WCLC 2024 Highlights - Exploring Latest Advances in Lung Cancer Treatment

Intro Hello and welcome back to the Oncology Brothers Podcast. I'm Rahul Gossain and as always I'm joined by my brother and Co host Rohed Gossain. Speaker 2 Hello everyone. We're excited to bring you the highlights from World Conference on Lung Cancer 2024. Hundreds of abstracts were presented here, but we have picked 4 studies that can help us reinforce our current standard of care practice in community settings. To guide us through this data, we are thrilled to have none other than Doctor Gilberto Lopez, Chief of Medical Oncology the and Thoracic Medical Oncologist at the Silvestro Comprehensive Cancer Center, University of Miami. Gilberto, thank you so much for joining us. Speaker 3 Today. Hi guys. Thank you for having me. Speaker 1 Alberto, we have quite a bit to cover in a short period of time. We'll be focusing on 4 abstracts starting off with the first study and exploratory analysis of Checkmate 816 versus Checkmate 770. Checkmate 816 vs Checkmate 770 Today as part of our standard of care treatment, we have neoadjuvant chemo immunotherapy approach, which is the Checkmate 816 or the sandwich approach with chemo immunotherapy upfront, then surgery followed by immunotherapy in post op space. We have quite a few options here, but the study design mimics Checkmate 770. Here we continue to struggle. How much benefit are we buying from post op immunotherapy because we don't have head to head trials? Gilberto, can you walk us through this study and its findings for us? Speaker 3 So this is a fascinating study in which it's kind of a network meta analysis with individual patient data. So it's the best that you can get without actually doing the randomized study. Looking back when we had new adjuvant chemotherapy alone or adjuvant chemotherapy alone, it really didn't matter if you gave it before or post op, as long as patients did get all of the platinum that they needed to get. And with this, unfortunately we really don't have a lot of guidance. We initially used to give just three cycles of chemotherapy and nivolumab and that was our first standard because that was the first true piece of data in the new edge of an immunotherapy plus chemo arena that came out. So we absolutely use that as our routine. And so once you do get approval of embalizumab and 1st the tizilizumab in the adjuvant setting, then you start having that discussion. If we used to have that routine that we used to give everything that has been proven in the adjuvant setting and we don't want to negate to any patients the benefit that you would get in that setting. That's when we started using a lot more of continuing the immunotherapy for a total of 1 year of treatment after the new adjuvant approach as well. And we, we did notice in our practice that patients that had complete FCR clearly had better prognosis. And of course, what is extremely interesting about this study is that overall you seem to have a benefit from adding that immunotherapy in the adjuvant setting as well as they call it very operative. There are some methodological issues that we do need to keep in mind. I don't think they invalidate the conclusions, but the fact that they censor from surgery and not a full intention to treat analysis does detract a little bit from the strength of this study methodologically. But I don't think we can negate the conclusions and extremely interesting. And you do show those slides for patients who had APCR, it seems that continuing the immunotherapy did not help much. And for patients that had a positive video, one of 1% and above, that did not seem to change the prognosis much either. I think that most of us intuitively believe and think that having APCR places, you had a very good prognostic box And those patients I would feel extremely comfortable not continuing the immunotherapy for a year. And we have a good number of patients that have been treated like that overall in the community and in academic centers. And one of the things that I'm not 100% sure yet is the patients with video one, greater than 1%, we didn't see that As for greater than 50% or greater than 80 or 90%. So it may be that that those specific subgroups are the ones that you really don't need to continue and there might be some in that one to 49 or 1 to 89 that might benefit from continuation of immunotherapy a little longer. So I think that this we will wait and I imagine that we're going to start seeing a lot more data with minimal residual disease and with those types of assays to try to guide therapy. I think every meeting we see more evidence that measuring minimal residual disease and lung cancer will probably pan out as an important prognostic and predictive factor. So I think this helps. I think it shows us a little bit of data in a comparative way that we didn't have before WCLC 24. I think that I still feel comfortable for patients with path CRS to not give adjuvant immuno. I'm not quite sure I'm comfortable yet to stop it for patients that do not have a path CR and have video one between 1 and 49. Speaker 2 Thanks so much for summarizing it so well because we have certainly learned quite a bit. But yes, there are some unanswered questions to what you stated. Pat CR well, questionable evidence where whether adjuvant immunotherapy is going to be helpful. One can actually rather stop it. But if no, Pat CR, certainly there is benefit. And as you stated with PDL 1 positive group questionable because we need to really see even longer term data and also more stratification whether 50% or more there. OK, now switching to your study. Speaker 3 Sir, important point. We do need longer follow up. That's a point to keep in mind. Speaker 2 Thank you. Speaker 3 My study Yes, your. Skipper Study Study skip IRR or skipper. Speaker 3 It's Skipper. This is slightly different than the trials and the presentations that we usually see at WCLC 24. We're trying to prevent infusion related reactions with amivantamab. Amivantamab is an important drug. We we're still setting what exactly its role will be, how much it's going to be used in first line with lazertanib and patients with the deformed mutation, which is an indication that is already approved in the US. We do not have an indication here for chemo plus amevantamab after ozimertinib and that's something that is already approved in Brazil and in Europe and that should come in the next couple months as well. And of course we use it with chemo in patients with Action 20 insertion mutations and up to 70% of patients have infusion rate actions. And this can be quite troublesome. This can be quite scary for patients in particular. And it is something that is very unusual for any drug that I know that it usually happens only in the first time you infuse the drug. And what we tried to do here is we did a Simon to stage design to look into four different prophylactic strategies. We looked at Dexed 4 and 8 milligrams. We looked at Montelukast and we looked at methotrexate and you had to have fewer than three adverse reactions to go on to stage 2 and fewer than 8 to go to stage to the expansion stage. And only the 8 milligrams twice daily dexamethasone starting two days before and still giving one extra dose before the IV dexamethasone that's usually in the label. That was the only arm and we got 40 patients in that. And the infusion reaction rate went down from about 70% historically to 22.5. So it is clearly an important difference. And this is something that we can do as early as with the next patient. We prescribe them Inventimet 4. So it is probably not going to be a standard for too long because we're expecting subcutaneous Ambiventimet to be approved before the end of the year. And with the subcutaneous we see a lot less of these IRRS or infusion or and and the subcutaneous is not going to be a quick injection, it's going to be a 5 minute infusion. So it's still kind of an infusion even though it is subcutaneous and that has a lot fewer IRRS related to it. We what we really need to work on is the rash. Rash is one of the main reasons I get second opinions for patients on amifentamab with excellent 20 or with sensitizing deform mutations. And this is something that we're still working on. There's a number of different strategies that we are testing to see if we can improve on the rash as well. Speaker 1 Berto, thank you so much for going over that. You know, whenever I'm looking about emivantamab or thinking about this drug, it reminds me of what we use in the community, Daratumumab for myeloma, very similar paradigm infusion reactions and we're starting to see that same approach here. So exactly to what you said, starting our next patients with emivantamab, we should be using prophylactic dexamethasone at least till we get the subcutaneous formulation available to decrease some of these infusion related events. All right, so now let's switch gears to focus on metastatic non small cell lung cancer where we might not have had any actionable mutations upfront. Metastatic non-small cell lung cancer (NSCLC) The current standard of care is single agent pembro if you have high PDO 1 and we combine this with chemotherapy if you have PDO 11 to 49%. Here we have Harmony 2 where we seen a novel PD1 and VEGF inhibitor being compared to pembrolizumab. Gilberto your thoughts here on the study design and its findings. Speaker 3 So this is a parallel to the study that I LED a few years ago, KEYNOTE 42, in which we randomized patients to receive chemo alone or with pembrolizumab for patients with video one of 1% and above. So it's the same patient population. And the reason I mentioned it is that I'm going to compare that pembrolizumab arm with the pembrolizumab arm for both 1 to 49 and 50 and above or when we did Keynote 42. And this is an extremely interesting study. We are trying to do the combination of VEGF and PD1 inhibition in the same drug. It's a tetravalent drug that blocks both VEGF and PD1 and we do have both preclinical and clinical evidence that this is worthwhile. We have evidence from studies such as EMPOWER 1:50 and from studies such as a combination of ramiserumab and pembrolizumab showing that you do get at least some progression for survival benefit when you use these drugs together. In the GFR mutant, we already had seen Harmony A at ASCO for patients that had been through Aussie Martini. Then we did see a benefit and that combination with chemo has been approved in China, although not in the US or not outside of Asia. And what we do see in this study does corroborate what we had thought in Orient 31 is another study of VEGF inhibition and PD1 or PD1 inhibition that shows some benefits. So it made perfect sense to try to do is, I think they were brave to do 1% and above. But if you really go to overall survival with Keynote 189 and so on, you would imagine that patients probably did not do worse in survival. Patients certainly do worse if they don't get chemo in PFS, and I would not propose using immunotherapy alone at this time for anyone with video ones between 1 and 49 unless patients have contraindications to chemotherapy. For those with 50 and above it's a reasonable option. I'm more often than not add on chemo to get better response rate and progressively survival, except for patients that have low volume of disease and really don't need that extra response from the chemotherapy. And the results as you're showing here, it's a hazard ratio of 0.51. It's not a hazard ratio that we see often. I'm going to mention before we talk about that though that 10 years ago I'm getting old at ASCO. We looked into what should be considered clinically significant or clinically relevant outcomes when we look at metastatic lung cancer. And we look at medium overall survival improvement and the hazard ratio that you should see. And what the experts came up with 10 years ago when the best we could do was about 10 months of medium survival with Kim, when was just that? About the time when we were able to add on the vocizumab and improve that survival to 12 months was that we should see hazard ratios of at least 0.8, preferably between 0.75 or better and at least three to four months in medium improvement in here Ivo or EVO and NESSIMA does fulfill those criteria. So in PFS we are seeing an improvement that's many months, almost six months and in the hazard ratio it's a change of 0.51. Again, progression for survival, not overall survival. So we would like to see those data before we bring it into the US There are two trials that are ongoing in ex China geographies and one is Harmony 3, which is chemotherapy plus pembro versus chemotherapy plus EVIL or Ivo. And those that I will certainly tell us if this is something we will be using here as well. But that's not something we're going to have next year. That's probably coming for 2026. There's an extension of Harmony A outside of China as well, and we should hear about that a little earlier. So this is extremely interesting. I think that this will pan out. If I had to bet, I would bet that it will work and that the drug eventually will be approved. And of course, we do need to see outside of China what those results will look like. But I'm very exciting. I think that this is something we will be using in the future. Speaker 2 Thanks for summarizing that, Gilberto. And as you stated, this concept has been actually tested very well in lung cancer space. As you mentioned in EMPOWER A-150 as well as Lung MAP, this IO wedgef inhibitor combination is active. We utilize this in hepatocellular carcinoma, ATIZO and MEV combination. We know immunotherapy by itself doesn't work and with VEGF combination it does wonders. So this is definitely exciting. But there are some limitations. We have to await global studies and also it'd be nice to see the comparator arm in intermediate group with chemo immunotherapy as opposed to just rather immunotherapy, which is pembrolizumab. All right, just before we close, we got tropion lung, lung O1. Tropion lung O1 If the disease was to progress in upfront treatment, we have no actionable mutations in those cases, then the choice will be dositaxel, remiceramab or clinical trial. Here in Tropion Longo 1, we see another antibody drug conjugate dado DXD targeting Trop 2, which is being compared to dositaxel, Though dositaxel has been a challenging drug and multiple studies have failed against that. So berto your thoughts on Tropion Longo 1 Sir? Speaker 3 So this is a drug looking for a better biomarker. We were underwhelmed by the results that we saw with overall survival. I think that we still believe that these drugs with Trop 2 as a target are very promising. I think that we still don't know who are the patients that will benefit the most. I think we learned a couple of things at WCOC 24 that will help the new biomarker tested with QCs Looking at the membrane ratio will be something that has some difficulties in terms of the infrastructure that needs to be created. But I'm sure where there's a will, there will be a way because it does seem to help at least with the PFS to identify which patients do better. So that's a classic continuous biomarker that hopefully will be brought to clinic in the near future and might help us select. But as it is right now and again, the drug is not approved by the FDA in any ways and AstraZeneca has submitted for approval in the non squamous subset. And I'll, I'll talk about that a little bit. So overall the result was negative. There were no significant difference in overall survival for the intent to treat population for PFS. That difference does seem to be relatively relevant or clinically relevant in patients with non squamous. You can see the the data here that the medium survival went from 12.3 to four point 14.6, so kind of two months, not quite the three to four months that we would like to see the hazard ratio point, but it does tell us that someone is responding. So some patients do benefit from this drug. I'm trying to find out who they are. They certainly are not the patients with squamous cell. You can see that those patients, the curves actually look inferior. The numbers were not statistically significantly different, but the curves look inferior for that versus dosotaxel. Dosotaxel is a hard nut to beat. It is a hard drug to beat. We see even with K Ras phase three trials difficulty in beating those attacks. So patients with genomic alterations, AGFR, ALC who received that ODXT actually did better and those curves looked more white out, more, more spread out than patients without genomic alterations. So that may be a subset of patients where we might start using it if the drug gets approved. So I think we have a lot more to learn. I do believe that the drug has activity. The question is, who are the patients that we should give it to? Speaker 1 Gilberto, thank you so much for going over that. A few things to unpack. If there's a silver lining here, it's maybe that the grade 3 and above side effects adverse events with dado DXD were tap it better than chemotherapy. With that said, overall this was a negative study, but you're absolutely correct that actionable mutation, once the disease has progressed sequencing be a data DXD. We're starting to see data from her three DXD as well. And then when we're talking about trope 2 agents, we've seen sensitism have failed against those attacks. So as well, this is rapidly evolving space. There's a lot happening. We'll eagerly wait to see what the data DXD future looks like. Is it going to be subset population? Is it going to be someone just with actionable mutations or non scram? So more to come here, but likely we will see this at least as a community generalist or lung cancer or this is also coming from breast cancer. So we've covered a lot here. Key abstracts from the World Conference on Lung Cancer 2024 Doctor Lopez, thank you so much for taking the time to share some key abstracts from the World Conference on Lung Cancer 2024, the 50th anniversary. For our listeners. Let us go over a quick recap. In this discussion we had a chance to focus on four key abstracts out of hundreds of studies presented at the World Conference on Lung Cancer 2024 with Doctor Gilberto Lopez from the Sylvester Comprehensive Cancer Center. Starting off with exploratory analysis comparing Checkmate 816 neoadjuvant chemo immunotherapy and Checkmate 77T, the sandwich approach with chemo immunotherapy, surgery and then immunotherapy in our clinic. We're now often moving on the periop approach in resectable non small cell lung cancer, but the true benefit from post immunotherapy for all our patients still remains unclear. Van recovered Skipper, focusing on how we can decrease some of the toxicities that come along with amivantamab as we continue to see this drug getting approved from multiple indications. Speaker 2 We also had a chance to focus on two studies in metastatic space with no actionable mutations, a novel PD1 and VETF bispecific antibody. Evonisumab looks very promising, but we will likely need global studies to ensure that this is the right medication for all our patients. At this conference, we also saw the data for Dado DXD being compared to DOSI, Taxol in second line and beyond for metastatic non small cell lung cancer. And we are perhaps seeing modest benefit in non squamous Histology here. Thank you for tuning in. Make sure to check out our other conference highlights and discussions around the current standard of care. We are the oncology brothers.