patients with osimertinib [Tagrisso] can either experience failure as a first-line treatment or as a second-line treatment, but in either treatment, the resistant pattern is similar. But for the resistance, we have to include the C797 mutation, second is the MET amplification, and then followed by HER2 amplification. After that, there is a long list of other possible causes. Now, for patients who have failed osimertinib previously, it is still the standard chemotherapy with platinum. The role of adding immunotherapy to the chemotherapy is still debatable but there are 2 studies coming up in 2022. One is the CheckMate 722, and the other is KEYNOTE-789. These studies help us know whether immunotherapy has a role in the osimertinib failure or TKI [tyrosine kinase inhibitor] failure.

There are a number of new agents that are quite promising for patients who have failed osimertinib, 1 of which is amivantamab [Rybrevant]. This is a bispecific antibody that targets both EGFR and MET. In the CHRYSALIS study, a patient who failed at osimertinib was treated with lazertinib [Leclaza], which is a third-generation TKI from Korea, with amivantamab. The response rate actually turned out to be 36%. The median progression-free survival is about 4.7 months. It is an early, but yet very encouraging data that a combination of lazertinib, which is a third-generation TKI, together with amivantamab, may have a degree of efficacy. The other talk of interest is that anti-HER3, an antibody-drug conjugant, that is called U3-1402. This is an agent with a relatively high payload of a very potent topoisomerase I inhibitor. This drug actually was reported to be efficacious by Pasi Janne at ASCO (American Society of Clinical Oncology). The response was about 39% and median progression-free survival is about 8.2 months. Obviously, they would have preferred developing in a phase 3 study. The early data is very encouraging. Those are the 2 top end therapies that are being investigated and probably will go to the next stage of development. The other 1 is MET amplification, and with that there is a potential combination of the EGFR-TKI with a MET inhibitor such as capmatinib [Tabrecta] or selumetinib [Koselugo]. A study from WCR this year suggests that the response rate of a patient who fails osimertinib and then goes on with osimertinib plus selumetinib, which is a MET inhibitor, is about 33%.

Solange Peters, MD, PhD: When a patient fails osimertinib, we like to stay targeted as long as possible. This remains the landmark of everything we do. If we continue trying to target the addiction, the driver of the tumor biology, and the malignant phenotype, it’s the most interesting thing to do before. Later on, you will have to go through chemotherapy of course. Thus, what we try to do first is use these new compounds. You have been seeing the data of osimertinib in combination with lazertinib and amivantamab, dual EGFR in metastatic disease and a monoclonal antibody. This result was showing a range of response rate around 40%. Of course, it’s still in clinical trials going through approvals in certain geographical regions but it would be a very interesting way to stay targeted. If you can document a MET amplification as being the mechanism of resistance, then you can combine a TKI with a MET inhibitor, gefitinib [Iressa] plus capmatinib, or you can use savolitinib [Orpathys] and osimertinib. These are still in clinical trials, but you can target metastatic disease with them. There are other compounds for targeting HER3, which looks to be a kind of mechanism of passing resistance over the HER3 pathway. We have this patritumab deruxtecan, which can be interesting in all patients with resistance. There are some trials, for example, the Orca-T trial, which is looking at defining resistance mechanism and a subsequent line of targeted therapy. This is very interesting because a patient can stay on targeted therapy. If you don’t have this option, or if you don’t find the drug or a target, then it’s time to utilize chemotherapy. Of course, depending on where you are, it can only be chemotherapy platinum pemetrexed probably, or a bit more. In our country, we sometimes like to believe in the combination of anti-PD-1 [programmed cell death protein 1], anti-PD-L1 [programmed death-ligand 1], and anti-angiogenic and using the IMpower150. So, using paclitaxel [Abraxane], carboplatin, bevacizumab [Avastin], and atezolizumab [Tecentriq], we can use it in Europe. Remember that this antiangiogenic data has been confirmed by the ORION trial presented at ESMO recently. There might be a role in combining IO [immuno-oncology therapy], chemotherapy, and antiangiogenic in this specific EGFR mutating non-small cell lung cancer. In the U.S., I know sometimes what they do, they continue to add chemotherapy on the top, which makes sense to protect the brain. So depending where you are, it could be chemotherapy only, chemotherapy/IO antiangiogenic, or it can be sometimes chemotherapy continuing the osimertinib. There are trials, KEYNOTE-189 for example, now available for analyzing the simple combination of chemotherapy/IO, but these trials are awaiting and the data is still unavailable. We know that the benefit of IO on EGFR mutating non-small cell lung cancer is restricted and modest. The reason why is because people don’t really use this before the data comes.

This transcript has been edited for clarity.