WCLC 2025 Highlights: FLAURA2, HARMONi, ALCHEMIST with Dr. Balazs Halmos

Unpacking WCLC 2025: FLAURA2 Overall Survival Data Hello and welcome back to the Oncology Brothers Podcast. I'm Rahul Ghosain here with my brother and Co host Rohit Ghosain. The World Conference on Lung Cancer 2025 just wrapped up and hundreds of abstracts were presented here. But today, we're going to focus on three key studies from this conference, starting off with Flora 2, then we'll switch gears to Harmony trial and then close off with Alchemist trial to go over this recent data. We're excited to welcome back Doctor Bolage Homos, a thoracic medical oncologist at the Montefiore Einstein Kansas Center. Bolage, thanks for being here today. Speaker 2 Great honor. Look forward to our conversations. Speaker 3 Bolage welcome. Let's start off with a bank here. One of the most eagerly awaited study out of the world along 2025 was Flora 2. To set the stage for EGFR mutated non small cell lung cancer, we have three potential options, osemertinib, osemertinib plus chemo which is Fluorid 2 regimen or amivantamab lazertenib based off of Mary Post's study. We've also seen the orals from revival with Amylaz combination. But we were now awaiting the Fluorid 2 oral survival data and that's what we saw here Large. Can you briefly touch on the study design of Fluorid 2 and the findings that is the overall survival data? Speaker 2 Absolutely, you know, really, really exciting data and it was in Barcelona, very exciting meeting. We'll pick 3 examples. It's like, you know, sampling some tapas here, but the first tapas is going to be the most tasty I think. Flora too. Of course we've all been blessed in a way with being able to use acinertinib for our patients. Classical mutation positive EGFR mutated non small cell lung cancer, fantastic drug, good outcomes, good tolerance. Hasn't it been nice to be able to just offer a pill and give 24 refills and ask your patient to return in two years that error is over because now be able to do better with combinations. And that includes both Mariposa and Flora 2 as well. We've learned about these advances over time, but we have not heard about the overall survival benefit of Flora 2 yet. So everybody was anxiously waiting. Is it less than Mariposa? Is it or what is it going to be? The study design is fairly straightforward. Large randomized trial of Aston Martin balloon versus platinum pematrexab, mostly carboplatinum pematrexab plus acimerteneab with a maintenance component of pematrexa plus acimertenab. Pivotal study. The primary endpoint was PFS that's been reached before, but in between the three of us, you know, when you add, you know 2 + 2, you do expect 4. So I mean a progression free survival benefit like is that a big surprise? We needed to see if the investment into building inconvenience, but even more so the adverse event profile of combination regimen, does it truly pay off? You know, does it extend overall survival in a clinically meaningful way? And this is where this was a huge presentation, but after Planchard from Gustav Rousse and we didn't exactly know what to expect. The estimations were six to nine months, maybe more than nine months. Maripusa was just about a year of median overall survival benefit. We looked at the data as it came out with a bit of a gasp because this came out that at the better end of the expectation just about a year of media and OS benefit and a hazard ratio of 0.77, very statistically significant and very clinically meaningful. So that is really amazing, you know, very impressive and nice, but also confusing to all the clinicians, including myself, because the Mariposa data looks near identical. In the middle of the presentation, the NUNA Journal of Medicine published the Mariposa data. So we're looking at it on our phones. We couldn't differentiate the two trials. Very similar data when it comes to outcomes. Differentiating FLAURA2 and Mariposa for Patient Selection Of course, there's differences between the trials in terms of study designs. Neither of them guaranteed crossover, but crossover was of course easy, convenient, you know, for Flora 2 chemotherapy, except for the time when there was a platinum shortage wasn't too difficult to find. For the Mariposa trial, crossover was not permitted. And over the time of the trial, only two patients received an event, an app. So that's, that's the subtle differences, but in reality, very substantial benefits, very different adverse event profile. So how will the condition differentiate between the two and decide who is appropriate for single agent Aston Martin? And here we need to start nuancing in many separate ways #1 is anybody still appropriate for single agent azimertinib? But you want to look at molecular tumor related and patient related elements of care. Patients who might not be great candidates for combination therapy, very elderly, have very limited burden of disease, have molecular factors such as Exxon 19 CTDNA negative no commutations might still you know kind of suggest a profile for single agent asimeritan could provide in a very substantial benefit. But beyond that, the typical patient nowadays should be considered for combination therapy. And if the commitment is to combination, then which combination to choose from? You need to present the address event profile and specifics of the two trials to the patient and has to be shared informed decision making it on the FLORA 2 trial. One comforting piece of information that we saw is, is that the average patient on the trial received chemotherapy for eight months. The progression free survival on the trial was around 30 months. So most patients were able to get the year of survival benefit not getting chemotherapy for years, but an average getting chemotherapy for eight months. And it doesn't say that you should stop chemotherapy at 8 months, but as a good clinician, if your patient starts to struggle with the maintenance Penotrex that you should feel empowered to feel comfortable stopping the maintenance or adjusting the maintenance. So I think that was very nice information from Flora too, and I definitely will incorporate it into my practice even more. So I think for the patient, the commitment is for first three months of significant induction chemotherapy and then kind of cruising altitude. The maintenance chemo will stay as long as the patient is willing to stay on it and look safe for Mariposa. Very different aspects. An excellent regimen changes the disease biology, resistance patterns shift. It looks like there's a bit of a flattening of the overall survival curve providing premise, but maybe not yet proof. There could be some long term beneficiaries of the combo, but it's a hefty combination when it comes to adverse event profile. Intravenous administration is challenged by the infusion reactions. There's a lot of EGF for related toxicity, skin, Pyrenicia, scalp, you know, toxicities also MAT related toxicities, you know, fluid retention, hypobeam anemia and lastly also a very high risk of venous thromboembiotic events to the point that the wax need to be prophylactically given at least for the first four months of treatment. So it's a substantial investment, but the company has done a great job, I might say in terms of elevating, you know the ability to provide the right supportive care. The skipper regimen, just you know, decks, you know, for the infusion reactions, the cocoon regimen for the skin reactions, yes, indeed do X for the VTS still struggling with the met related issues, but with those reductions that can get alleviated as well. We've improved and there's a sub Q version coming which would definitely change the safety profile as well. Both have their special challenges, but on the right hand of an excellent oncologist, excellent community oncology, there should be No Fear. This should be deliverable in a Safeway so that patients can reach that overall survival benefit one year, but at the same time maintain a functional life. There will be some side effects, but hopefully a manageable range. And if ultimately the chemotherapy needs to be peeled off, then I think we're more comfortable to do that nowadays with the data we have available. Speaker 1 Absolutely. There's a lot to unpack here, which is exciting. Also Mertineb as a single agent for a very tiny population, combination being the way to go for majority of our patients. And then we brought up the combination. Also Martin, up with chemotherapy because we've been doing this for a longer period of time. When it comes to Mariposa, anytime we're leaning into this, we have to keep that skip IRR and cocoon data in mind. Any role of CTDNA here where you can probably start to peel off some of these medications earlier on? Speaker 2 That's a great question, but also a challenging 1. So there's two elements to it. I think CTDNA now provides more value not just in frontline biomarker testing, but to prognosticate. So of course we've been, we've been helped greatly by CT DNA to help tissue, you know, based biomarker testing expedite, you know, the processes. But now we also learn that if you see a patient with an EGFR mutated lung cancer, whether they are CT DNA positive or negative, they fall into two very different categories as to their outcomes. So it's a piece of prognostic information, you know, just like CNS metastasis, liver metastasis, P53 commutation. So I feel even more compelled to get a CTD. And as a baseline, even if I know the patients biomarker status, it doesn't just offer the biomarker knowledge, it offers prognostic information. So I can nuance my decision as a single agent versus combination. Now there's additional uses of CTDNA. There's questions about CTDNA clearance. It's one thing that somebody's positive, but can you start a patient on acinertinib and if you see that they clear, just stick with that acinertinib. That's the research question at present. Maybe not totally unreasonable for a clinician to lean into it from time to time, but that's not a already validate together using the baseline positivity as a guide to sort of get that normal grams right, single agent versus combination very helpful tool. Speaker 3 CTDNA is a hot topic for now, not ready for prime time but certainly being utilized for prognostication purposes. So where we stand today is we have similar OS data from Mariposa regimen which is Amylaz and Flora 2 now with OC plus chemotherapy. As you said blarged patient shared decision making is the key here. If one is on single agent OC martinib for each year for a positive disease and the disease was to progress from compelled data, we have evidence that option of chemotherapy does exist or if one is on Aussie chemo and then perhaps progresses, we have Detroit sort of Amy chemo based off of Mariposa two study. We also have data DXD which was recently approved. HARMONi Trial: Bi-specific Antibody's Complex Findings But here at World Lung, you also saw data from Harmony trial. Can you touch on the mechanism of action of this new BI antibody and the study design of Harmony and its findings? Speaker 2 I have to say this is a very interesting trial, very interesting agent, but also twisting and turning development path. This is a molecule that has gotten a lot of lot of press, a lot of excitement around its design. It's a bi specific antibody binding boot PD one. As far as VEGF now why would that be helpful? I had to scratch my head for a while. They claim and maybe the claim is true. Maybe it still needs to be proven that why this works is because through VEGF dimers, these bispecific antibodies can create aggregates of antibodies in a way but depleting VEGF from the circulation better than a single antibody and providing binding on the immune cell surface to lead to even better PDF one blockade. There's a cooperative interaction leading to synergy. Maybe higher potential for activity than just adding VEGF targeting to PDF 1 targeting. This is the speculation. Let's see if we can prove the pudding here. Randomized trials, have we seen a number of them? And this is one of the highlights. Harmony looking at patients with EGF from mutated disease, a disease where there's been signals of activity, activity for budget targeting, but very little signals of activity for immunotherapy to work. OK. So here we take patients on third line EGF for TKI upon progression, just the type of patient Rohid mentioned, this is not chemotherapy plus or Dubai specific. We've learned before that there's a PFS benefit to this combination, which was intriguing. But we've also learned a couple of press releases going back and forth, OS benefit that wasn't reached, and then maybe an OS benefit that was reached. Presentation a couple of days ago was key, like what's going on with this trial? And I admit that it was a little bit of deflating when at the end of the day, because there was a setup that this is going to be a practice changing big positive, it ended up not being positive in terms of statistical significance. As you can see, it must have been very painful for the team to look at the 0.05 7. Based on their statistics, I think they needed to reach 0.045 but they failed to reach OS. The PFS benefit is there but not super substantial. So at the moment it doesn't look like a positive trial. I might also say it's a complicated one as it looks at a Chinese patient population plus adding a court of European and US patient. So it's not a clean phase three study. It's a bit of a mix and match. As a result of those struggles. It doesn't look like the FDA will sign off on this at present. In the discussion at word long, the discussant highlighted this certainly is not leading to any kind of Symphony, you know, you know here. So confusion at present challenging the whole field. It's not the only molecule. This was the lead molecule. There's like 100 of them behind, you know, kind of dependent on the success of the biology mentioned. So do we not trust this whole biology? Well, I wouldn't take it that far because there's a second trial that was presented to be positive on PFS and that's not comparing the non EGF or mutated like wild type patients, pembro versus Ivanessimab. That's a patient population where we do believe in immunotherapy has benefits, maybe a cleaner testing ground for Ivanessimab that PFS benefit with A has a ratio of 0.5, if that translates to Nos benefit, I think there's kind of a rescue strategy here, but we have to see it. We need to see clean trustable data that are clinically relevant. So it's only hope for the next chapter, but for now this is a bit on the back burner or practice will not change. Speaker 1 You mentioned that this has been a twisted and a complicated path in the past. We've also debated the utility of immunotherapy in our EGFR positive patients. I believe it was I am Power 150 where we had a tizzylizumab, bevacizumab and chemotherapy. In that study, there was a very small number of EGFR positive disease, but we've again questioned how much benefit are we buying for the immunotherapy in our EGFR positive patients. OK, Harmoni trial is not ready for prime time use. It's not approved yet. But today Rohit mentioned a few treatment options if the disease was to progress on the front line, be a single agent osmertinib or your combination Flora 2 or Mariposa. How are you moving forward? What are you doing today in your clinic? Speaker 2 If it's a Flora 2 regimen that the patient progresses upon, I think now the challenging question that we need to raise what has been the chemotherapy free interval and you know, we bring it up as, as, as this is that there's some some guidance as to, you know, how much of A chemotherapy free interval patients should have. Hopefully we'll learn it from Flora 2. I, I, I, I trust that the AstraZeneca team will generate this information. If a patient has been off chemotherapy for two years by the time they progress, maybe a re challenge is not inappropriate. And that's what I'm hearing from colleagues, many of them do that. And if you re challenge with chemotherapy then you have the decision, do you use Mariposa too? The patient has not seen any Ventanella and Ventanad. Maybe that's the most evidence based strategy at present, but somewhat more toxic than chemotherapy alone. Or do we tap into the compile study which was just presented that were lung that not continues. Acemerton upon progression suggested a nice PFS and who has benefits. Sadly, it's a small trial that's not definitive, but intriguing enough that it's a practice that we've done anyways, especially for patients with CNS disease provides some justification that chemo plus continued Acemerton. It might not be inappropriate in some cases. And then of course, chemotherapy alone or the DXD potentially for some patients who might not want to be re exposed to chemotherapy or an event ANAB alone. Possibly there's some data in that respect as well, although not super active, but maybe MET IHC can select patients with a higher level of activity of an event ANAB. And lastly, we should never forget that we're still in the area of precision medicine. So anytime there's progression, reconsidering the molecular landscape could come up with justifiable combinations. MET EGF for sorry there's a math amplification. Things of that nature are always important to consider. Speaker 3 Right, retesting for NGS is certainly the key and not for getting the localized treatment options if it is a solitary mass to resort to that. Multidisciplinary is certainly the key aspect here. ALCHEMIST Trial: Crizotinib in Adjuvant ALK+ Disease Moving right along onto our last abstract, we have alchemist study where in resected an adjuvant space currently in ALK positive disease. We have been utilizing electinib. The drug utilized was crozotinib for ALK positive disease after surgery followed by adjuvant chemo. Your takeaways from this study, Sir? Speaker 2 Yeah, this was a very interesting presentation. It was like a Back to the Future type movie hearing about chryzatinib when in the meantime phylectinib leapfrogged chryzatinib in many different ways. And maybe a lectinib has been leapfrogged by by others as well. But this is this is a story of running clinical trials in a national group setting. The trial when it started out was very logical. The Alchemist trial looked for precision medicine in the adjuvant space or latinib for EGA for, you know, chryzatinib for patients. But it took a long time. It took a long time to accrue. By that time the Elena trial data became available and we'll remember that the Elena trial is super positive as the PFS has the ratio of 0.24. The Elena trial didn't randomize patients after adjuvant chemotherapy. It randomized patients against adjuvant chemotherapy. If you're evidence based, you give electinib for those patients, not chemo plus electinib. We can argue what is the right decision, but not the conversation today. The trial did not offer chemotherapy for the treated patients. Patients were randomized to the first Gen. PKI chisatinib after chemotherapy and the post up radiation. Two years of treatment, 150 patients accrued altogether. The study was stubbed when the Alina trial data became available and the very long maturation of the data because these patients did actually quite well. The median DFS is 75 months. When you look at the primary endpoint of DFS, it is stunningly negative, which is so surprising in the precision medicine era to see an adjuvant trial where the the DFS curve just don't separate. So you have to start thinking, was there something wrong here? And I think patients on the chryzatinib are many of them dropped off of chryzatinib due to toxicities. And chryzatinib is not the best act TKI, it doesn't have CNF penetration to begin with. A lot of challenges with the drug. And the study may be that that just, you know, block the ability to detect the benefit that we see from ADORA and from Helena. So what is the conclusion? Well, it definitely doesn't impact practice, right? Because we have a better drug from a cleaner study available. It definitely doesn't take anything away from Medora Alina. Precision medicine is here to stay. We need to offer EGF for LTTS for the right patients. But I think the warning here is, and Doctor Gerber who's done a wonderful job running this trial and presenting the data highlighted well, we cannot just give adjuvant targeted therapy to anyone. We need to think about that adjuvant targeted therapy. It might be appealing to give something to a patient with her B2 positive disease in a couple of months of TDXD or something else for bad positive patients. But we have to think a little bit and unless that drug is in the realm of the osmertinib and electinib exceeding safety, exceeding efficacy and CNS penetration, they're better off being evidence based and, and and not not rushing to prematurely using these drugs. So I think it was a little bit of a warning that let's just let's just carefully think and maybe some of those drugs will fall into the categories matching with all these three boxes. But unless that's the case, just a little bit of pass for the field as to simply broadening without data the adjuvant use of other targeted therapies. Precision Medicine and NGS: WCLC 2025 Final Recap Indeed, large is alectinib remains the current standard of care treatment for two years after surgery for al positive non small cell lung cancer large any last thoughts from the world lung 2025 before we close. Speaker 2 Well, I just hope that you enjoyed our selection of tapas here. I don't know if you can open a bottle of Cava, but with flora too, we're entering a new era. So all of us have to practice those nuancing skills. Decision medicine is definitely here to stay. In fact, is expanding as to having it to use our, you know, armamentarium, including CTDNA, everything else. So exciting times, a little bit more difficult than before, but our patients are doing better as a result. That's the reason for that cava to be open. Speaker 1 Choose to that cava again, just because our patients are living longer with flora two, we are seeing a close to a year overall survival benefit. These are exciting times. And I'll echo Bludge what you said looking at this data, precision medicine is here to say and this continues to reinforce the importance of NGS collage. Thank you so much for taking the time to walk us through these important studies from world long for our listeners. Let us go over a quick recap. Speaker 3 In today's discussion with Doctor Balaji Holmos from Montefiore and Einstein Comprehensive Cancer Center, we had a chance to touch on few key studies from the World Conference on Lung Cancer 2025. Flora 2 which is ausimertnib with chemotherapy upfront for metastatic EGFR positive non small cell lung cancer showed significant oral survival benefit when compared to single agent ausimertnib. This is coming at a cost of side effects from chemotherapy, but the difference is close to 10 months of survival benefit. That is 47.5 months of median overall survival with chemotherapy plus osimertinib arm versus 37.6 months with osimertinib alone and. Speaker 1 Then we also had a chance to touch on Harmoni study which is looking at a new PD1 and VEGF dual blocking agent along with chemotherapy in patients who had progressive disease after frontline treatment in EGFR positive disease. Here we need more mature data but this current study was negative as the P value was over .05. We also now have data DXD in this particular space. Speaker 3 And then to close, we touched on the role of chrosotinib in adjuvant AL positive disease. This was a negative study, which reinforces that alectinib remains the current standard of care for AL positive disease in adjuvant space. Thanks for joining us. We look forward to seeing you at the upcoming conferences. That is SABCS and ASH 2025. We are the oncology brothers.