This transcript has been lightly edited for clarity.
Eric K. Singhi, MD: Welcome, everyone, to today’s episode of Leading Thoughts: Lung Cancer. My name is Eric Singhi. I’m a thoracic medical oncologist at The University of Texas MD Anderson Cancer Center. I’m joined by my esteemed colleagues, dear friends. Dr. Maya Khalil, if you’d like to introduce yourself first.
Maya Khalil, MD: Sure. I’m Maya Khalil. I’m one of the thoracic oncologists at the University of Alabama in Birmingham (UAB). I’m excited to be here.
Dr. Singhi: Thanks, Maya. We are also joined by Dr. Sandip Patel. If you can introduce yourself as well?
Dr. Patel: Sure. Hi, I am Sandip Patel, a medical oncologist at the University of California San Diego.
Dr. Singhi: Great to have you both here. As you know, 2024 is winding down. We’re looking into 2025 and beyond. Today, we will focus on talking about things that you’re excited about for the year 2025 with regard to lung cancer treatments and advancements for our patients. And then maybe we will also talk about some challenges that are still stuck with us in 2025 in clinical practice. Sandip, I’ll start with you first. What is a clinical challenge that you’re looking forward to advancing in 2025, helping our patients? What would you say?
Dr. Patel: I think we’ve solved many issues, but we have yet to solve many issues as well for our patients. The mortality in cancer overall in the United States has improved over the past several years, and it is really driven by improvement in metastatic non-small cell lung cancer. I think we still struggle with ensuring that patients get appropriate molecular testing. Because it turns out, the best treatment for a targeted aberration for which we have a small molecule, especially the never-smoking-related mutations, tends to be upfront treatment – tends to be targeted therapy and not to be immunotherapy. So that is still a missing opportunity for many patients. It can be done in the blood as well, which makes it a lot easier by cell-free DNA.
I think, equally, many of us are involved in trials of antibody drug conjugates (ADCs). Outside of HER2, we really don’t have a biomarker to determine which patients may benefit from a particular ADC strategy: target, payload resistance, and things like that. I am really looking forward to some of the novel biomarkers. We saw digital pathology kind of quantitative continuous scoring for datopotamab deruxtecan, a TROP2-targeting ADC, presented at the World Conference in Lung Cancer in 2024. Are there other ways we can utilize artificial intelligence and other approaches to match the patient with their best therapy?
Dr. Singhi: I really love all those points that you touched on, Sandip. I think there’s a lot of excitement, a lot of potential, to help our patients in clinic with all of those different realms that you mentioned. Maybe Maya, I’ll ask you a question first. When we are talking about molecular testing, biomarker testing, and trying to get the message out there to patients that regardless of what they look like, where they are coming from, and where they are getting their care, how do we improve in 2025 to make sure that every patient with non-small cell lung cancer has biomarker testing? And not just select biomarker testing, but also comprehensive biomarker testing?
Dr. Khalil: I agree. I think that although we’ve talked about this for years now, this is still not happening in all patients. I think a lot of it falls on education, not just for the oncologists or the healthcare team, but also for the patients. I think we have done a lot of work recently, spreading the word and educating patients about, “Hey, if you have lung cancer and your first visit with your oncologist, if you don’t get asked about this or don’t have that mentioned, why don’t you suggest the idea of getting molecular testing?” Also, there are patient advocacy groups out there that have done a fantastic job at making sure that patients are prepared for that and making sure that they ask about that. I mean, sometimes you send the test, and then, a lot of times, life happens, and you might miss the result.
I have seen a couple patients where they had, let’s say, an EGFR or ALK alteration. But then in the thick of it, this was missed, and they were on standard-of-care treatment with chemotherapy and immune therapy. Then, after the fact, that was realized. One other thing to talk about is, especially for people who have a nonsmoking history, to make it a point for them to know that, “Hey, you might want to start maybe a cycle of chemotherapy if you’re symptomatic, but also make sure that you know your mutation status before you start your treatment.” I think between the healthcare team, the patients, and the patient advocates, all the different EGFR resistors, and ALK, and KRAS, and all those fantastic groups, I think we’re bound to see this being more in the frontline setting.
Dr. Singhi: I really like how you pointed out all the different stakeholders who are involved, from the providers to the patients to the patient advocacy groups. I think in 2025, collaboration is going to be huge. It is going to be key to really make sure that no one is missed with regard to a biomarker testing standpoint. Sandip, I’ll jump back to you. You mentioned ADCs and how we have had generally over this last year a lot of overpromise but maybe underdeliver. We’ve talked about trying to find better biomarkers to guide treatments in the ADC setting. Are there any ADCs, any clinical trials, that you’re excited about that are ongoing? Any promise maybe for patients in this sector?
Dr. Patel: I think there are a couple of reasonable ways we can go about investigating ADCs. I think with HER2, because we have a biomarker, we’ve had a better time developing agents, whether it is mutation-specific or immunohistochemistry complex-specific. Where we have struggled a bit is without a biomarker: HER3, TROP2, and DLL3, if we’re at least talking about bispecifics. So, thinking about novel ways of addressing measurement of the target is going to be hugely important. There are trials basically in each of these scenarios that are utilizing novel approaches to try to select for patients who may benefit. But at the current time, honestly, the best biomarker has been the histology and the prior treatment that they’ve had, which I think is insufficient.
Dr. Singhi: That is a really good point in thinking about how we can further advance getting these drugs to have more promise, more efficacy, and of course, also thinking about the toxicity that comes with it. Maya, maybe I can ask you a little bit more about the HER2 space, because we kind of jumped into that. We saw a lot of exciting studies in 2024 with oral targeted options for these patients. Are there any options that you’re excited to hear more about with regard to that space in 2025?
Dr. Khalil: Yeah. As it stands right now, for HER2-mutated lung cancer, we have ADCs that we are using, but we have had some novel drugs. Zongertinib is one that we have hands-on experience with on a trial even at UAB, where you do see that even after patients have seen ADCs, which is the majority of the patients who get on this trial, you do see good overall responses and, I will say, probably good tolerance – even better in some cases than with ADCs. These are some agents that I think... Having an oral drug as opposed to an intravenous drug is always alluring for us and our patients, and I think that’s something to look forward to, as well as intracranial bioavailability.
Dr. Singhi: I think you raised some really good points about that space, thinking about the toxicities that are involved. Obviously, we know that diarrhea is a common one, and things like rash. We need to really make sure that management is a priority with regard to supportive care. But then, also, that oral promise is really exciting with regard to quality of life for patients, so I’m excited for that too.
Maybe we can jump to a different biomarker, maybe KRAS-G12C. It is often such a heterogeneous group of patients with regard to thinking about the different co-mutations that are involved. PD-L1 expression matters; patients with a smoking history and without a smoking history can also develop this disease. Maybe Sandip, what’s coming in the KRAS-G12C space or even non-KRAS-G12C space? What are you excited about?
Dr. Patel: Yeah. I think in KRAS-G12C, the barrier historically has been the ability to combine with immune checkpoint blockade due to liver toxicity, although there may be some novel agents that can overcome that. So, I am excited to see some of those data. I think there has also really been a renaissance of non-KRAS-G12C targets that are pan-KRAS or other mutation-specific inhibitors, protein glues. The list goes on and on. So, I think there’s the potential for development of agents for non-KRAS-G12C as well. As a friendly reminder right now, the current two agents we have, adagrasib and sotorasib, are only approved second-line after immunotherapy in immunotherapy-eligible patients with KRAS-G12C. If your patient has G12D, G12V, or any of the other mutations, those agents won’t work. That’s where these other agents may play a role.
Dr. Khalil: Absolutely.
Dr. Singhi: Yeah, a lot of promise there. Go ahead, Maya.
Dr. Khalil: With some of the newer agents in KRAS-G12C specifically, we’ve seen a lot less hepatotoxicity. I mean, we talk about the difficulties with [KRAS inhibitors], but there are trials that are going on combining those with immunotherapy in the earlier-stage setting. I feel that it’s a timely thing to do because this was a hindrance to the older agents, the hepatotoxicity. So that is something to look forward to.
Dr. Singhi: I think the other study that I’m excited about in this space is the TRITON study, which is ongoing, where we’re looking at patients who may harbor some of those additional risk factors – aggressive biology factors with co-mutations, an STK11/LKB1 – and thinking about whether there is a role for dual immunotherapy in the front-line setting versus our tried and trusted KEYNOTE-189 regimen, with chemotherapy plus pembrolizumab. It will be exciting to see in a phase 3 setting how dual immunotherapy actually stacks up. How does it do for these patients? I agree, a lot of excitement. Another space we can talk about is emerging immunotherapies for these patients. Thinking about tumor-infiltrating lymphocytes (TILs) and lung cancer vaccines. What have you guys heard? Maybe Sandip, I’ll start with you. What are you excited about with emerging types of immunotherapy?
Dr. Patel: I think all of these are areas of interest. You mentioned mRNA, kind of new antigen-based vaccines more in the resection space, especially for patients without pathological complete response, potentially in combination with PD-1 inhibition. Secondarily, thinking about TILs and T-cell receptors. I mean, there has been a renaissance really of cell therapies, not only in the hematological indices but now in melanoma and synovial sarcoma as well. And so potentially in lung cancer. But I think the future is bright. I think one area we have not seen the promise we were hoping is in the anti–T-cell immunoreceptor with immunoglobulin and ITIM domain targeting access, where the studies have not read out positive from what we’ve seen so far.
How much of this relates to the drug? How much of this relates to patient selection or lack of biomarker? I think this remains to be seen. But the idea that we’re not going to have too many other PD-1s that work across multiple different disease states: We’re going to need to understand the biology a little better and develop… cell-based approaches, vaccine approaches, or novel immunotherapy approaches. I think this is one area trials are going to have to spend a lot more effort on, because we may have picked the lowest-lying fruit with PD-1 axis inhibitors.
Dr. Khalil: Absolutely. I mean, the other story that I think would be worth mentioning is combining the old and the new: the VEGF and PD-1 combinations. We’ve seen that with the ivonescimab story. We alluded to that during another conversation, where you have seen improvement in the frontline setting compared to just pembrolizumab, adding VEGF targeting to immune therapy. We also have those data hopefully maturing at some point with the Pragmatica-Lung trial in the second-line setting and beyond. I think maybe we can borrow from the older drugs and combine them in terms of good strategies with the newer ones, hopefully to improve on our patients’ outcomes.
Dr. Singhi: Yeah, I really like that. I also like how you are talking about a comeback story for some of these drugs. We even talked about, in an earlier episode, lurbinectedin maintenance therapy for small cell lung cancer. Is it going to make a comeback? What are we going to do with this drug for our patients? I think that’s really exciting. One last thing, Maya: In 2025, is there’s a clinical challenge or problem you would like to have solved on your wish list? What would you say?
Dr. Khalil: One thing that’s on my mind, since now we are using a lot more combinations of EGFR-targeted therapies, amivantamab in combination with whatever EGFR inhibitor is out there is causing a lot of rash. One study that I was hopeful to see some approval come out from is the PALOMA-3 trial. I think the subcutaneous formulation of amivantamab is going to be something that will solve a lot of the infusion reactions, but will also, maybe hopefully, help with some of the other toxicities.
Dr. Singhi: Yeah, that’s a great point. That is definitely on my wish list for 2025 as well. All right, guys. Well, it was great to connect with you and think about the future and the maybe bright advancements that are ahead for our patients with lung cancer. Thanks for being here, and thanks for joining us for another episode of Leading Thoughts: Lung Cancer.
Dr. Patel: Thanks. Happy New Year.
Dr. Khalil: Happy New Year.
