Dr Alex Spira – Virginia Cancer Specialists Research Institute, Fairfax, USA
Dr Joshua Sabari – NYU Langone Health, New York, USA
AS: Hi, I’m Alex Spira, I’m a medical oncologist with Virginia Cancer Specialists and US Oncology, and I’m here with Dr Sabari today to talk about some of the updates from ESMO this year. It was a packed ESMO and there was a lot of new information, especially in regards to EGFR targeted therapies. We’ll spend a little bit of time today talking about the CHRYSALIS study, specifically with amivantamab and lazertinib. So, Dr Sabari, what are your initial thoughts about this?
JS: Thank you Dr Spira. So Josh Sabari, thoracic medical oncology at NYU Langone Health, a Perlmutter cancer centre in New York. I’m looking forward to a great discussion on EGFR, it’s near and dear to my heart. The CHRYSALIS study is a very interesting study; let me just frame this a little. This is for patients who have progression on third generation EGFR TKI and we’ll really focus on that subset of patients today, Dr Spira, if that’s alright. I thought very impressive, so 36% response rate for patients who have progression post third generation EGFR TKI. Now what does that mean? What resistance mechanisms are seen in that setting? Post Tagrisso most patients are developing a smorgasbord or, in New York, that’s a wide variety of alterations, resistance mechanisms. The most common ones that we see are c-MET amplification in the 15-20% range and C797S, a point mutation, also about 15-20%. Remind me, we can talk about the BLU compound pre-clinically as well this weekend. But in that patient population, J&J developed a compound, amivantamab, which is an EGFR bispecific antibody that blocks both c-MET and EGFR. Dr Spira, what do you think about the mechanism of this drug and the bispecific nature? Do you think this has a real modality moving forward?
AS: I think it’s a phenomenal way to address this. I actually talked about this, Josh, that the major two areas of resistance are C797S and c-MET. So this hits those two major things on both ends. Secondarily, it’s a different mechanism of action. Osimertinib is a small molecule that gets into cells and this really binds on the outside of cells. So there is a separate view that even if you don’t have those mutations there’s a reasonable novel mechanism of action to attack this. So it attacks things on both ends and, to me, this is a long ongoing study, this is, in essence, the end of a phase I study; previously both molecules were studied separately. We found, first of all, that you can give both together in full doses, which is great, it’s never a fait accompli. But, more importantly, you can keep the lazertinib on. From my standpoint the small molecules still have a big role in CNS penetration. A lot of these patients, the drugs will fail them in terms of brain metastases or brain relapses. So the combination there is really getting at two major issues for this. So mechanistically it sounds great and scientifically there are two things – we should focus on the refractory cohort. There is about a 37%, call it more than one-third, response rate which is great, there was significantly more benefit than that, but in this setting where you are basically obliged to do chemotherapy it has a real, real track record. The secondary interesting point is that the response rates in the naïve population were 100%. It’s really hard to know what to do with that because…
JS: Probably the lazertinib.
AS: It’s probably lazertinib, it could be both. But the question is, in that range the fundamental question is how durable will those responses be, how long will they be and is it worth the slightly increased toxicity? So in the front line setting there are some great questions but, for me, the big take-home, as you said, is in this relapsed refractory population. What do you think about the toxicity, Josh?
JS: Toxicity is interesting. So we know from amivantamab, the EGFR bispecific antibody, there is this interesting infusion related reaction. So, about 60-65% of patients on day 1 of the infusion will have this infusion reaction – abdominal discomfort, this heat flushing, potentially even fevers and chills – interestingly mitigated very well by splitting the dose over two days and pre-treating with steroids and Tylenol and Benadryl. So, to me as an investigator and as a clinician, the infusion reaction was not such a major issue clinically. Out in the community it’s going to be important that we monitor this and watch this closely.
More interesting to me, the toxicities that we’re seeing are these EGFR mediated on-targeted toxicity of wildtype inhibition of EGFR such as the rash and the diarrhoea, not uncommon to what we see with other EGFR inhibitors. To me overall I was not that impressed at the toxicity. Obviously amivantamab on its own has some toxicity, combining with lazertinib did not seem to significantly increase the toxicity. I agree with you, Dr Spira, that getting CNS penetration with this combination is going to be critical. One of my major concerns with this drug, amivantamab, was lack of CNS activity. Now with the lazertinib combination we’re seeing hopefully, or we’re going to see hopefully, robust CNS activity.
So toxicity, to me, not such a major issue for the compound. More importantly, I think we’re going to see great activity moving forward. Alex, do you think this drug has a potential role, then, or this combination of amivantamab and lazertinib, for moving into the front line setting down the line?
AS: I think there’s a lot of interest in the front line. I think the challenge that you’ll have in the front line is as follows. Number one is that osimertinib is a very well tolerated drug with really minimal side effects and it’s oral. So it’s not just is this a better combination, and if it’s a better combination, great, but it’s not just adding a better drug, it’s the toxicity that is clearly increased with the bispecific. Secondarily the administration of an IV infusion – it is a tough thing for patients to swallow in that scenario. That being said, the response rates of 100% are phenomenal and the front-line studies do need to be looked at very closely to see how well it works and to see how well it works for the long term. The challenge, as you know, is that the median PFS and OS… the median PFS for first line osimertinib is phenomenal so it’s going to take a long time to show some really good positive data.
There are also some other combination studies in the works, specifically osimertinib with chemo. So it’s an interesting landscape that is getting competitive which means it’s going to be hard to accrue patients and also hard to show a true meaningful benefit. That being said, if you can delay the time to resistance and get these patients more time there’s a huge interest there for all of us. I think it will be exciting to see how this all plays out. The first line studies that are being planned with this combination are super-exciting and there’s a huge interest to enrol.
The last point, Josh, is just to echo what you said. We’ve had a whole bunch of patients on the study. While there is more toxicity than with single agent osimertinib or lazertinib, it’s very manageable. The infusion related reactions are not a big deal for most people. Certainly the EGFR wildtype toxicity is certainly manageable as well. What do you think about the up and coming studies? What do you think the role is going to be for this and what’s the development process looking like?
JS: I think it’s really interesting. I’m pretty new at the oncology game and thoracic oncology. I developed in the erlotinib, gefitinib era where you always wanted to look at another TKI that could potentially have better resistance coverage. Obviously with second generation afatinib we still saw T790M emergence and with osimertinib we thought we had the best drug on the planet. And it is a really good drug, you mentioned PFS 18-19 months, we saw overall survival from Dr Ramalingam recently in the New England Journal paper – 38-39 months – so pretty impressive data. The question is how do we build upon that, how do we improve upon that? The heterogeneity of post-third generation EGFR TKI resistance mechanism is a complex problem, it’s complicated. So lots of questions of looking if the patient gets a first generation inhibitor, second generation inhibitor, then goes on to third generation inhibitor, is that different evolutionary-wise than a patient who just got a third generation inhibitor?
So I think it’s going to be complicated. I think the easier play here is to think about moving these drugs into the front line. So, Dr Spira, I think you’re working on one of the front line studies of chemo plus an EGFR inhibitor, do you think that’s a better opportunity or better approach for preventing resistance mechanisms? Hitting with a blow torch versus using a targeted therapy combination approach from the get go?
AS: I always think that the targeted therapy approach, it’s the scientist in both of us. Here you have a specific problem so the scientist in me wants to believe that the targeted approach is going to be better. So I think those are going to be the approaches. Now, whether or not it’s looking at amivantamab and lazertinib in combination with chemo or chemo plus osimertinib, I think the jury is going to still be out for a very long time for that. It’s just going to take a while for those studies to accrue and then you have such long, durable PFS and OS, it’s going to take a while to really show the benefit. So we’re not going to have that information in the next 12-24 months by any stretch. But, for me at least, it’s a targeted therapy.
For me, and I’m curious what your take is on this, clearly there’s a big understanding that these drugs, we believe, work in C797S and c-MET but there is also, obviously, a theory that they can work in any mechanism of resistance, just looking at the monoclonal and the way it works. Are you checking people for mutations post-osimertinib? Most people aren’t; it’s been hard enough to check in the front-line setting. What are your thoughts, are you checking now or are you going to check more?
JS: Yes, I’m checking in plasma. Usually I use Guardant360 because it’s covered and it’s easily accessible but a biopsy is really a discussion with the patient and oftentimes it doesn’t really guide therapy, as you mentioned Dr Spira. So it’s a tough question, it’s a tough call with patients. Now, I have identified patients with obviously transformation and when a patient has rapidly growing disease it’s important to biopsy to rule out squamous [?] transformation or small cell transformation, but you can count those on a hand. So the key question here is is this going to get approval broad potential resistance mechanism, non-biomarker selected, or is it going to be biomarker selected. I think that with the lazertinib combination with amivantamab they’re going for a more broad approach. If you look at the earlier phase I study one of the cohorts was selecting for patients with c-MET or C797S or other alterations. But thinking about the broad applicability of this compound, in order to really move it forward I do think it needs to be a more broad approach.
That point you made earlier about this blocking other mutations in EGFR, we see not an accelerated approval, excuse me, a breakthrough designation, that’s what it is. There’s a breakthrough designation there. So I do think we’re going to see this drug have activity broadly in EGFR. Again, the mechanism of action is unique to this bispecific approach. It has potential on-target activity binding the receptor in the membrane. It potentially also has immune activity, again I haven’t seen great pre-clinical data to date but it’s an interesting potential combination across all resistance mechanisms. I hope for this drug a future would be to move it to the front-line setting but you’re right, Dr Spira, we’re not going to see results until 2-3 years because of how good osimertinib is in the front-line setting.
AS: You know, Dr Sabari, you also mentioned a lot about the exon 20 and there was not a big update here at ESMO but there have been preliminary data presented before. So that’s going to be the next exciting thing. We only have a few minutes left. It was interesting because I was looking at all the ESMO online information this year and there was a lot on EGFR. Two things that I noticed was the BLU molecule specifically looking at some resistance mutations. There was also a lot about VEGF and osimertinib or even the first generation drugs. To me, that was plus/minus. I think there was some interesting positive data but nothing really panned out. Last year that was the new and up and coming thing and, for me, that was a little bit less of an issue based upon some of the survival statistics. Also part of the issue is in the targeted therapy world we want to think about a target and we’re hard-pressed to really see the role of VEGF inhibition there. I’m curious to your thoughts and what do you think about the BLU molecule from Blueprint?
JS: I’ll start with the BLU molecule, pre-clinically it looks really exciting, it hits triple mutations, it hits T790M and C797S so that’s a really exciting potential. It’s a fourth generation allosteric inhibitor, we’ve seen other allosteric inhibitors in this space that have some toxicity. So I’d be excited to test this drug moving down into the future. Again, pre-clinical data only we don’t have any human data to date but definitely a move forward. We know that C797S has been very difficult to target in our patients. You’re right, there was a tonne of EGFR data presented this weekend and that’s a really important sign and litmus test of our field and how active it is and how we need therapies for our patients in this space. So I do think it’s a rapidly, rapidly evolving space.
Interestingly, a lot of the studies, as you mentioned, focussing more on the early line or front line setting. I was involved in an early study with a first generation inhibitor, Avastin, PFS improvement but unfortunately no OS. It seems like that pans out as well here. We have an ongoing study with osimertinib and ramucirumab right now, a randomised phase II study, and maybe that will be less exciting at the moment – is ramucirumab potentially different than bevacizumab, we’ll see. I don’t clearly understand the rationale for combining a VEGF inhibitor with an EGFR inhibitor but there is some pre-clinical data to support the combination. Again, I think the point being we need better strategies from the front-line setting and we can’t become complacent with a 17-18 month PFS with osimertinib, we need to improve upon that. When I tell a young patient who is newly diagnosed with EGFR mutant lung cancer, exon 19 del or LA58R, that this drug will work for a time but not forever, it eeks me inside, I wish we had better potential opportunities.
AS: I agree completely, Dr Sabari. For the last 12-18 months we got away, there was a big excitement and one of the studies was the update on chemotherapy, one of the IMpower studies, I think 150 with carbo, paclitaxel, bevacizumab and atezolizumab. It got a little bit away for about 12-24 months so it’s super-exciting to see we’re back on, let’s really focus on the targets and mechanism of resistance and we are. So with amivantamab and lazertinib there’s clearly thinking about that. So it’s back to being a super-exciting time where the science really trumps everything. We’re just going to have to see how it’s all going to play out which is not 100% clear right now.
So I think we’re pretty much done on time. I think that was a great ESMO, a lot about the EGFR world so very exciting there. Any last comments, Dr Sabari?
JS: No, I think this is an exciting time in the targeted therapeutics field. I think it’s exciting for our patients. A couple of other drugs we didn’t mention but the U3-1402 and others, HER3-ADC also with 25-30% response rate post-third generation EGFR TKI. So I think this is an interesting time. Hopefully, as you mentioned, we move away from this flamethrower approach of using chemo and immunotherapy in this setting. We know that there are some potential toxicities there. I’m really excited to getting back to looking at targeted therapeutic strategies in this patient population.
AS: No, I agree completely. The last thing I’ll say is once my patients have been on a targeted therapy that’s all they want so they’re very hard pressed to switch to something that’s the flamethrower, nuclear bomb approach which is chemotherapy. So it’s super-exciting to have these options both on trial and hopefully off of trial as they get FDA approved. So thanks very much. Thank you ecancer for having us.
JS: Thank you.