Of course we know about the EGFR mutation exon 20 insertion. This is a long-term problem that actually they don’t respond well to the classical EGFR TKI. Only in recent years have we got specific drugs that may target the EGFR exon 20 insertion. In this year’s WCLC we had two abstracts with significant updates that may potentially change our practice. One is on mobocertinib which is the other name for TAK-788 and the other one is amivantamab.

So maybe I’ll just start off with the TAK-788 or mobocertinib. Now, this is a TKI and it actually specifically targets the exon 20 insertion for both EGFR and HER2. In this year’s WCLC abstract they actually had looked into two cohorts, one cohort is actually from the EXCLAIM study, the other one is actually from the platinum-based; it is a phase II extension. In these two the first sample size is about 96 patients, the other one is 114 patients. In both of the studies the response rate was actually adequate. They had two types of response rate, one is by the independent review committee, the other one is by investigator. For the independent review committee the response rate was 26% and 23% respectively, then for the investigator it’s 35% and 32%. So in a sense we get the idea that it’s somewhere around 20-30% but understand the fact that there is a little bit of difference between the investigator and the independent committee. But then the progression free survival, the median is 7.3; in both cohorts it was exactly the same.

One word of note is the fact that this drug actually has some degree of toxicity of some concern, which is diarrhoea. About 90-92% of patients had diarrhoea and then 20% of them actually had grade 3 diarrhoea. So those are the essence of the data we have on TAK-788.

My thinking on that is that there is no doubt that this is an effective drug. They got some response rate and the response is good, the question is where is the best place for this drug? Should it be first line or second line? As a second line drug probably it will be definitely better than docetaxel but when it’s compared with chemotherapy and IO the current data may not be in such a competitive angle. So for future development we’ll have to ask that question very specifically.

The other drug is a bispecific antibody targeting EGFR and MEK, amivantamab. In this year’s abstract it is actually an extension of the prior knowledge, the fact that the dosage of this drug was 1050mg for patients who are less than 80kg and if they are over 80kg it would be the 1400mg. This so-called extended phase II study has helped us to report the response rate of 40% with a median duration of response about 11.1 months and the median progression free survival of 8.3 months.

One thing that we have to be careful of is the fact that they actually have slightly different response rates depending on the site of insertion. In the site of insertion in the far loop, which is actually insertion sites 773 to 775, the response rate tended to be slightly lower. However, this is a very small sample size and we will probably investigate it a bit further. But it’s interesting, the fact that a different insertion site may provide us with a slightly different outcome.

Toxicity-wise there is also diarrhoea but only in 12% and about 3.5% of the patients had grade 3 toxicity. So overall I think that this all has to share a good efficacy similar to the mobocertinib, however, the toxicity in terms of diarrhoea is actually a bit better.

My comment is still the same, that when it comes to second line there’s no doubt there’s a good chance of being better than the second line standard chemotherapy. But when in first line, the response rate at this juncture, it may or may not be better than standard chemotherapy plus or minus immunotherapy. However, given the better toxicity profile there is a potential for the combination of the chemotherapy with amivantamab. So I trust that there will be a phase III study ongoing with this combination. So that would be my comment on these two drugs with these two interesting abstracts from WCLC 2020.

What is best practice in the management of these patients?

For EGFR exon 20 insertion in most of the standard PCR, especially if you use cobas, they may actually already include some of the EGFR exon 20 insertions. However, we have to understand the fact that with the PCR they may not include all the different insertion sites. So occasionally you may miss some insertion sites. So to try not to miss it the best way, of course, is next generation sequencing then they will include most, if not all, of the insertion sites. So this is the standard and also next generation sequencing can be in the plasma or in the tissue.

Now, in the future I think we should be looking for plasma-based tests specifically for EGFR exon 20 insertion sites because actually [?? 5:31] includes about 3-5% of all EGFR mutations. So we try to be more comprehensive and not to miss any of the insertion sites for the exon 20 insertion. So that is the standard practice I think we have to watch out for.

Now, the second part is the treatment. The first line treatment at this moment we still have to confine it to chemotherapy plus or minus immunotherapy because up to this moment there is no data to suggest any of these drugs are actually better than the standard chemotherapy plus or minus immunotherapy. So that will be my current belief now; certainly with the upcoming study and hopefully the positive result in phase III then we may change our mind. But based on the current data it would be very difficult to jump and conclude with the fact that this single agent may be better than the standard chemotherapy.

Are there other updates that you would like to highlight?

There is another paper that is on a rare mutation of exon 18 and a drug called neratinib. Now, that is actually a relatively small study, it’s about less than ten patients, although it does suggest that there is a good response rate but certainly I think it’s far to conclude that this is a drug that is actually necessarily better than the other TKIs. To remind you of the fact that the other EGFR TKIs, including the existing second generation EGFR TKIs such as afatinib, they actually do have efficacy on exon 18 as well.

When we talk about EGFR then what excites me most is about the application in the adjuvant setting. The ADAURA data was already published last year in August by Professor Yi-Long Wu from China but this year at the WCLC there are two subsequent papers, abstracts, to support those data. First is actually on looking into the quality of life; the second paper is actually looking at the role of adjuvant chemotherapy in the patients who are mutation positive.

First, about the quality of life, it was presented very nicely and they look at both physical and mental quality of life using a very standard procedure to capture the patient reported outcomes. It confirmed that actually there’s no difference between the osimertinib group and the placebo group in terms of the change in quality of life and also the time to progression of the quality of life. So, in a sense, we are reassured that the TKI really doesn’t change the quality of life of the patients as much.

The second is about the chemotherapy subgroup. Now, in this particular study where patients are at stage 1b, 2 or 3, receive three years of osimertinib or three years of placebo. They are actually allowed at the doctor’s discretion to give chemotherapy as adjuvant or not. Now, in the whole study there are about 60% of patients who received the adjuvant chemotherapy and 40% did not. As expected, in the patients with stage 1a there is actually only a very small percentage of patients who received adjuvant chemotherapy but then in stage 2 and 3 it’s over 70% or more to have received adjuvant chemotherapy. But when they looked into the subgroup analysis actually there’s no difference in outcome in terms of the hazard ratio whether the patient received the chemotherapy or did not receive the chemotherapy. So at this juncture it’s actually a little bit debateable whether chemotherapy should be given with the three years of osimertinib or not.