Frontline EGFR+ mNSCLC: Does Evidence Favor Osimertinib Optimization or Alternative EGFR/MET Bispecific Approach?​ (Round 1)

Drs Lopes and Rodriguez debate the evidence supporting optimization of an osimertinib backbone vs an EGFR/MET bispecific approach for frontline treatment of EGFR+ mNSCLC.

To hear arguments related to the impact of time toxicity, quality of life, and cost of frontline EGFR+ mNSCLC treatment selection — osimertinib- vs amivantamab-based regimens, see Round 2.

To hear arguments related to the impact of frontline EGFR+ mNSCLC treatment selection on subsequent available therapies — osimertinib- vs amivantamab-based regimens, see Round 3.

Transcript

Dr Santos Castillero: Targeting EGFR. So as you remember, the story started years ago, back in 2002, 2001, when we have EGFR, for the first time. We have gefitinib, initially, then erlotinib, and we didn't have any clue of why these TKI were working. And perhaps for old people like me, because I think I was a fellow at that time, there was a publication [inaudible 00:00:31] Dr Langer and Dr Garon would remember the publication in JCO, people that were in hospice and they were getting out of hospice and lung cancer, no one knows why. But they were getting a pill and they were getting out of a hospice. And we didn't have any clue that there was something that called EGFR mutation until 2006, '07, ’08, and the presentation in 2008 by Dr Tony Mok, which basically put TKI at a frontline in test of chemotherapy. And that was the IPASS study. 

And then the things continue moving on and new medication were coming up, second generations TKI. And finally we were able to find a third generation TKI call osimertinib, which became the king and the preferred regimen since 2018 with a strong PFS. And then 2019, solidifying his position when it proved overall survival over first generation TKI. So we know what osi does. Basically go to the TKI domain, shove down the signal into the nucleus inducing apoptosis and avoid all this proliferation of these tumor cells that has this mutation. And platinum-based therapy using pemetrexed, we know that it's going to attack those rapid dividing cells, this raw DNA replication, classic effect of the chemotherapy. 

So this chemo has come as an addition to osimertinib, and that is the thing that Dr Lopes will take us in a few minutes. Then as I mentioned before, things are also evolving. And now we have for the first time a combination of multi-target, I would say multi-target treatment for EGFR mutant because one of them is amivantamab, a bispecific monoclonal antibody that target two receptor, will cause dual blockade of EGFR and MET. And by doing that, they will cause internalization of the two receptors, which are going to be degraded by the lysosome machinery. And also there are data already that may induce immune modulation. There are two mechanisms that has been proposed. One is trogocytosis by the macrophage, and the other one is ADCC, antibody dependent cellular cytotoxicity by the natural killer cells. And then the sponsor of this trial also decide to use a third generation TKI called lazertinib, which basically will target the intracellular EGFR domain. So this is a dual blockade for EGFR. And this is exactly what Dr Estelamari Rodriguez will talk to us in a few minutes. 

So the first round. There is a problem here because both of them are from the same institution. So we will watch that if there is anything from Dr Lopes in Monday to Dr Rodriguez.  

So the first round is the following: frontline treatment landscape, have we evolved from osi? Have we moved forward? Should we [be] using combination therapy? What is the pivotal trial that will guide us on the frontline therapy of EGFR. And Dr Lopes will take the first opportunity to defend that position. So will you take us if on Monday we will be clear? 

Dr Lopes: So I don't think everything's going to be clear by Monday, but I'm hoping that you're going to be confused at a higher level. And that's all we can hope for when we really don't have a direct comparison between the two strategies. So we're going to be kind of going over what we have seen over the last 20 years. Edgardo already gave us a little bit of a brief introduction as how we got to here. And my part of the discussion is how do we optimize using osimertinib? So osimertinib from 2017, 2018 became one of the most commonly used first line options. It reigned absolute from the moment we saw the overall survival data because you have better progression-free survival, you have better overall survival, and you have better tolerability as well. So this is as much of a home run as you can have a home run in oncology with hazard ratios that were extremely not just statistically significant, but also clinically relevant. 

And that's the idea. How do we actually go from here? So this is FLAURA. This was initially presented by Tony Mok at ESMO 2017, and then we saw the overall survival data presented and published about a year, year and a half later. Suresh presented it. And here we see the overall survival data. Without a doubt, you can certainly drive, I wouldn't say a truck, but you can certainly drive a nice size Defender Range Rover into it. And it is without a doubt the first new standard. Again, better overall survival, better progression-free survival, better response rate, and better tolerability. So it wasn't that hard to choose it, except for cost. So in places where cost is an issue, that's where we continue using some of our older standards, gefitinib, erlotinib, and a few others that have been developed outside of the US and that we don't use here. 

A funny story about gefitinib is that the very first phase 1 trial that I designed and was able to get funding for was a combination of gefitinib and bortezomib. We had some preclinical data in the lab showing that proteasome inhibition could actually increase the efficacy and beared some interest in EGFR pathways. And this is way before we had actually the data on the mutations. And the day I got approval from the IRB to actually start the trial, having funding and everything else, that was the day gefitinib was taken off the market in the US. And that is one of the stories I always tell my fellows because a career always has setbacks and always has things that do not work, even though you have worked on it for three years to get it through. 

I still used a lot of gefitinib because after I finished fellowship, I actually moved to Asia. We were one of the sites for IPASS in Singapore. And I have followed all of the development of these inhibitors, including the ones that we don't use in this country. And I have been API for a number of these studies. Interestingly, I'm the one who presented the data for SKIPPirr, which is the prevention of infusion reactions with amivantamab-lazertinib. So I kind of didn't really take a peak. I think Estela wanted to be nice to me and gave me the one that we still use more often. But again, FLAURA2 is what established that if we do start with chemo in addition to osimertinib versus osimertinib alone, we actually do have better results. 

And here you see the details about 550 patients reminding everyone that the initial approval and the initial use of osimertinib is deletion 19 and L858R mutations, and that's what we did in FLAURA2. Patients who were randomized one-to-one to get chemo plus osi or osi alone. And patients who did get chemo also continued the pemetrexed in addition to the osimertinib in the maintenance phase. Primary endpoint was progression-free survival with overall survival and others as secondary endpoints. And it's extremely interesting that we do see a little bit of a crisscrossing. This is something that we have seen in a number of EGFR trials and IPASS. When we looked at the IIT population, the curves absolutely crisscrossed. And that told us we had two populations in that study. IPASS was not selected by mutation. IPASS patients were selected by phenotype. They were non-smokers, Asian, and mostly were women as well. But it really saw a benefit only for those patients that retrospectively had EGFR mutations.  

So I don't know what that second population here is. That is not a big crisscrossing, but without a doubt for most of the follow-up in this study, chemotherapy plus osi did better than osi alone. And we look at three years, 51% versus 63%, and at four years, 41% versus 49%, with a hazard ratio of 0.77 and a P value of 0.02. So without a doubt, this is an improvement.  

In terms of safety summary, it is extremely important to realize that carboplatin and pemetrexed is a very well tolerated regimen. Most of us have been using it for decades. And of course, it is associated with more adverse events than osimertinib alone, but nothing that we're not used to discussing or seeing. And as such, almost 90% of patients were able to continue on treatment without discontinuation due to treatment-related ARs in the chemo arm. 11% of patients did permanently discontinue. And this is something important to remember when we treat patients. There were dose interruptions in 44% and 10% of patients had dose reductions. Do remember that by what we're going to see with the different toxicity that we see with amivantamab and lazertinib without putting you in any worse position. 

Dr Rodriguez: Thank you. So I have to say, I think in our clinics we learned to know this data on both sides. And we actually have patients that you have these long conversations and it's kind of doing a Great Debate in front of a patient, because I think you really have to know the data to really be able to advise patients. So this is a MARIPOSA trial. So we're going to be talking about amivantamab, a bispecific antibody to both EGFR and MET, in combination with an oral TKI lazertinib. And in this trial, patients were randomized to that combination, osimertinib monotherapy, and lazertinib alone. The data that was later submitted and the comparison we'll be discussing will be the monotherapy with this combination. 

Now, this is the non-chemo regimen. When we describe it to patients, it doesn't mean no toxicity, it just means no chemo. And I will actually say that even if chemo is well tolerated, it's not tolerated by all. So there is room for treatments that don't have chemo and understanding what that toxicity is about. And in these regimens, patients were able to continue until disease progression. And there was a significant amount of patients that either discontinue or held treatment, and that's true in the real world. 

But this is really the amazing, another amazing curve. And I will kind of highlight that there is something that happens funny in the first six months of both of these data sets, where the monotherapy group is a little bit better than everybody who got something extra. So keep that in mind, that there might be people who may be too frail, that maybe monotherapy is an option for them. But that being said, what we really care when patients come to us is, how can I be cured? How can I be here longer, for our patients? And this is a really exciting part of both of these datasets, that we have made improvements. Monotherapy is no longer the standard for patients who want to be here longer. 

So we already showed the data for FLAURA. The data for MARIPOSA is even slightly better. And they have showed ... And if you were, we were at World Lung [Conference], and the same that they were presented the FLAURA data, they present the New England Journal published the data for survival reaching more than 12 month difference between the monotherapy and the combination. So really if patients ask you about how can I be here longer? You have to talk to them about monotherapy. It's a hazard ratio of 0.75 and the difference more than 12 months. 

Now, this is the problem with this regimen. And if I had a little like ‘X’, I will tell you that this safety analysis can be redone in the real world because at least three big things that are listed here are no longer the case. So COVID, no longer the case. So about something like 20, one, two, three, four, five, like 26% of people had COVID in this arm that had amivantamab. So that impacted how they experienced this regimen. And then a big amount of them, more than 40% of patients, had some VTE event. And obviously after this was recognized, all these patients are not anticoagulated for three months. So those two things are under control. And then there's another thing that is under control. Thank you, Dr Lopes. Dr Lopes was the author and presenter of the SKIPPirr trial that had to do with infusion-related reactions. Very big group of patients, 63% of patients and more, had these infusion reactions. That has been ameliorated by ... Thank you, doctor. 

Dr Lopes: I've been making a career of answering questions that become useless as soon as I answer them, both with KEYNOTE-042 as well as with SCIPirr. 

Dr Rodriguez: It was very useful for a second there that you could premedicate people with steroids. But now we have a subQ formulation that almost gets rid of this. So I just want you to imagine this curve without it. I think the thing that will remain in this analysis is the rash. So 86% of patients had some kind of rash, and severe rash 26%. And that's still there. But we have data on how to ameliorate and mitigate some of those symptoms by being proactive. But definitely no chemo side effects. So you didn't see nausea, you didn't see renal insufficiency, anemia, less fatigue. So these are things that patients may care about. Thank you, Dr Lopes for the SKIPPirr data. So the SKIPPirr data just showed that basically we can get rid of a lot of these infusion-related reactions, which is a bad experience for the patient. 

And it also required that patients stayed in the unit for a long time, four, five hours, and come back on the second day in the first cycle. And then they keep having this infusion-related reactions. And thank god that we don't have to deal with that. And the amivantamab subQ formulation is making this process easier and less upsetting for patients that get these reactions. COCOON is the next answer of how to fix this kind of protocol by doing a lot of the very aggressive dermatologic care with a lot of antibiotics and creams and lotions. And it's really something that requires a patient that is willing to do all of this. But with that, they were able to show that you can reduce from 83% to 66% all toxicity. And the severe ones also you can decrease more than 30%. So really a very impressive difference.