What testing and diagnostics techniques are used in exon 20 lung cancer?

 

EGFR exon 20 has been around since the beginning but before then we actually don’t have a very

active treatment so we just kinda packed the package with the EGFR screening using cobas, using

veroscreen. So exon 20 was included but not elaborately included so what the problem is the fact

that because this so called EGFR testing is not designed for exon 20 so it would miss some of the

insertions, for one, and also there may be the possibility of false positives. So in a sense we cannot

adopt entirely the standard EGFR mutation testing to give us the best answer for EGFR exon 20

insertion.

 

To better look into that NGS is a solution. It will cover all the important insertion sites using NGS but,

of course, it will probably be a little bit more expensive. If you really want to lower the cost you can

actually do single sequencing but then it will require a bigger tissue sample and the sensitivity may be

lower. So those are the few options that we can look into this day for more elaborate investigations or

molecular testing of the EGFR exon 20 insertion.

 

When should we test for EGFR exon 20 mutations?

 

This is a very important question on the timing of testing. The timing of testing has got a lot to do with

the lines of therapy that have been approved. At this moment we don’t have strong data on the first

line indication for the use of amivantamab or mobocertinib. Both drugs have been approved by the

FDA but mostly in the second line setting. So, in a sense, it’s nice to have often testing so you know

that you are dealing with EGFR exon 20 in the beginning. But, on the other hand, if the patient is

EGFR negative and there’s no other driver oncogene, it will be important to do NGS either as a

second line situation or first line situation in a way to look for the EGFR exon 20 insertion.

So the option is that you can do it as a second line after failing the first line therapy but ideally that you

can do it up front.

 

What are the different molecular characteristics for this type of lung cancer and what are their

impacts?

 

We have to be very careful when you say EGFR exon 20 mutations because there are different types

of EGFR exon 20 mutation. The most common one, actually, is the EGFR exon 20 T790M mutation.

This one actually usually occurs as quite resistant after failing a first or second generation EGFR TKI.

Then that is actually associated with resistance to the TKI therefore the prognosis is actually a bit

worse if you look at the residual study. But then that actually ties into the subsequent therapy with

the third generation TKI and then accordingly for patients who are T790M positive treated with

osimertinib as the third line the median overall survival is actually 24 months which is actually not too

bad if you’ve got an effective drug for it. So that is the most common type of EGFR exon 20 mutation;

The less common types are the EGFR exon 20 insertions. There are multiple insertion sites. In

selective retrospective studies, including some from this year’s ASCO, there are data suggesting that

it’s associated with a worse survival. But it’s worse survival in a way that there is no targeted therapy

available at that time of this database. So how would the newly approved treatment impact on the

survival, that remains to be defined. But, in general, we thought of EGFR exon 20 insertions as a

negative predictor of survival or a negative prognostic factor.

 

There are also miscellaneous less common exon 20 mutations but then because they are relatively

uncommon we do not have a comprehensive picture on their prognostic value. So those are the

implications of the EGFR exon 20 mutations on survival.

 

Can you describe the best practice with liquid biopsies?

 

Using a liquid biopsy essentially is for patients who do not have sufficient tissue. In the United States,

which is a quote-unquote rich country, sometimes they do both tissue and liquid together and cross-

reference each other. But, to me, it’s a waste of the resources. I think we should use the tissue, the

best we can, because that will provide the best source of DNA. Only if the tissue is not available then

we may resort to plasma DNA as a so-called liquid biopsy as a source of NGS.

 

But another category is a patient with an already established driver oncogene treated with a TKI and

you do not want to re-biopsy those patients and you try to look for a resistant gene using the liquid

biopsy. That will be another category of implication. So we have to be very careful to put in a specific

indication and objective when we apply the use of this liquid biopsy.

 

What recent treatment data have we seen for EGFR exon 20 NSCLC?

 

There have been some exciting developments for EGFR exon 20 insertion management in the past

few years. Namely there are two drugs, amivantamab and then mobocertinib, that have been

approved and there are a number of other agents that are under investigation. First I’ll talk about the

approved agents.

 

Amivantamab, which is a bispecific antibody that targets both EGFR and MAP and that may also have

an impact on the immune cell that may effect on the cancer management. The single arm study has

demonstrated a response rate of about 40% and then with the median progression free survival this is

about 7 months. So the data is quite exciting and provides, as a vehicle, for the FDA to approve this

drug. The major toxicity of this drug is actually infusion reaction which is manageable and mostly in

the first few cycles. So slowly this agent, amivantamab, has become part of the standard as a second

line treatment for patients with EGFR exon 20 insertion.

 

Another one is actually mobocertinib which is a tyrosine kinase inhibitor. It’s a potent one and specific

for the exon 20 insertion. The response rate is about 28% and then the progression free survival is

durable and therefore it’s also accepted by the FDA as a second line agent. But the problem with this

agent is GI toxicity and skin rash. The GI toxicity of diarrhoea is actually close to 90% of the patients

and has to be vigorously managed and also dose reduced to accommodate this toxicity.

 

So both official agents with a different mechanism of action. They may work one after the other, we

don’t have the data on sequential therapy but both should be recognised for potential usage. There

are other agents like DZD9008, the recent data coming from ASCO this year reported a response

level of 50% which is quite encouraging but then the data need to mature and need to be approved

eventually by the FDA before we can use this agent.

 

Also there is another agent called CLN-081 which also reported some early data from ASCO this year

that is very encouraging but, again, this remains to be defined and also remains to be approved in the

future.

 

So hopefully in the future we will have multiple different medications that are available for our patients

with EGFR exon 20 insertions.