Potential Treatments for Uncommon EGFR Mutations in NSCLC

Neal Navani, MRCP, MSc, PhD: Let’s turn briefly to some uncommon EGFR mutations. Solange, we see these occasionally in our clinical practice. What are some of the more interesting, exciting, and latest data in this area?

Solange Peters, MD, PhD: As I said, the major topic within not only research but also clinical trials and meeting presentations is that there are some rare mutations in the ERBB family, HER2 [human epidermal growth factor receptor 2] and EGFR. If I speak about it, there are 2 very similar mutations that are inserts in the exon 20 of the HER2 or the EGFR genes, which have been interestingly—biologically, in terms of how the protein folded did impact how it can drive an oncogenic mechanism leading to the malignant phenotype, but also how it resists the inhibition by the usual compounds we use. This is very similar in EGFR and HER2, so that’s quite interesting. Also interesting is that researchers have tested a panel of drugs specifically in these 2, HER2 or EGFR exon 20, with variable efficacy and differential efficacy in EGFR vs HER2. Maybe some need to be stressed.

First, looking at those with EGFR exon 20 mutations—which represents a very small portion of our patients, probably 1% of our patients with adenocarcinoma—reveals that these patients have oncogenic diseases that appear to be pretty resistant to the usual EGFR inhibitors. Having seen the development at least of 2 compounds, we have to keep these in mind. The first compound is mobocertinib, TAK-788, which is a compound that has been developed in a phase 1/2 development program showing efficacy and promising results. With the recent update of the data at the International Association for the Study of Lung Cancer World Conference on Lung Cancer—if I’m not wrong, it basically showed very promising response rates. We unfortunately go down a little to a cohort of about 100 patients and a response rate that’s in the range—if I look at the numbers—of a 23% rate, which is a little less than we saw in the first data set. It was more in the range of 40%. There was a bit more efficacy after platinum exposure, but mechanistically I’m not sure why. This is something that’s amazingly interesting. In second-line treatment, it’s better than docetaxel, but I’m not sure this is a challenger for frontline treatment because that’s mainly chemotherapy or chemotherapy with platinum.

Remember the way it’s being developed: It’s compared with mobocertinib; it’s compared with platinum with chemotherapy. We must be careful that it’s really something that we would like to look at in the future and maybe consider it as a second-line treatment. The second drug that has to be mentioned, because it’s very often presented, is mobocertinib. To summarize its toxicity, this is the class of drug of the old days of EGFR inhibition: rash, diarrhea, gastritis. You know that from afatinib and dacomitinib. That’s what you need. The reason is it might be difficult to combine it with chemotherapy, for example; but let’s see what the future brings. The other drug that’s interesting, when dealing with EGFR exon 20 mutations, is amivantamab. Amivantamab is a bispecific monoclonal antibody targeting the usual EGFR on 1 side, but on the other side it targets the usual oncogene MET. Remember, MET can be mutated: It can be mutated in skipping, it can be amplified, and it can be overexpressed. It’s really something driving oncogenic features. This is quite interesting. Amivantamab has been tested in the setting of EGFR resistance but also in the treatment of this exon 20 EGFR mutation with promising results. The response rate was 36%. There was a PFS [progression-free survival] duration of 8-plus months—so these are quite nice data, which would of course compete and probably overpass docetaxel in evaluating second-line treatments. Amivantamab is being evaluated as a frontline treatment, but this time in combination with chemotherapy vs chemotherapy alone. We’ll see what’s going to happen. It’s very important to look at these data. We have challenges in terms of not trying to give docetaxel as a second-line treatment to these patients. Last but not least, we must consider poziotinib. Do you remember poziotinib’s story? It’s a drug that we don’t like so much because it’s pretty toxic at the GI [gastrointestinal] level; it causes fatigue, mucosal inflammation, and diarrhea. It was evaluated for the treatment of HER2 and EGFR exon 20 insertion, and the other way around—contrary to mobocertinib, it looks like it was slightly more efficient in the treatment of HER2 with a response rate between 25% and 30%, and the response rate was only 10% to 15% in the treatment of those with EGFR exon 20 mutations. This will probably lead to some development in HER2, but you must remember that HER2 has a bit more attractiveness looking at trastuzumab deruxtecan, this antibody-drug conjugate. Maybe poziotinib has a lost the race in the treatment of HER2 because of the other drugs, and in EGFR because of amivantamab and mobocertinib. That’s where we are in the treatment of these rare disease entities. It’s quite important to keep in mind that even in these very small subsets, the pharma industry is helping us develop strategies beyond chemotherapy. That’s very important.

The last things are the data of neratinib in this third category of actionable mutations or exon 18 mutations. I see a pretty good number of them. I don’t know about my colleagues, but these are the mutations we see sometimes: the exon 18 EGFR mutations, and we struggle a little with these mutations. Neratinib biologically shows efficacy in preclinical models, and cell culture in this exon 18 was showing a nice response rate of 40%. Neratinib also has some toxicity; our breast cancer colleagues know the drug very well, a little better than we do, but there’s also room for the development of this drug in this area. That’s where we are with these rare mutations. There will be further developments, but it’s quite good to see that sometimes a strategy might not always have to be used in the front line. For marketing, this may make sense, but for the patients, having a second choice, a plan B in their pockets, is also very important. It’s good to see your oncologist have another idea once what you usually take isn’t efficient anymore. These drugs fill this gap nicely.

Transcript Edited for Clarity