From Biology to Best Practice: Sequencing Current and Emerging Therapies in EGFR-Mutated NSCLC Beyond Progression

So I will just introduce the biomarkers perspective in EGFR mutated non-small cell lung cancer, in general, in non-small cell lung cancer.

So when you think about EGFR field of development, it's quite important not to miss a single patient at the initial diagnosis.

And we know it now since more than fifteen years, having the knowledge of the presence of an EGFR mutation dramatically changes your treatment strategy, but also the prognosis of your patients, thanks to personalized treatment.

More importantly, too, to be able to also think, uh, about biomarkers at progression on targeted therapy, an EGFR TKI most of the time, in order to make sure that if you can remain personalized and targeted because you have identified the mechanism, you can potentially, again, tailor your treatment to the new biology of the tumor.

So does biomarker testing guide treatment not just for advanced metastatic, but also in early disease? So to make it more complex, the answer is unfortunately yes.

You need to know this biomarker not only in advanced disease, but also in early stage.

And these slides aim at illustrating why, but it can be even longer.

In term of early stage, early stage disease, now we know, for example, that when you have an EGFR mutation, but also an ALK rearrangement, a RET rearrangement, first of all, the usual chemo IO is not the good choice.

And more importantly, there is, uh, I would say a room for targeted therapies in the adjuvant setting in EGFR, in ALK, and in RET.

So basically you shouldn't give chemo IO upfront, and you should keep the room for targeted therapy in the adjuvant setting.

And it's even right when your local treatment is not surgery, but for example, chemoradiation in stage three for EGFR muta- mutant non-small cell lung cancer, where the LAURHAT trial has established that you can dramatically improve the disease-free survival and the survival by giving osimertinib after the completion of chemoradiation.

So here again, no immunotherapy, but an EGFR targeted therapy.

So of course, in stage one, two, and three, you need to know that you have an EGFR mutation.

Why should we conduct biomarker testing in EGFR mutation at progression? I told you also at progression.

It's because we have been describing for all of this oncogene addiction kind of field, some mechanism of resistance.

It can be bypass oncogenic signaling pathway, finding a new way to have the malignant phenotype for a cancer cell.

And these, uh, bypass tracks can be also targeted or blocked.

Of course, you have on-target secondary mutation.

In EGFR, we know very well the C797S way to prevent the binding, uh, of osimertinib and re- a histologic transformation, meaning that suddenly your tumor become a small cell or a squamous cell carcinoma.

And you need to know that because your treatment, as you have understood, will be dramatically different depending what you encounter as a mechanism of resistance.

And this slide is a usual pie telling you what was described as existing mechanism of resistance to EGFR tyrosine kinase inhibitors.

So you can see there are many different mechanism with a little less than half of the patient without a described mechanism with the unknown pattern of resistance mechanism.

And in order to constitute this pie, ideally tissue biopsy should be done because in the tissue you can find the histological transformation, but you can also find more rearrangements.

Remember, liquid biopsy are not very good to look at RNA.

But if you can't do a biopsy on tissue, we are still very happy to have a liquid biopsy to try to at most identify this actionable new pathway, uh, of resistance.

So I will just introduce the biomarkers perspective in EGFR mutated non-small cell lung cancer, in general, in non-small cell lung cancer.

So when you think about EGFR field of development, it's quite important not to miss a single patient at the initial diagnosis.

And we know it now since more than fifteen years, having the knowledge of the presence of an EGFR mutation dramatically changes your treatment strategy, but also the prognosis of your patients, thanks to personalized treatment.

More importantly, too, to be able to also think, uh, about biomarkers at progression on targeted therapy, an EGFR TKI most of the time, in order to make sure that if you can remain personalized and targeted because you have identified the mechanism, you can potentially, again, tailor your treatment to the new biology of the tumor.

So does biomarker testing guide treatment not just for advanced metastatic, but also in early disease? So to make it more complex, the answer is unfortunately yes.

You need to know this biomarker not only in advanced disease, but also in early stage.

And these slides aim at illustrating why, but it can be even longer.

In term of early stage, early stage disease, now we know, for example, that when you have an EGFR mutation, but also an ALK rearrangement, a RET rearrangement, first of all, the usual chemo IO is not the good choice.

And more importantly, there is, uh, I would say a room for targeted therapies in the adjuvant setting in EGFR, in ALK, and in RET.

So basically you shouldn't give chemo IO upfront, and you should keep the room for targeted therapy in the adjuvant setting.

And it's even right when your local treatment is not surgery, but for example, chemoradiation in stage three for EGFR muta- mutant non-small cell lung cancer, where the LAURHAT trial has established that you can dramatically improve the disease-free survival and the survival by giving osimertinib after the completion of chemoradiation.

So here again, no immunotherapy, but an EGFR targeted therapy.

So of course, in stage one, two, and three, you need to know that you have an EGFR mutation.

Why should we conduct biomarker testing in EGFR mutation at progression? I told you also at progression.

It's because we have been describing for all of this oncogene addiction kind of field, some mechanism of resistance.

It can be bypass oncogenic signaling pathway, finding a new way to have the malignant phenotype for a cancer cell.

And these, uh, bypass tracks can be also targeted or blocked.

Of course, you have on-target secondary mutation.

In EGFR, we know very well the C797S way to prevent the binding, uh, of osimertinib and re- a histologic transformation, meaning that suddenly your tumor become a small cell or a squamous cell carcinoma.

And you need to know that because your treatment, as you have understood, will be dramatically different depending what you encounter as a mechanism of resistance.

And this slide is a usual pie telling you what was described as existing mechanism of resistance to EGFR tyrosine kinase inhibitors.

So you can see there are many different mechanism with a little less than half of the patient without a described mechanism with the unknown pattern of resistance mechanism.

And in order to constitute this pie, ideally tissue biopsy should be done because in the tissue you can find the histological transformation, but you can also find more rearrangements.

Remember, liquid biopsy are not very good to look at RNA.

But if you can't do a biopsy on tissue, we are still very happy to have a liquid biopsy to try to at most identify this actionable new pathway, uh, of resistance.