This transcript has been lightly edited for clarity.
Maya Khalil, MD: Welcome, everybody, to this episode of Leading Thoughts: Lung Cancer. This is kind of a wrap-up of 2024. I have my two colleagues here that are joining me. I’ll start with you, Eric. Go ahead.
Eric K. Singhi, MD: Hi, my name is Eric Singhi. I’m a thoracic medical oncologist and assistant professor at MD Anderson. Excited to be here.
Dr. Khalil: Thank you. Sandip?
Sandip P. Patel, MD: Hi, I’m Sandip Patel. I’m a medical oncologist, professor of medicine here at the University of California San Diego. Great to be joining folks to wrap up a really interesting year in thoracic oncology for our patients.
Dr. Khalil: I agree. And I’m a thoracic oncologist at UAB, University of Alabama in Birmingham. And we were talking before we started that this was a year packed with lung cancer advancements. I’ll start with you, Eric. What were the main either approvals or big stories of 2024 for early-stage non-small lung cancer?
Dr. Singhi: Yeah, Maya. It’s actually really funny. I was just looking last week: I don’t know if you have the Spotify app, but I got my “Spotify Wrapped.” And I got to see all the top artists, and all the fun songs I’ve listened to. This feels like a lung cancer treatments “Wrapped” episode, almost. I really like this idea of going through things and appreciating what has happened this year.
We can start with early-stage disease. I think there has been a lot of exciting advancements, both for patients without driver alterations and those with driver alterations. And so, one I’ll tackle first is for patients without driver alterations with early-stage disease. We had two U.S. Food and Drug Administration (FDA) approvals this year in the perioperative setting, so before and after surgery.
One is for nivolumab, and that’s based on the CHECKMATE-77T study. And then also we had durvalumab approved, and that’s based on the AEGEAN study. We saw event-free survival improvement, pathological complete response improvement as compared to chemotherapy alone. It is exciting to be able to have these options. Of course, with more options comes more nuanced treatment decision making. But it’s nice to have those options for patients.
Dr. Khalil: Right. And Sandip, what are some of the highlights that you would think of for this past year in the metastatic setting for non-small cell lung cancer? I know we had a lot of updates this year in that space.
Dr. Patel: I think it’s hard to choose, there have been so many. I think at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, our big cancer meeting, there were two plenaries in thoracic oncology, which to my knowledge is the first time that has happened. The first involved postchemoradiation use of osimertinib, so the LAURA trial. After concurrent chemoradiation for unresectable stage III disease, patients received osimertinib. The LAURA study led to an FDA approval and National Comprehensive Cancer Network practice change.
And then in small cell lung cancer, so speaking of a slightly different disease, after it was presented in a plenary, the FDA approved the use of durvalumab, an anti-PDL1 agent, after curative intent concurrent chemoradiation in limited-stage small cell lung cancer. And so we’re seeing advances in targeted therapy and immunotherapy, not only in diseases in which we made great strides, like non-small cell lung cancer, but starting to see some of those improvements in small cell lung cancer as well, hopefully.
Dr. Khalil: Yeah. Aside from that, we also noticed a lot of drugs that are being developed for mutation-driven lung cancer. We’ve seen multiple things happen in the EGFR space. I guess we can go back to you, Eric. What were the major highlights from all the front-line and second-line, but mainly front-line, and all the options that we have for EGFR-mutated lung cancer?
Dr. Singhi: Maya, this is a great question. We actually just went over this with the fellows a week or two ago and talked about how it is an exciting time to really see all these anti-EGFR therapies evolving for our patients in the front-line setting, and then even in the subsequent-line setting. What we saw was an FDA approval from FLAURA2, which combines osimertinib with platinum-based chemotherapy. We were able to see that there is a progression-free survival benefit. We are still waiting for the mature overall survival data. But it is really nice to have that option in thinking through specific subgroups of patients that might benefit from a front-line combination strategy.
We also had an FDA approval for another front-line combination strategy based on the MARIPOSA study. We saw amivantamab bispecific EGFR/MET drug in combination with lazertinib, which is a third-generation oral tyrosine kinase inhibitor against EGFR. We now have that option to pull as well for patients. And then as you alluded to, for patients who progress on targeted therapy, we even now have an approval from MARIPOSA-2, which combines amivantamab with platinum-based chemotherapy.
I think there are some key questions here with all these approvals: How are we going to sequence? How do we identify the patient who benefits from a front-line combination strategy versus tried-and-trusted oral osimertinib alone? Lots of great questions, lots of great avenues of research, and excitement to see these approvals.
Dr. Khalil: Absolutely. I would also add that in the EGFR exon 20 insertion mutations, we also saw chemo and amivantamab approved in that setting, also based on improved progression-free survival.
I’ll go back to you, Sandip, for ALK-positive non-small cell lung cancer. We did see some data coming out in lorlatinib and all that. What was a takeaway, if you want, for this year for ALK-mutated non-small cell lung cancer?
Dr. Patel: I think that this space has evolved. We have adjuvant options, with adjuvant alectinib for three years. I give it with chemotherapy, although in the study you typically do not give chemotherapy, and then go to alectinib. From the CROWN trial, we had a five-year progression-free survival update. So, speaking of ASCO being a busy meeting, we saw some data where really, especially for intracranial progression-free survival, it was really impressive. Also, some data I think that were really nice to have that we can dose reduce and not compromise progression-free survival, which at least for me is really important, and I imagine for others, because many times we do our best to handle some of the side effects. And our best option because the patients are going to be on the treatment for so long, because it is so effective, is in fact a dose reduction for them. I think these were really interesting data on a disease in which we’ve transformed our approach.
The key, though, I think to many of the topics we’ve discussed is the appropriate use of next-generation sequencing and finding these patients. That’s really how we’ve tackled non-small cell lung cancers: dividing it into discrete individual diseases. There is not much else that really relates between a patient with an EGFR mutation and a KRAS G12C mutation, aside from the fact that under a microscope, their tumors look somewhat similar. The idea that we want to get appropriate testing, either by tissue or by cell-free DNA, is just so important to make sure that patients get on the right treatment.
Dr. Khalil: Absolutely. I would also echo that in the resectable setting of non-small cell lung cancer, we still have to get that information on molecular data even before we consider immunotherapy combinations in that setting and/or adjuvant targeted therapies. I think you alluded to that also, Sandip, the small cell lung cancer space, the ADRIATIC trial, the approval, hot off the press, for durvalumab. There were also other advancements in small cell lung cancer. I would want to open the door for that, because I think small cell lung cancer care this year was moving a bit more than usual, which is always a good thing to see for this patient population.
Dr. Patel: I agree completely. I think for some of the novel targets, we’ve seen B7-H3 and sEH, among others. I think antibody-drug conjugates (ADCs) are really quite interesting. With tarlatamab, many of us have started using this in the standard-of-care setting. That’s a bispecific antibody targeting DLL3 and CD3. And because of this step-up dosing with inpatient cytokine release syndrome (CRS) risk, which is something typically our hematologic malignancy doctors had to be very familiar with, now we have to be as well.
I think this is a drug that many of us have utilized, especially with some updated data around benefit in the central nervous system, which I think was somewhat surprising in a post-PDL1 setting. I think we are starting to see some of the benefits of these therapies go into more difficult-to-treat diseases. There is at least an announcement of positive data on maintenance lurbinectedin in combination, as well in the frontline space. And so small cell lung cancer has transformed somewhat in the past year as well, although we have a lot that remains to do to help those patients.
Dr. Khalil: Yeah, there’s a lot to do.
Dr. Singhi: I was going to chime in, too. I think, Sandip, you’ve summarized it really nicely. It’s exciting to be able to see these advancements in small cell lung cancer, when there haven’t been these advancements for decades. They always put the small cell lung cancer section or session in the back, and it’s kind of the last thing. Now we’re moving it forward and we are talking about big changes in small cell lung cancer. But with all these advancements obviously comes the need for education, like you talked about, with CRS toxicity and immune effector cell–associated neurotoxicity syndrome (ICANS) toxicity, managing that and implementing these changes so we can get all of these practice-changing updates to our patients. But with that objective response rate of about 40% with tarlatamab in previously treated patients, that’s meaningful. We really do have to figure out, as a community, how to get these advancements to our patients. I absolutely agree.
Dr. Khalil: With tarlatamab, we were part of the trial. And initially, of course, all patients were being started as inpatient, and then slowly we became more comfortable. We were doing it as outpatient. As the standard of care, we are getting referrals, and we have done all of the patients so far as inpatient. But we’re starting to think about, “Okay, how do we transition to this kind of outpatient tarlatamab in the right setting and in the right patient?” How are you guys doing that? And are you seeing a lot of CRS? Are you doing prophylactic tocilizumab? What’s your experience with that?
Dr. Patel: At our institution, these patients come on the same service that the melanoma tumor-infiltrating lymphocyte patients and some of the phase 1 bispecific patients come on the solid tumor side, because it effectively becomes an CRS and ICANS monitoring service for solid tumor patients. And so really the key there, is that the first dose is really quite minimal. It’s almost like a test dose. It is really the second dose where you start to potentially see CRS and ICANS. Early tocilizumab is very efficacious, with dexamethasone as second line. There are case reports of anakinra being a reasonable salvage.
But as a general rule of thumb, most of these patients will do well. And this is very different than the CD19-targeting CAR T cells in terms of how severe things are. Some of these side effects can be quite subtle. And it’s actually something we see with other bispecifics as well. As mentioned earlier, as we’re looking into ADCs, with some of those toxicities, you’re really going to have to be very cognizant for our patients. Especially interstitial lung disease, which is more of an outpatient toxicity, but actually gives me a little more anxiety when I’m taking care of patients than some of the toxicities we talked about here that are more inpatient. So we’re thinking about these B7-H3- and SEZ6-targeting ADCs as future directions in small cell as well.
Dr. Khalil: Yeah, absolutely. Eric, how has your experience been?
Dr. Singhi: Yeah, it’s been pretty similar. So thankfully, we have Carl M. Gay, MD, PhD, who specializes in small cell lung cancer at my institution. He is really leading the task force, along with some of our small cell experts, and adapting and implementing that process. But yes, we’re adhering to the step-up schedule as recommended. Patients are going in for their first two inpatient doses. We actually are putting together sort of a real-world experience of what our patients have been like. We will be sharing that hopefully soon. It is exciting to see some advancements for our patients and really navigate that process together collectively.
Dr. Khalil: Absolutely. Aside from the approvals that we discussed today, any other big stories or takeaways from this loaded year in lung cancer for 2024?
Dr. Singhi: I think one thing that I think was interesting was the HARMONi-2 study. Obviously, ivonescimab came into the potential treatment landscape for our patients. That novel drug bispecific antibody targets PD-1 and targets VEGF. What we heard at the World Conference on Lung Cancer was head-to-head data with pembrolizumab in that study. Granted, it was a phase 3 study, but only restricted to China. We have a lot more to learn. But this is really the first randomized phase 3 study that showed a clinically significant improvement in efficacy with a novel drug as compared to pembrolizumab head-on in advanced non-small cell lung cancer. I’m excited to see the story of ivonescimab, what that is going to look like in 2025. I did think that that was something to mention as well for this wrap up, this “Lung Cancer Wrapped,” if you will.
Dr. Patel: That’s a really good one, Eric. I was going to pick that one, but just to not repeat you, I’m going to pick something different. I think, historically, we talk about EGFR mutation period. And obviously now there are exon 20 insertions, there are PAK mutations. Eric, obviously, you and your colleagues have done a lot in that space. Now there are drugs that actually target that differential biology. And so it’s not enough just to give the street name anymore. You really have to give the full address, right? Do they have an EGFR exon 19 deletion, exon 20 insertion? Do they have an atypical PAK mutation? It turns out that we have some really nice drugs that may be approved over the next year or so for these niches. And the beauty of this is that you don’t necessarily need to do tissue-based DNA plus RNA sequencing, although that probably is the most in-depth sequencing we have. A lot of these can be identified by cell-free DNA.
And in thinking of the future, we talk about ADCs in small cell lung cancer, but also when we talk about drugs like datopotamab, which is a TROP-2-targeting ADC, there was some really nice work presented about using a digital pathology, artificial intelligence (AI)-driven biomarker for internalization to try to discern which patients respond or not, which to my knowledge is the first use of AI and pathology to predict patients who may respond. And so that’s going on in studies as well. I think it’s been a really interesting year in thoracic oncology, but I think next year, it will be equally if not more so.
Dr. Khalil: I agree. Piggybacking off of ADCs as well, the NeoCOAST 2 trial was also very interesting in terms of improving on this kind of benchmark that we didn’t dream of using pathological complete response in the perioperative non-small cell cancer space just a few years ago. But adding ADCs upfront with immune therapy in the perioperative space is probably going to prove to be a good valid strategy to improve that pathologic complete response. I think the pathological complete response was in the 35% range as opposed to the 20% that we see with just chemo and immunotherapy. A lot of excitement there, I agree. All right, we’re going to wrap it up for this one. Great to see you, and hopefully we’ll see you in the next year.
Dr. Patel: Likewise. Happy holidays. Happy New Year.
Dr. Singhi: Thanks, guys. Happy New Year.
