EGFR+ Advanced NSCLC Resistant to Frontline TKIs: C797S Mutation

Expert perspectives on the management of C797S-mutated non–small cell lung cancer following failure of frontline TKIs.


Tony S.K. Mok, MD: So that is the MET. Now let’s take on another one. Are we hopeful that we are going to have an inhibitor on the C797S? Is there any drug in sight, Tetsuya?

Tetsuya Mitsudomi, MD, PhD: Yes. The situation may be different when the osimertinib is used as a first-line or secondary. If osimertinib is used as a first-line [therapy], then C797S is the first secondary mutation. In that case, the second generation TKI [tyrosine kinase inhibitor] will work. If you use a first or second generation as a first line, then osimertinib, then you will get the C797S. In that case you have the triple mutation; activating mutation plus T790M plus C797S. In that case, we need a fourth generation drug. I know that some companies are developing fourth generation TKIs, but now that many people use osimertinib as a first-line treatment I’ve been wondering [what] the role of those fourth generation TKIs will be.

Tony S.K. Mok, MD: You mentioned the fact that osimertinib failure, C797S, the first-generation work. Is it mostly preclinical? There’s no clinical?

Tetsuya Mitsudomi, MD, PhD: Right, yes.

Tony S.K. Mok, MD: Also there’s a cis and trans issue that only cis may work and trans doesn’t work. Also, in our routine testing, we cannot decide whether it is cis or trans. We need NGS [next-generation sequencing] before we can decide whether it’s cis or trans, right?

Tetsuya Mitsudomi, MD, PhD: Yes, but I think that in the case of the double mutation, activating plus C797S mutation, the trans/cis will not be the issue. If it’s a triple, then cis or trans will be the issue, but mostly, those are the cis mutation. So combining the first generation will probably not work, so we need a fourth generation.

Yi-Long Wu, MD, PhD: I think the fourth generation TKIs are focused on C797S. I think this is too small of a population. In my mind, I want to use the ADC [antibody-drug conjugate] drugs, such as HER3 [human epidermal growth factor receptor 3], to overcome this resistance, not that fourth generation TKI. So all the fourth generation TKI is also not so good for the C797S.

Tony S.K. Mok, MD: Yi-Long, just to get on your point, that [INAUDIBLE]. That the response rate above 39% and the median progression-free survival of 8.2 months [INAUDIBLE] medium sized, single-arm study. Then the question is, how would you select the patient? It’s not a dramatically high response rate because the standard chemotherapy may also give you a 37% response rate. So how would you select [a] patient if you want try to use an anti-HER3 ADC? Lu Shun?

Shun Lu, MD, PhD: Right now, we have several strategies. One is the HER3 ADC, as you mentioned. Another is the Johnson & Johnson study Korean colleagues already presented on the bispecific lazertinib. I already published the results in 1 study, using chemo plus IO [immunotherapy] plus Avastin [bevacizumab], biosimilar [INAUDIBLE], with several strategy. But only, as you mentioned, Tony, the [INAUDIBLE] study is the single arm, phase 1/2 study. But although they say they covered all the drug resistance, we still needed to select the patients to compare with the standard of the chemotherapy. Right now we have no clear biomarker. For the Johnson & Johnson, they have several signal. They say that for MET amplification, EGFR mutant, maybe [the] Johnson & Johnson combination gets more benefit. For this kind of patient, they can do the randomized study with chemotherapy. We have several strategies right now.

Tony S.K. Mok, MD: Myung-Ju?

Myung-Ju Ahn, MD: I agree. The HER3 ADC has quite promising research, but there’s no correlation with the HER3 expression. So EGFR is quite complex when they have a heterodimer with other alternate pathways. So I think the HER3 ADC, even in the heavily treated patient, the response rate is quite good, but we don’t have any predictive biomarkers so it can be the second- or third-line treatment. For C797S, we don’t have any data yet of the first generation TKIs, so why don’t you wait and we can do the trial first?

Tetsuya Mitsudomi, MD, PhD: Actually, I was happy to chair the doctoral presentation at ESMO [European Society for Medical Oncology annual meeting] for the ORIENT-31 [study]. Myung-Ju was discussed at that time, and I was so impressed with your results. Hopefully, we would like to see the OS [overall survival] benefit later.

Transcript edited for clarity.

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