BB: Welcome to this ecancer round table expert discussion on EGFR. We are live from ASCO and
we will discuss the latest news on the EGFR field. I’m Benjamin Besse, I’m a medical
oncologist in Gustave Roussy in Paris and I am with a huge friend and expert in this field,
EF: Hi Benjamin. Hello, my name is Enriqueta Felip, I’m a medical oncologist working at Vall
d’Hebron University Hospital in Barcelona, Spain, happy to be here today.
AM: My name is Dr Anna Minchom, I’m a consultant medical oncologist and I work at the Royal
Marsden and the Institute of Cancer Research in the UK and it’s a pleasure to be here today.
BB: And Antonio.
AP: Hi, I’m Antonio Passaro, I’m a medical oncologist in Milan, Italy.
BB: So let’s start with first line in a classical EGFR mutation, exon 19, exon 21. We have seen quite
interesting data in the relapsed field, so mostly after first line osimertinib. Do you have any
interesting data you want to comment? Maybe we can start with the combo of amivantamab
AM: This is an interesting study. This is a phase II study, the CHRYSALIS study looking at, as you
say, the combination of amivantamab, which we know is an EGFR and MET bispecific
antibody, in combination with lazertinib which is a third generation EGFR TKI. Patients in this
study were pre-treated with osimertinib and platinum-based chemotherapy and some patients
were more heavily pre-treated than that. 160 patients or so on trial and the data is interesting.
Response rates in the region of 33% and progression free survival of around five months. The
toxicity profile is that which we are familiar with with the combination of EGFR inhibition and
MET inhibition. I think it’s an interesting area to watch – we know that MET drives EGFR TKI
resistance in a significant proportion of patients. It is interesting as well because we do know
that EGFR inhibition if we retreat with EGFR TKIs we do sometimes get a response. So it
remains to be seen how much benefit this actually brings as a combination rather than just an
EGFR retreatment paradigm.
BB: So the toxicity is a bit different. While there is this EGFR toxicity we are familiar with, there is
this MET toxicity we are familiar with, there is this infusion related reaction, Antonio, do you
want to comment? Is it something difficult to manage or is it…?
AP: It’s a new kind of toxicity if we consider the EGFR positive disease in our clinical practice. This
kind of toxicity, infusion reaction, that we are starting to manage using these drugs in exon 20
insertion positive mutations, I think it is a little bit problematic only in the first months of
treatment and generally is mild, G1, G2, during the time this kind of toxicity is coming out and is
a very, very good, manageable profile for this kind of drug. So I think that considering also the
CHRYSALIS-2 trial we need to understand the long-term profiling for toxicity in the clinical
setting because here we have a heavily pre-treated patient with a tumour with up to 14 lines of
treatment. I think it will be interesting to evaluate the impact of long-term toxicity in this kind of
BB: We were used in the EGFR field to re-biopsy and adapt the treatment to the re-biopsy.
Enriqueta, is it something in this study that was mandatory? So is it only for the MET amplified
patients or it’s all comers?
EF: In the trial there is a need to re-biopsy just before starting treatment but we can include the
patient irrespective of the results of this re-biopsy. So this is something that we are doing also
in the clinical practice. We can discuss but if my patients progress to osimertinib we are doing a
re-biopsy or liquid biopsy. But it’s true that now in the standard of care we can treat the patients
with chemotherapy without the results of a re-biopsy. So it’s something that we are going to
learn, to try to have a more personalised approach even in clinical trials but it’s for this, for
learning, and to have more information on individual patients.
BB: And anything interesting in this field of relapsed EGFR patients after osimertinib?
EF: There is another agent now, that is patritumab deruxtecan, that is an ADC targeting HER3. We
have seen also very promising results in this scenario of patients previously treated with
osimertinib. So ADCs, antibody-drug conjugates, will have also a role in patients with EGFR
mutation and disease relapse.
BB: And maybe this year the first data on the fourth generation EGFR inhibitor but it’s a completely
different field. Antonio, what do you expect in the next months for the first line setting? Any
studies you are expecting to see?
AP: Yes, the upcoming results, of course, identifying the combination in the first line setting. Also
here at ASCO we have some data that confirm that the combination of chemotherapy plus
tyrosine kinase inhibitors are interesting in this kind of setting. Maybe because the use of
chemotherapy is able to reduce the concomitant mutation and the overall different kinds of
alteration that in this kind of disease now is every day improving our understanding. Here I think
this will be important. The other treatment strategy for the first line setting, of course, is the
combination of amivantamab plus lazertinib, evaluated in the MARIPOSA trial that is one of the
most interesting approaches using double inhibition for these kinds of patients. Also the
patritumab deruxtecan, the other ADC in this kind of setting. So I think that the future of the
EGFR disease also in first line will be more interesting than now.
BB: Yes, osimertinib will be challenged as a standard of care first line, definitely, in the next months.
Okay, so refractory, first line, let’s move to stage 3. So stage 3 chemoradiation followed by
durvalumab – any new data on durvalumab in EGFR mutated NSCLC patients?
EF: Yes, there is a presentation here at ASCO now analysing the patients included in the PACIFIC
trial. There are 35 patients with EGFR mutations and new data that [INAUDIBLE] presented and
there are no differences in PFS, no differences in overall survival when compared to placebo
versus durvalumab. So it’s true that it’s a retrospective analysis, only 35 patients included, but I
think it’s underlining that monotherapy with immunotherapy is not really active in patients with
BB: So what would be your standard of care – EGFR mutated NSCLC stage 3 chemoradiation?
Durvalumab yes/no? Anna?
AM: It’s hard to deny patients access to a drug that is licensed for them. I totally agree but I feel that
I don’t imagine that immunotherapy is going to be the way forward for these patients. We
already know, we already have the data post-surgery, for adjuvant osimertinib and there will be
a read-out from a study of osimertinib post-chemoradiation in this space. So I don’t think it’s the
future but it is a conversation to have with patients at the moment in that there is a drug there
you can access and you fully inform them about the data that we’ve just discussed and make
that decision together.
AP: Yes, I agree with Anna and I think that we need to consider the long-term toxicity profile using
the immune checkpoint inhibitors in this kind of disease, considering the radiotherapy toxicity
and also the long-term possibility of the use of tyrosine kinase inhibitors during the time. Here I
think that the benefit of the immune checkpoint inhibitors are now durvalumab is not in the right
room for this kind of patient.
EF: Yes, I think we have to discuss, of course, with the patient but the results in this subset analysis
are negative, it’s in line with what we have seen. We have durvalumab only in PD-L1 positive
patients and also the concern of potential toxicity, of disease relapse with osimertinib. So my
recommendation probably is not to treat them with durvalumab and only chemoradiotherapy.
BB: Yes, I think we are all aligned on that. Very good, so let’s move to the exon 20. It’s a rare EGFR
mutation but it’s now frequently identified in our patients. Any new treatment in the field?
Anyone want to comment?
AP: So I think now is a very exciting moment for this kind of setting that, in my opinion, is a very
different disease, exon 20 insertion mutation. In the past months we know two drugs have
received EMA and FDA approval – amivantamab and mobocertinib. Here at ASCO we have
data about a new tyrosine kinase inhibitor presented by Helena Yu, the CLN-081, that show
very interesting consideration balancing efficacy and toxicity and also evaluating the brain
penetration. I think this is a very important point for this kind of patient.
BB: So the drug has been presented. My only comment would be that it’s only 40% or 39 patients.
We have seen very promising initial efficacy with poziotinib, with mobocertinib on very small
subsets of patients and when the trial enlarged and with the follow-up sometimes we were a bit
disappointed. I think it’s a very interesting agent but maybe we should wait for more mature
data. Amivantamab also is active, any news in the field?
EF: We know that amivantamab in this group of patients is active now in post-platinum with a
progression free survival of around 8.3 months so it’s an active agent; also mobocertinib. We
don’t know for sure what is the sequence, that we need to discuss in this patient population.
Also to highlight the relevance of NGS when we determine this kind of mutation and also NGS
may well be challenging in some institutions. So we need to diagnose EGFR exon 20 insertions
and we need NGS to do that.
BB: So far for these patients first line it’s chemo, it’s the only drug that is approved because
mobocertinib and amivantamab are for pre-treated patients. What is your standard of care?
Because I agree, exon 20 is a bit different disease – chemo/IO, chemo? What is your standard
of care in this disease?
AM: I think we treat it like an EGFR mutation now with the concerns about immunotherapy, both in
terms of potential efficacy in this patient group and in terms of the potential for immunotherapy
followed by targeted drugs and the potential for toxicity. It’s not fully established yet and these
conversations are around the evidence we have so far and it’s very much an evolving field. But
I think platinum-based chemotherapy followed by targeted drug – whatever, mobocertinib or
AP: I completely agree here and this point is also confirmed in the two phase III randomised trials
that are evaluating the role of these new drugs in the first line in combination with
chemotherapy for amivantamab alone and in the comparative with chemotherapy for
mobocertinib. So I think that’s a discussion for stage 3, to use immune checkpoint inhibitors
here have a not very clear benefit but also it’s important to consider for us the long-term
possibility of survival of this kind of patient and the increasing rate of toxicity using different
kinds of this kind of agent.
BB: I agree, the first line will probably change with the results of these two phase III. Enriqueta,
what is your…?
EF: Chemotherapy alone and it’s true that in this patient population sometimes I add bevacizumab.
I have a personal experience, very good, with chemotherapy plus antiangiogenic agents in
patients with EGFR exon 20 insertions but not immunotherapy.
BB: No, I fully agree. There is something with EGFR in general and the antiangiogenic agents,
definitely. MET is one of the main resistance mechanisms, expression. I haven’t seen new data
on the field of MET as a resistance mechanism to EGFR inhibitors but MET exon 14 mutation is
rare, it’s elderly patients, sometimes smokers, but I think we have seen new data at ASCO.
Enriqueta, do you want to comment?
EF: Yes, there is a presentation with amivantamab in patients with MET exon 14 skipping mutations
with very good results. The majority of patients were TKI naïve, so not previously treated with
capmatinib or tepotinib and with a response rate around 47%, I remember. There is also a
small group of patients previously treated with MET inhibitors also with a 17-18% response
rate. So a new active agent in this scenario of MET exon 14 skipping mutations.
BB: And so far what is your management of these patients when they come first line? What is your
standard of care?
AM: In the UK we can use tepotinib.
BB: As a first line treatment?
AM: Yes, we have access to that now. Actually we can use it in any line so individual clinicians
make that decision. It’s maybe a slightly unusual choice in the UK to have that access that is
ambivalent to which line of therapy. So I would actually tend to use a MET inhibitor first line. I’m
sure others use chemotherapy and would use a MET inhibitor second line.
BB: And the fact that the MET exon 20 population, the median age is 74, is it a challenge when you
treat patients with a TKI or amivantamab?
AM: In terms of the TKI, yes, it is a challenge. The cumulative toxicity of oedema can be quite tough
and it’s difficult to manage without having pauses in treatment, I find. So cumulatively some
patients it can be a challenge. Amivantamab we obviously don’t have access, yet, to in this
setting but we know from the trial data that there are similar challenges – sometimes with the
oedema and, of course, infusion reactions that we’ve mentioned previously.
BB: Antonio, management in first line?
AP: In Italy and in different kinds of Europe we cannot use, at the present time, the tyrosine kinase
inhibitors in first line. I think here the discussion about chemo or chemo/IO is a little bit different
considering the EGFR positive disease. As you discussed before, consider the smoking habit,
it’s a little bit of a different disease in which I think we can consider, we can discuss with the
patient eventually the use of a combination – chemo plus IO. Always keep in mind that there
will be the possibility to use a tyrosine kinase inhibitor in second line and the cumulative effect
of toxicity is a key evaluation here also for patients, in particular for elderly patients with more
than 65 years.
EF: Yes, in Spain it’s the same situation – we don’t have access to tepotinib or capmatinib in first
line for patients with MET exon 14. We consider, in this case, immunotherapy as
immunotherapy or immunotherapy plus chemotherapy according to the PD-L1. This has
reimbursement issues in my country but, yes, we consider it in this case. There are more
smoker patients, as you mentioned, and we consider. Then in second line we can use tepotinib
or capmatinib mow.
BB: And to end this conversation maybe we can talk a few minutes around the early, early setting,
the resected NSCLC patients. Because we have seen the data – osimertinib can be prescribed
as an adjuvant drug – but we have also seen interesting data on a pre-op chemo/IO
combination so that might be now an option potentially also for EGFR mutated NSCLC. Any
ideas around that?
AM: There are lots of decisions to be made, isn’t there? I think the neoadjuvant data is really
interesting, really exciting. I think the potential to perhaps give a short course of chemo/IO and
improve outcomes is really exciting. Where EGFR fits into that – I think we have to wait and
see. It’s complicated, it’s going to be difficult to know.
AP: Yes, the same for me. So the feeling to use immune checkpoint inhibitors in EGFR positive
disease or ALK positive disease is not good from my point of view, considering the biology, and
also in the neoadjuvant setting here. So I think that the future will be followed by a sandwich
approach of a neoadjuvant followed by adjuvant including tyrosine kinase inhibitor, maybe, plus
chemotherapy. But the role of immune checkpoint inhibitors here should be investigated very,
BB: And I was surprised in this neoadjuvant trial by the rate of resection that was not 100%, let’s
say, even in stage 2 disease which might be a challenge. Enriqueta, you’re the [INAUDIBLE] lady,
so one of the first randomised trials of pre-op and post-op, any ideas around that?
EF: No, as you mentioned, the neoadjuvant for the disease are really important now after the
publication of CheckMate-816. When we published the [INAUDIBLE] trial ten years ago we had a
lot of discussion at the end – everybody mentioned that perhaps it’s better to give adjuvant
chemotherapy. But now the situation is changing and it’s true that there are patients without
resection but in the CheckMate-816 there are 63% of the patients with stage 3a, they are
diagnosed preoperatively. So we discussed, perhaps three years ago, if these patients were
candidates for surgery. So they are not exactly the same, the patients included in the
preoperative strategies and the adjuvant strategies. In the preoperative strategies, CheckMate-
816, we have patients with clinical staging stage 3; in the postoperative are patients resected
with pathological N2 disease that perhaps were not identified pre-surgery. In the EGFR
mutation I would [INAUDIBLE] CheckMate, exclude those patients with no EGFR mutations. This
was the situation. I think we need to test also patients with early stage disease.
BB: So, thank you very much. The lung cancer field is moving so fast that our discussion today
could be different in one year. We thank you very much for your kind attention of this ecancer