Beyond First Line: How Osimertinib- vs Amivantamab-Based Treatment Shapes What Comes Next (Round 3)

Drs Lopes and Rodriguez debate how frontline osimertinib- vs amivantamab-based strategies influence subsequent treatment sequencing and long-term management.

To hear arguments related to the pivotal data supporting frontline EGFR+ mNSCLC therapies — osimertinib- vs amivantamab-based regimens, see Round 1.

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 return to the series, click here.

Transcript

Dr Santos Castillero: Okay. And then round three. So if you were in the outstanding lecture from our colleague, Elena Yu, she mentioned what we do in first line will affect second line and third line. So remember, when we see a patient in EGFR mutation in our clinic, it's not a sprint, it's not a fast race, it's a marathon. So I always try to teach that to my residents or fellows that pass through my clinics. I see a patient with EGFR mutation, okay, [inaudible 00:00:33]. I just smile saying I wish that this patient go five, 10 years, who knows? So it's our responsibility to be sure that that happen. So choose the best based on your knowledge, but all we think what is coming after. Second, third, fourth line. And as long as they leave, more research is coming behind. So first round, Dr Lopes, what will be your second, third line if you start with FLAURA2 or osimertinib alone because you are on the TKI side? 

Dr Lopes: So that's a great question because we all have patients who have been on osimertinib for quite some time. I have a couple of patients, actually I still have one patient who's been on erlotinib for 15 years and one patient on crizotinib, different disease for 15 years as well. So this is not the general rule. The vast majority of patients that have TKI driven disease or mutation driven disease on TKIs will eventually progress and will need second line treatment. So that's the biggest challenge we have today with TKIs in non-small cell lung cancer. We can get responses right away. Patients can have disease control sometimes for years when we're talking about EGFR, LCROS1 and RET, but eventually the vast majority of patients progress. So we don't still have any trials where we can see a nice plateau as we do see for those patients who respond to immunotherapy. 

So this is the biggest challenge we have try to making those tumors hot from an immunologic point of view. But while we're not quite there and we really don't have anything except for maybe PD-L1/VEGF bispecific in the horizon, what we can really look into is what we have seen already. So do I still use osimertinib? I still have a few patients that have been in osimertinib alone. Some because we had started two, three years ago, and they have complete responses. So when exposed to the data that we get from FLAURA2 and MARIPOSA, they really don't want to add anything else because there's really no point right now. But we also have patients that have been on it and are progressing. And the truth is for our second line strategies, we're now in data-free zones because the vast majority of these studies actually used osimertinib alone in the first line and then patients got randomized to something. 

And this is COMPEL. I would not sell this as a definitive study. It's an extremely interesting set of data, but it's not a definitive study. We have about 50, 49 patients in each arm. And before COMPEL, we had at least five different trials with gefitinib or erlotinib continuation after patients progressed on first line EGFR TKI. And except for one or two of those studies showing a little bit of a PFS benefit, we really did not see an overall survival benefit. And the largest of those studies absolutely did not show an overall survival benefit. Also, many of us imagined that as long as patients got chemo after they got the osimertinib, we would not see an overall survival difference in FLAURA2. And I would say that 90% of us were proven wrong because we do see it. And the biggest question is we also see in EGFR mutant disease, the same phenomenon we have seen for 30 to 50 years in lung cancer trials. 

In the transition between first line and second line and second line and third line, we do lose a quarter to a third of patients every time. So we do need to use the most effective regimen in the first line. For those patients that have been on osimertinib, one of the things that we have been doing around the time when we were seeing the PFS data and then the OS data was to add on chemo to those patients on osimertinib. And the COMPEL data pretty much confirms the bias of those of us who believed in this. And this is what you see in these numbers. Here is median progression-free survival, improving from 4.4 to 8.4 months, has a ratio of 0.43, and this is statistically significant. Interestingly, we don't have the slide, but there is a very strong trend for doubling medium overall survival as well. 

So that brings the interesting question. Did we see a benefit in FLAURA2 because patients went on to get chemo, because most patients did get chemo in the second line after they got osimertinib in FLAURA2, but did we get a benefit because we did not continue the osimertinib? And that's an unanswered question. I have my biases and we can discuss that.  

So this is subsequent therapy in FLAURA2. We see in green that 72% of patients got platinum-based chemo and 3% got non-platinum, and then 7% got EGFR targeted therapy, other than osimertinib for patients outside of the US that often include in different third generation TKIs, I don't know that any of that happened here and 14% other. I would be very curious to know what the other was. Some of it may have been EGFR targeted therapy in a clinical trial and so on and so forth. 

So that's the big question that we don't have a good answer for. Are there patients that we could start on osimertinib and then add on chemo if we find a reason? So every subset analysis we have seen at FLAURA2 or MARIPOSA for that matter has shown that any risk group, if you have p53 co-mutations, if you have brain metastasis, if you have positive ctDNA in your liquid biopsy, all those patients have worse prognosis and they all seem to benefit from getting combination, chemo plus osi or ami plus lazer. So we really don't have a good enough risk group that we feel comfortable today, at least in terms of overall survival. So you'll see that in most academic centers, we are using one of the two strategies. And for second and third line, then we have a few options. We had several studies looking into this after osimertinib. 

The one that is approved in the US is MARIPOSA2. So patients got amivantamab and PEM-based chemo plus/minus lazertinib versus PEM-based chemo with a platinum after progression of osimertinib, and we saw a benefit. If a patient has met overexpression and/or amplification, we have the SAFFRON phase 3 study ongoing, but we have early data from the phase 1 and phase 2 studies suggesting that we do see a benefit by adding savolitinib. And we also used to use data from IMpower150, a very small subset analysis showing that if you did get that regimen and you had an EGFR mutation, you did seem to have a benefit in overall survival. A number of phase three trials afterwards without a VEGF component did not show any benefit in overall survival. Those trials that did have a VEGF component such as ORIENT-31 did show a benefit in PFS, but not necessarily in overall survival. 

And I think that we will see data from HARMONi corroborating the idea that VEGF plus PD-1 inhibition may be important. We don't have clarity. The FDA is going to be letting us know if they believe in that in November, and we do have a few more clinical trials that are ongoing. That's a strategy that is approved in China to use ivonescimab. And again, that's not approved in this country, so that's absolutely out of any CME talks. And finally, within this country, we have been using the TROPION-Lung data and Datopotamab has become an option for patients with EGFR mutation after failure of other treatments. And I think that brings us back to Estela. 

Dr Rodriguez: Great. Thank you. And thank you for making this easier for me because you said two things. You said that a lot of patients are making to second line therapy. So we have to start there. So that's the reason for amivantamab. Amivantinab was designed with the understanding that many of these patients will get MET-related resistance, and this is why patients will progress on monotherapy. So amivantanab was developed to address the resistant mutation first, but we do have data about what patients who progress, what they had after that. So 67% of patients who receive ami-laz went to receive a subsequent therapy. And this is important to know because this difference of a year between one arm and the other has been argued that in an international trial, the control arm was not getting effective care. And I think at least the majority of those patients went on to get chemo. 

They went to get an EGFR TKI or targeted therapy, but there was a good amount of chemo over or close to half or more of the patients. So that is critical. But the other thing that they show you here that the time to a subsequent therapy, they couldn't estimate it initially because they were really doing that. They were delaying progressions on patients by treating this resistant pathway early. But we have now a lot of fun kind of play what you want to play musical chairs here, what you started with, what you moved to. So there's a lot of options. I think we had some of that discussed this morning that if patients have brain METs, they can have local therapy and continue laz-ami. And I will note that in the new NCCN guidelines, this combination of ami-laz has a higher recommendation based on their data from MARIPOSA in the brain. 

So that is a good data to use when you have patients that are minimally symptomatic and you don't really have to change the treatment. You can just treat the brain and continue. But if you're symptomatic systemically, especially liver meds, visceral disease, I think the next best option for these patients is going to be chemo. If you can get amivantanab covered, and that has a lot to do if you progress, you have been on ami-laz and you had discontinued ami or decreased it, and now you can rechallenge with ami, with chemo that's reasonable. There are patients that are just going to get chemo alone. I think we talked about it this morning that it's important to find resistant pathways. And what they have shown from this dataset is that they're not seeing MET as a resistant... They almost got rid of that as a possibility. Although I will tell you that every time I look for MET amplification or mutation, I never find that when people progress, but it is a part of the process. 

When patients have limited progression, again, use radiation and you can continue the same treatment. And the same thing that was discussed by Dr Lopes that now we have other options, including all Docetaxel ramucirumab or TROP2 inhibitors and integrating immunotherapy in the mix here. So consider rebiopsy. If patients are asymptomatic, consider radiation so that you can do the most of this treatment. And that being said, in both, we didn't cover this, how many patients discontinue these regimens. And I think that's really important because it speaks to what the next line of therapy... If you still had a year benefit from this after over half of the patient discontinuing the regimen, it means two things to me, either that we had a really good salvage regimen or were really good doctors, or that patients, the biology of this disease is evolving so that maybe people are living longer for all of those reasons. 

Thank you. 

Dr Santos Castillero: Very good. Thank you, Dr Rodriguez and Dr Lopes for this brilliant presentation. So we're going back to the question, to the polling. 

Speaker 4: We have one more slide. 

Dr Santos Castillero: Ah, one more slide? Closing thoughts. Summary. Yes. Ah, the summary. Okay. So we have, thank you, Mrs. Okam. So EGFR monotherapy is still a viable option. That was one of my final thought for today. For each of you, in what scenario, Estelamari Rodriguez, you first, would you use the osimertinib alone, mono? 

Dr Rodriguez: So I have older patients that don't want chemo or any toxicity. So that's a perfect regimen with a good survival for these patients. And then I have patients who don't want to come in. So I mean, both of these regimens, you have to come in and it's been wonderful to have patients that don't feel like cancer patients because they don't come often. They come every three to four months. 

Dr Lopes: Yeah, we have patients that live in the Caribbean and they really hate the idea of having to come every three weeks to get maintenance. In those situations, if patients are in good shape and they really want to go for that survival, one interesting point that we didn't discuss is that the medium cycles of pemetrexed in FLAURA2 was around 7 or 8, and that is what we try to get patients through. We do have data from before, and again, in non-EGFR populations, that when you continue pemetrexed, you do get about a six-month benefit in overall survival. How much of that is true in EGFR mutants? We really have no idea, but we do know that in FLAURA2, patients stopped after a little bit more than six cycles. So I often try to get patients to get a very minimum of four if they really don't want to keep coming back, but I usually do as a standard continue it until toxicity. 

But I have a much lower threshold to not keep on pushing it after we clearly saw that data. So the idea is you should continue it while patients feel well, but once they start having longer-term toxicity, and with pemetrexed, that does happen. We do have patients that do develop edema, as I mentioned. We have patients that have fatigue, so it's not necessarily fully benign. It is as good as chemo can get, but it's not fully devoid of adverse events. So I think that that is one of the things that we often do, try to give a few cycles at least. The majority of patients that I have on osimertinib alone that we started probably only two patients more recently, are older patients who really do not want to be coming to clinic and who have a performance status that is a little not ideal. 

Dr Santos Castillero: Yes, I'm glad you mentioned that the patient from the Caribbean. One of my patients you saw this week, and she has been on osi alone for six years, not probably until now they found something there like I need to do a biopsy. And the patient is a physician and we know she understand all the data wherever she prefer to go the easy way. So I said, when you need a mediastinoscopy because it's in anterior metastatic, there's no way that we can get to IR or the other option is empirically do a radiation therapy [inaudible 00:14:56] and also liquid biopsy. So liquid biopsy is improbably just to be sure that we don't find any of those TP53 RD1 that sometimes appears and then I will go more toward a biopsy, be sure that we don't miss transformation. 

On the second thing, here see the intensifying combination, I think that perhaps is the way to go for most of the patient. I like what Dr Rodriguez and Lopes presented, both then improve overall survival. There is no question. We need to give the best therapy because Dr Lopes mentioned, and it's incredible that after so many years, 40, 50 years on research in lung cancer, every time that we move from first line to second line, second line to third line, it doesn't matter what therapy, [inaudible 00:15:44], although it's more we lost 33% of the patient, one third of the patient will not move to second line, will not move to third line, everyone that will move on. 

So osi and amivantanab combination strategy show distinct benefit-risk profile with different efficacy and safety trade-offs, very well presented by Dr Rodriguez, attacking the number one mechanism of resistance, which is MET amplification, both goes with some kind of cost and patient needs to be more willing to do all these kind of ways how to mitigate all the toxicity, but thank God that we have some way to do it. 

So toxicity goes beyond the tolerability and the thing that this remain offer. So something that we need to take into consideration, certainly the amount of dollars, I think that was per year, between all these payers, is significant. And finally the frontline treatment option will impact the second and the third line that we will go through. And I like that both of you present all the option that we have and is not as easy as it used to be, which is good for our patients. 

Dr Lopes: Good, yes.