JB:         Hi everyone, my name is Josh Bauml. I’m a medical oncologist at the University of Pennsylvania. I’m joined here by Dr Joshua Sabari from NYU, also a medical oncologist. Welcome to this ecancer expert discussion. Excited today to talk to you about updates from the CHRYSALIS trial. Dr Sabari, actually you gave a presentation at the WCLC virtually, we were all virtually in Singapore. Can you tell me a little bit about what did we hear about this trial?

JS:         Thanks Dr Bauml and thanks to ecancer. So the CHRYSALIS study is a phase I study: dose escalation followed by dose expansion, particularly looking at patients who have EGFR exon 20 insertion mutation who were previously treated with platinum doublet therapy. So, to throw it back to you, Dr Bauml, exon 20, is that common? What do you see? How do you treat it? What is this patient population like?

JB:         Yes, so this is a growing disease group. We actually presented some interesting data there which found that EGFR exon 20 is not that uncommon amongst EGFR mutations but historically was very resistant to tyrosine kinase inhibitors. What we saw at some data that we presented at WCLC was that the older PCR-based tests that looked at EGFR were probably missing about half of the exon 20 insertions that were there. So it’s even more common than we know about but with modern next generation sequencing we’re seeing this. It’s about 12% of all EGFR mutations which is a lot when you consider the fact that 90%, or 85-90%, is made up of L858R and exon 19 so this is the vast majority of that third group. This patient population, similar to other EGFR mutations, tend to be younger, tend to be never smokers or light smokers. So this is a patient population with a real need. We’re seeing some very interesting data; we’ve seen some before with amivantamab but what did you see in this trial?

JS:         I completely agree, very tough to treat population; standard of care right now is chemotherapy alone. So this study looked at a drug called JNJ-372, now named amivantamab, which is an EGFR and cMET bispecific antibody, so a very interesting, novel construct. Most drugs in this space are tyrosine kinase inhibitors or small molecules. So this study looked at patients, again, who have EGFR exon 20 insertion mutations who progressed on prior chemotherapy. The response rate here was about 40%, median progression free survival of 8.3 months so, in my opinion, actually quite astounding results for our patients. Josh, how does this compare to what’s currently available for patients in the second line setting?

JB:         It’s much better than what we have in the second line setting. In the second line setting we’ve got things like docetaxel and for these patients we might have immunotherapy if you didn’t use it in the first line. These patients don’t tend to benefit that much from immunotherapy. So a 40% response rate is really very meaningful. How did the toxicity profile look?

JS:         Interestingly, the toxicities that we saw with the drug amivantamab were pretty classic for EGFR mediated as well as cMET mediated toxicity. So some of the EGFR mediated toxicities we saw were rash and paronychia. Interestingly, we did not see a lot of diarrhoea, only about 12%. Some of the MET mediated toxicities were hypoalbuminaemia as well as lower extremity oedema; most of these toxicities were grade 1 and 2. One of the unique toxicities for this compound was an infusion related reaction. So on cycle 1, day 1 patients  about 30-40 minutes into the infusion had rash, potentially abdominal discomfort, maybe some nausea. Then after discontinuing the therapy that day most of those symptoms resolved and patients were treated on the second day, cycle 1, day 2, with the full infusion. Fortunately, the infusion related reaction did not prevent patients from continuing on the therapy. So, to me, it’s a toxicity to know about but one that was very well managed on the study. So, Josh,  what are some of the toxicities you’ve seen on other therapies in the exon 20 space and how do you think this data compared to those other toxicities?

JB:         The other drugs, as you mentioned, that have been looked at in this space are tyrosine kinase inhibitors. The reason why this drug tends not to respond to tyrosine kinase inhibitors is the drugs just can’t get in the pocket well enough. So the drugs that are specific enough for the exon 20 pocket, drugs like poziotinib that was the first one in the space, they were toxic. So mucositis was really severe, diarrhoea was a major issue. So that drug was developed and we were initially very hopeful about it but there was a high rate of dose discontinuation, of dose reduction, as a result of that toxicity. Mobocertinib, for which we saw some data presented at WCLC as well, similarly is a TKI. It also has a pretty substantial amount of diarrhoea – about 30% grade 3 diarrhoea, which is a lot of diarrhoea. So just balancing the toxicity is a major issue. This infusion related reaction that we see with amivantamab, it’s really a unique thing. What I counsel my patients on it is I say, ‘Look, it’s dramatic, it’s not dangerous for the vast majority of the time.’ You have it, you see it, patients can get quite red, they can be uncomfortable but it goes away and never comes back. It’s really quite a unique toxicity amongst other drugs. How do you see the future of the management of exon 20 given the drugs that we have in this space?

JS:         Yes, that’s a great question, Dr Bauml. We talked about some of the TKIs, the small molecules. I think as we get more specific EGFR exon 20 hopefully we will see less diarrhoea, less rash that has plagued the earlier first or even second generation exon 20 inhibitors. With the JNJ-372 or amivantamab it’s unique, it’s an antibody directed therapy. We saw from our study that it actually hit exon 20 at the near loop, the helical, as well as a broad array of the exon 20 insertion mutations. Something that I’m personally interested in is potentially combining this compound with other agents, potentially maybe TKIs if they become a little bit cleaner over time. But, Dr Bauml, I saw the mobocertinib data, the TAK-788 data, and initially very exciting data presented early on but the response rates seemed to come down a little bit – 25% here – and again with the toxicity I worry about the compound moving forward. One thing that I hope to see is I hope to see more combinations and more combinations that will be better tolerated. One thing that Janssen is doing at the moment, there is a randomised phase III study, the PAPILLON study, which is combining the JNJ-372, the amivantamab, plus chemotherapy with the goal of potentially moving this agent into the front line setting. So, again, a very complicated space. Dr Bauml, what are some of the newer TKIs, some of the newer next generation, third generation and potentially later, TKIs in the exon 20 space?

JB:         There are a lot of drugs in this space that are trying to get there. I think one of the major limitations of mobocertinib, poziotinib and amivantamab is the lack of CNS penetration. That is going to be a major weakness as we look through the study because we know that this kind of disease does have the ability to progress in the brain. So I totally agree with you that the combination with tyrosine kinase inhibitors and specifically CNS penetrant tyrosine kinase inhibitors, which I believe you’re involved in the development of some of these newer drugs at your site, right?

JS:         Yes. We have a compound from Cullinan Oncology, CLN-081; another very interesting compound from Black Diamond Therapeutics, the BDTX-189. I think the hope here, like you mentioned, Dr Bauml, is to really think about combination strategy moving forward. This is not EGFR exon 19 del and L858R where progression free survival on the FLAURA study was 18.9 months; our progression free survival in this study was 8.3 months. So we’re a far cry away from where we were or are with other targeted therapies. Again, it’s a testament to how difficult this is to target. So, Dr Bauml, what do you think down the line, 3-5 years from now, how are we going to be treating our patients with EGFR exon 20 insertion mutant non-small cell lung cancer?

JB:         I certainly hope we’ll be using targeted therapies like amivantamab in the first line. Whether that is in combination with chemotherapy where there is biologic plausibility for the use or perhaps with a combination of tyrosine kinase inhibitors, whether those are EGFR exon 20 specific or if the EGFR targeting effect has the ability to make it more sensitised to other TKIs. We know that in vitro EGFR exon 20 has diminished but present sensitivity to a drug like osimertinib which is well tolerated. So Janssen is also evaluating the combination of amivantamab with lazertinib, another third generation TKI. So this is a space where I think it is going to constantly change. The other thing which I think is important about amivantamab in general and specific to this setting is trying to understand a bit more about what is happening with those 40% of patients. Is there something about the exon 20? Is there something on the cell surface that is directing the response? Because that would really help to guide who we can give amivantamab alone or who we could give a combination approach to.

JS:         A very interesting point. Dr Bauml, a lot of people are using osimertinib 160mg in this population, really based off of data from Dr Zofia Piotrowska presented at I think it was ASCO 2020 in the ECOG-ACRIN study. Are you using that in practice and what do you think about that data? How does that fit in? I think it was about a 24% response rate in that single arm phase II.

JB:         Yes, so when I don’t have access to a clinical trial, which of course is always my priority, but if, for instance, the cohorts are closed and I don’t have access to something I think it’s a very reasonable thing to do off label. But the response rate is disappointing and the toxicity of using 160mg is real. There is a higher rate of rash and diarrhoea with that dose of osimertinib and I’ve had patients who simply cannot tolerate it. So this is an area where there’s a real need for improvement. I’m hopeful with these data that we’re going to see an approval for amivantamab in the near future, particularly given the fact that it has been granted breakthrough designation by the FDA.

So, with that, I want to thank you so much, Dr Sabari, for talking to me about this and I want to thank you all for your kind attention and I hope to see you soon at the next ecancer expert discussion.