Latest in testing and diagnostics in exon 20 NSCLC

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Published: 4 Jun 2022
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Dr Antonio Passaro and Prof Paul Hofman

Dr Antonio Passaro (European Institute of Oncology, Milan, Italy) and Prof Paul Hofman (University of Côte d’Azur, Côte d’Azur, France) discuss testing and diagnostics in exon 20 NSCLC. 

They initially talk about the impact of EGFR exon 20 mutation subtypes on lung cancer prognosis and also discuss the molecular characteristics of EGFR exon20 mutations in NSCLC patients and their impact on prognosis. 

Dr Passaro and Prof Hofman compare mobocertinib versus amivantamab in patients with non–small cell lung cancer (NSCLC) with EGFR exon 20 insertions (ex20ins). Dr Passaro mentions the phase 1/2a study of CLN-081 in patients with NSCLC with EGFR exon 20 insertion mutations. 

They talk about the molecular analysis of circulating tumour DNA (ctDNA) in patients with EGFR exon 20 insertion-positive advanced NSCLC treated with mobocertinib. Prof Hofman concludes by explaining the best practice with liquid biopsies.

This programme is supported by an unrestricted educational grant from Janssen.

AP: Welcome to the ecancer discussion focussing on testing and diagnostics of patients with exon 20 mutation non-small cell lung cancer. I am Antonio Passaro, I’m a medical oncologist from Milan, Italy, and it is my great pleasure today to discuss this very interesting site with Professor Hofman from Nice, France. Professor Hofman, good morning.

PH: Welcome everyone, also it’s my great pleasure to be here today with Antonio Passaro. I am a clinical and molecular biologist in Nice University, France. 

AP: During this ASCO we saw a very different kind of poster and presentation discussing the importance to test to identify exon 20 mutations. In my opinion, the different kind of poster and presentation identified a clinical issue. So it’s important to discriminate exon 20 insertion mutations from exon 20 mutations, from exon 20 mutations for patients with resistant disease. What’s your point of view, considering your expertise in pathology here?

PH: Yes, it’s definitely a very important topic and we need to take care about the distinction between a mutation, point mutation, and insertion, it’s totally different. For example, we have the T79M mutation, it’s a real mutation, and we have also other insertions. So in terms of resistance, for example, it’s totally different, we have different kinds of resistance according to the insertion or the mutation in this kind of exon 20 EGFR genomic alteration. So we need to be sure that the oncologist but also the molecular pathologist knows exactly what can be the distinction between mutation and insertion because sometimes we have some misunderstanding about that. So it’s totally different I guess.

AP: Yes. This, from my point of view, is a very clinical problem because we are discussing from two different diseases for which we can use different drugs. So, as you know, the use of first and second generation tyrosine kinase inhibitors for EGFR is not able to inhibit the exon 20 insertion mutation. So do you have any comments about the data that were presented about the characteristics of the different kinds of mutation? Also the potential methods to identify or discriminate these kinds of alterations?

PH: We know now that PCR is not a good method for the distinction between all these insertions and mutations so definitely we need now to use NGS systematically in all our patients because we can miss a lot of insertions if we use only PCR. I think it’s very important because in terms of resistance mechanisms we know that when we have a T79 mutation, for example, the resistance mechanism, we need definitely to switch to a third generation of TKIs. But, of course, it’s totally different when we have deletion, it’s totally different. So we need to focus definitively on these different genomic alterations by doing NGS systematically in all our patients.

AP: Okay. Do you think that this is feasible considering the economic point of view and also the penetration, these kinds of methods in the NGS compared to PCR, in different countries, considering the US, European countries also, as the market and also balancing the expertise of our colleagues worldwide?

PH: It’s a very, very important question because we know that according to the country we can have discrepancies for the availability to get NGS or not in house. Of course, if we send the samples to some centralised lab outside, for example, Europe, it can be easy but it’s very expensive. I think definitively now we need to develop NGS in house with different panels, of course. It could be more expensive but considering that now we have a lot of targets to look for, if we add different PCR methods anyway it will be more expensive than if we use NGS panels. So I think now we need to switch to NGS systematically. This depends on the country, considering the reimbursement, the participation of the pharma for the test cost etc. So it depends on the country and the organisation. Sometimes we can have support from the Ministry of Health and Research, for example, for doing that. So there are different kinds of organisation according to the country. But now I think it’s obvious that we need to do NGS systematically, not only in late stage but also in the early stage.

AP: Yes. Of course this is the way for the future management of patients with exon 20 insertion mutations in which at the present time we have different kinds of drugs approved by the FDA and EMA like mobocertinib, tyrosine kinase inhibitors or amivantamab, a monoclonal antibody. During this ASCO there was also a presentation by Helena Yu about a new drug, CLN-081, a new tyrosine kinase inhibitor with a very good activity and some singular brain penetration. In my opinion there was a very interesting presentation that focussed on the potential use of ctDNA and liquid biopsy to identify alterations, exon 20 mutations and insertions. Considering this topic, do you think that the use of liquid biopsy, ctDNA evaluation, that is a very [inaudible] is feasible or not for the clinical practice so we are ready to use these methods in clinical practice, or we are at the beginning of the history?

PH: In my point of view, we shouldn’t be at the beginning because now liquid biopsies, since ten years we are talking about liquid biopsy for EGFR detection. For example, mutation, we know that it’s quite sensitive. But for the different EGFR mutations or insertions, on the insertion of the exon 20, the sensitivity is not 100% in comparison with a tissue biopsy, it’s around 70-75%. So we need to take care; if we have negative results we need to know if it’s a real negative result or a false negative result because there is a technical problem by using a liquid biopsy. Sometimes the pre-analytical phase is quite difficult to manage because we know that we need to have a good time between the veinal puncture, the centrifugation etc. and we need also to have also sensitive methods for the liquid biopsy. So negative results should be real negative results or a false negative result. Of course if we have negative results by doing liquid biopsy we need to do a tissue biopsy to be sure that the insertion is there or not because the importance of the results is critical for the patients.

AP: Thank you. So would you like to share with us three key points from oncologists and pathologists to keep in mind to consider the exon 20 mutation and insertion testing and diagnostics?

PH: Yes, first of all we need to use NGS systematically now if it’s possible. But we will miss more than 50% of the insertions if we use PCR; we know it’s published in the literature. So 50% is a lot if we use PCR so we need to do NGS first. Then, if it’s possible in front line for advanced non-small cell lung cancer, if it’s possible, we need to do both tissue and liquid biopsy at the same time. I think it’s quite difficult right now in terms of organisation, reimbursement. It induces a lot of workload in the lab for the staff members but if it’s possible in front line to do both liquid biopsy and tissue biopsy.  If not, we can start by doing a tissue biopsy and if the tissue biopsy is negative we can switch on the liquid biopsy. It’s critical, it’s very critical.

Of course, now in terms of impact according to the results, of course, amivantamab versus mobocertinib versus a new drug, from my point of view it’s quite difficult to say, ‘Okay, which would be the best drug?’ We need to take care about the brain penetration of these drugs to make comparisons, of course, and also the toxicity because depending on the toxicity we will switch from a drug to another one. I have to say that the mechanism of action of these different drugs are different. So sometimes we can have resistance to some drugs and we can switch to another one in the follow-up of the patient maybe.

AP: Yes, of course. I agree with you about two different drugs with a different mechanism of action but in my opinion we need to repeat and confirm that this is a new kind of disease. We need to consider exon 20 insertion mutation as a new kind of disease with a specific drug that we need to use in clinical practice, prioritise these kinds of patients also for clinical trials in the first line setting where the need is very, very high. I think that this, coming back also from another presentation that presented a comparison of data of amivantamab and mobocertinib presented by [inaudible] using a meta-analysis that confirmed that these two drugs are very similar evaluating the efficacy. In my opinion the message that we need to treat this kind of patient with the drugs. So thank you, Professor Hofman. That was my great pleasure to discuss with all of you this very interesting data and presentation presented during the ASCO 2022 and thank you ecancer for the support.