Devika Das, MD: Welcome to another episode of “Leading Thoughts: Lung Cancer.” I’m Devika Das. I’m a thoracic medical oncologist at the University of Alabama at Birmingham, and I’m joined by two of my amazing friends and colleagues, Dr. Jack West and Dr. Aggarwal. I’ll let them introduce themselves. Dr. West?
H. Jack West, MD: Hi, I’m Jack West. I’m an associate professor in medical oncology focused in thoracic oncology at the City of Hope Comprehensive Cancer Center in the Los Angeles area. Thanks so much.
Dr. Das: Dr. Aggarwal?
Charu Aggarwal, MD, MPH: Hi, I am Charu Aggarwal. I’m the Leslye M. Heisler Associate Professor for Lung Cancer Excellence at the University of Pennsylvania’s Abramson Cancer Center. Delighted to be here.
Dr. Das: I thought, since this is another episode that is in an immediate post-ASCO setting, that we would discuss a trial that was presented as a late-breaking abstract. It was an oral presentation from Ticiana Leil, MD, from the Winship Cancer Institute. This really deals with a new form of therapy in metastatic NSCLC. The study was a global randomized phase 3 study called LUNAR that assessed TTFields therapy, along with standard of care, which in this case was investigator’s choice of immune checkpoint inhibitor (ICI) or docetaxel in patients who were previously treated with platinum-based therapy in metastatic NSCLC. So just broadly, TTFields are electrical fields that are delivered through a device that the patient wears through transducers. The way it is proposed to work is that it delivers electrical signals that disrupt the mitosis – the cell signaling – and subsequently causes induction of immunogenic cell death.
Essentially, in this study, adults with NSCLC who progressed on or after platinum therapy were randomized 1:1 to TTFields plus standard of care or standard of care alone. The primary endpoint for this study was overall survival, and key secondary endpoints were overall survival in the ICI arm and in the docetaxel subgroups. Some other key endpoints…looked at were progression-free survival and adverse events (AEs). Essentially, patients were randomized between 2017 and 2021; 276 patients were randomized to receive either the therapy with the TTFields plus standard of care or standard of care alone. Most of these patients were male. There was a good mix of nonsquamous and squamous histologies. About 56% were nonsquamous; 96% of the patients had a good performance status of 0 or 1, and about 89% of those patients had gotten one prior line of systemic therapy.
[It should] be noted that only 31% had gotten prior ICI in a frontline therapy.
What [the researchers] did report out was the overall survival in this study, which was favoring the TTFields arm, with a minimum follow-up of 12 months, at 13.2 months versus 10 months. They also reported that, in patients who got the ICI arm plus TTFields, their overall survival was statistically significant and better at 18.5 months versus 10.6 months. In the docetaxel subgroup, though, even though the benefit was numerically a little bit higher, at 11.1 months versus 8.9 months, that was not statistically significant. The rate of AEs in the study was fairly similar between the two groups. There was a higher incidence of dermatitis in the patients that used the TTFields. However, there were no other major toxicities that were different between the two arms. The study’s conclusion was that this is showing an overall survival benefit in the second-line setting and could be included as part of second-line therapy, along with standard of care, in metastatic NSCLC.
Some things to note: The patients in the study who had a squamous histology did better than those with a nonsquamous histology. About 50% of the patients had unknown PD-L1 status. Interestingly, like I said, the overall survival benefit – while it was seen – there was no progression-free survival benefits in either of the arms.
Having summarized that study, my question to my colleagues here is, we know that this study happened between 2017 and 2021, when there were significant changes in second-line and frontline standard of care, which might not have been reflected in the standard of care chosen in the study. What do you think about this overall survival benefit that we saw in the study, and is that clinically practice-changing in your opinion? I’m going to start with Dr. Aggarwal.
Dr. Aggarwal: Thank you for summarizing those data really well. This was a late-breaking abstract. The trial was positive because it met its primary endpoint of a demonstrated overall survival advantage of using this device versus standard of care in patients with second-line NSCLC, regardless of histology. Practically, I don’t know if this benefit is being driven by immunotherapy primarily. I can’t really mechanistically explain why else we would be really achieving this benefit. I think the authors hypothesized that there may be some synergy between immunotherapy, as well as the device. I think one thing that’s very clear is that adoption may be an issue. We know that these are quite bulky, [and] patients have to wear this for a long time...
We are at the brink of several new studies potentially reading out. I think we’ll have a lot to talk about this fall, with TROPION-LUNG01 reading out potentially this fall, which is evaluating an antibody drug conjugate targeting TROP2 versus docetaxel.
Could that then become our standard of care? We already have second-line targeted therapies. We are not really impressed with sotorasib, or adagrasib for that matter. We will happily take that over docetaxel, given the toxicity profile. Then let’s not forget HER2, EGFR exon 20 – we are talking about at least 20% of our patient population, maybe 15% of our patient population, being eligible for targeted therapy already, and that’s among the nonsquamous NSCLC patients. I don’t know how the uptake of this device will be, and I am curious to see what others think.
Dr. Das: Jack, do you have a different take on this?
Dr. West: I wouldn’t say different. I think I have a kind of more definitive speculation that it’s going to be muted to minimal, I think, really, for the reasons Charu outlined. I mean, I would say we don’t have that many trials that show an overall survival benefit. Kudos for that. I mean, first of all, overall survival was the primary endpoint. I would never take that for granted. I really appreciate that and wish that that had been the primary endpoint for CodeBreak200 or other trials. I really think that’s laudable, and I think it’s always worth a close look.
But for the reasons Charu mentioned... First of all, there wasn’t a benefit seen with docetaxel, which in the United States and most of the world has become the clear second-line standard of care. Most patients are now getting immunotherapy alone or combined with chemotherapy in the first-line setting. That’s largely obviated. There was no significant improvement in overall survival with docetaxel, which we’ve all been hoping to move past for 20 years, but it’s been harder than you might envision.
Then, as Charu enumerated, and you [Dr. Das] alluded [to] as well, the cumbersome nature of this is a challenge that people have to carry an apparatus – wear an apparatus. You have the battery pack, and you’re wearing it all the waking day. I think the real question is, “Is the juice worth the squeeze?” I think that, for the vast majority of patients, that’s not going to be the case. If I had a really interested patient who came in after reading about it and said, “I want this.” I wouldn’t have any trouble offering it, but I really think I wouldn’t want to twist the arm of any of my patients to do this. I think that it might be something to talk about, but I suspect that a lot of my patients would dismiss it either after reflection or out of hand.
Dr. Das: That’s a great point, and you alluded to it…Does it all offer any quality-of-life benefit? I don’t think we saw those data. I would be interested in seeing that because, again, when we’re trying to see in which setting would this fit in, things that are missing that we don’t know yet [include] the quality of life. Is this an option for a frail patient who can’t take treatment? We don’t know the answer to that. Really, what they didn’t report out on yet is the local regional effect versus the systemic effect. Were there any differences in that?
Again, unless there is something different that really attracts me [and suggests] “Hey, this is an option for a frailer patient who can’t get other therapy,” I myself will not be offering this to everybody.
Dr. West: One other point I might make is we’re trying to figure out why the patients who received immunotherapy did better. No one has a great explanation right now. I think there might be some reason to explore that further. I mean, maybe [we need to look] at the patients who have high PD-L1 levels or just get a sense of whether it really is synergistic with immunotherapy in some way. Hard to envision, I agree. But I don’t know that I’d throw that out categorically. Then, I’m just wondering, one of the points that Dr. Leal mentioned was that the patients on the immunotherapy arm were on it a little longer, not a lot longer, but a little longer, which is kind of in keeping with the trials we were looking at a decade ago, showing that second-line immunotherapy is more effective than second-line docetaxel. Yes, that was well-established in trial after trial.
Maybe it has something to do with them being on TTFields for longer. It’s a kind of confounding factor. If you were on it, and it was working, you were also receiving TTFields for longer. I don’t know if there’s going to be enough momentum to really study this further. I would be stunned if this becomes a widely adopted standard of care. I think the question more is whether there is an opportunity to study this further and maybe identify a subset of patients for whom it’s a better option? You mentioned squamous, and there might be features based on volumes and how localized disease is, where it makes more sense. I mean, just given how we don’t have so many options, so we shouldn’t be too cavalier about tossing anything that could be helpful. But I don’t think it’s going to be a broad benefit.
Dr. Das: Thank you, Jack. Charu, again, without putting words in your mouth, is this something you’re going to discuss with your patients when they come in into clinic, provided there is a U.S. Food and Drug Administration approval in the future?
Dr. Aggarwal: Wow. I think that oncology is becoming so much more challenging. It’s like approvals come to us faster than we can even digest data these days. I think if the approval comes through, I think it would behoove us to at least discuss with patients. Patients often rely on physicians to put these approvals in the right context. I think putting it in the right context to say that quality of life matters; the real advantage of a particular intervention matters. I think it’ll just have to be framed in a shared decision-making conversation.
Dr. Das: That’s such a great point. Again, looking at cost and quality of life, it’s a great time to be a thoracic oncologist. All three of us can agree. We have so many different options. Again, it’s like you said, it’s really on us to make sure we frame it the right way for our patients so that we can make the best decisions for them. Another great episode post-ASCO, and I am looking forward to meeting with you guys again next time.
Dr. West: Thanks so much. Great time. Great job discussion.
Dr. Aggarwal: See you soon.
This transcript has been lightly edited for clarity.
