NovoCure Limited (NVCR) Earnings Call Transcript & Summary

Hello, everyone. For those of you who don't know me, I'm Bill Doyle. I'm the Executive Chairman of NovoCure, and I'd like to welcome everyone who's in the room today and also everyone who is participating via the webcast to the very end of ASCO 2023 for our investor session to discuss the results that we disclosed today of the LUNAR trial in non-small cell lung cancer. And I want to start and say notwithstanding the initial market reaction, which, of course, we're all cognizant of, this is a critically important day for NovoCure. 23 years ago, NovoCure was founded to take advantage of a brand-new approach to fighting cancer. We always start these talks by reminding everyone that we're a physics-based modality. We treat cancer using electric fields. Electric fields are forces that as gravity exerts forces on masses and as magnetic fields exert forces on ferrous metals, electric fields exert forces on charged components of cells and allow us to push and pull on those components in order to disrupt many cell processes. In the early days, we focused exclusively on the effect on mitosis, where electric fields prevented tubulin spindle formation and resulted in cancer cell death. In the now 23 years of preclinical and clinical research, we've learned much more about what these forces, in fact, do inside cells. And that research has led us to further understand the broad applicability of the platform. We know that any place in the body where we can create an electric field of a therapeutic intensity, and that's an electric field of 1 to 3 volts per centimeter, we can tune those electric fields to enter target cancer cells. And when they enter those target cancer cells, they create cancer cell death, cancer cell stress, immunogenic cell death and allow a number of different strategies beyond just combination with chemotherapy, but combinations with not only standard of care chemotherapies but new chemotherapies in particular indications, in exciting new research and research that we're going to describe in Phase III data today, combinations with immunotherapy and other combinations, PARP inhibitors, radiation, all of which we are now exploring in subsequent clinical trials. So it's my great pleasure today to be the person to introduce the agenda. We're going to start, and I'll introduce the participants up here on stage in a minute. But we're going to start with a presentation of the LUNAR data, the same data that were presented earlier this morning at ASCO. And we're going to leave plenty of time for Q&A so that everyone can have a chance to ask your questions, particularly of the key opinion leaders who are joining us today. Again, I couldn't be more pleased to introduce the first author of the study, Dr. Ticiana Leal from Emory. She did a magnificent job earlier today presenting to the assembled crowd at ASCO; and the senior author on the abstract, Dr. Corey Langer from UPenn, someone that if any of you are familiar with the progress that's been made in lung cancer over the last decades, you know that Corey has been at the center of these advances. Our MC is our own Pritesh Shah, and he will be guiding the Q&A. So with no further ado, I'm going to turn the clicker over to Dr. Leal.

Thank you. Okay. So here's a redo of our ASCO presentation today from our oral abstract session. An honor to present on behalf of my co-authors, the Tumor Treating Fields therapy with standard of care in metastatic non-small cell lung cancer after platinum-based therapies, a randomized Phase III LUNAR study. Metastatic non-small cell lung cancer remains largely incurable. In patients with metastatic non-small cell lung cancer without a driver mutation, platinum-based chemotherapy and immune checkpoint inhibitors are standard frontline therapy. However, most patients develop disease progression and 5-year survival is only 9%. Treatment options that extend survival beyond progression are limited. Current approaches include chemotherapy, mainly docetaxel plus minus ramucirumab or immune checkpoint inhibitors for eligible patients. There remains a high unmet need for new, effective and well-tolerated therapies for patients in the second line and beyond. Tumor Treating Fields are electric fields that exert physical forces on electrically charged components and have been shown to disrupt mitosis in cancer cells. Under TTFields, this disruption of mitosis leads to aneuploidy, an induction of endoplasmic reticulum stress. Downstream effects include immunogenic cell death, triggering a systemic antitumor immune response. Preclinical evidence has demonstrated the activity of TTFields with immune checkpoint inhibitors or taxanes. On the left-hand corner, you're seeing the combination of TTFields plus paclitaxel versus paclitaxel alone, demonstrating decreased cell viability in non-small cell lung cancer cell lines. In the right-hand panel, the combination of TTFields and anti-PD-1 in tumor-bearing mice led to greater reduction in tumor volume compared to control or either modality alone. TTFields therapy is a noninvasive anticancer modality. The electric fields are generated by a wearable medical device and delivered to the chest, to the tumors by 2 pairs of rays. The device is delivered to the patient at their home by a device support technician who provides education for the patient and their family, and it is recommended for continuous use. TTFields therapy is currently approved in glioblastoma and malignant pleural mesothelioma. Prior to the LUNAR study, a pilot study demonstrated the safety and the feasibility of TTFields therapy with pemetrexed in advanced non-small cell lung cancer. The LUNAR study is a randomized Phase III global study designed to evaluate the safety and efficacy of TTFields with standard of care compared to standard of care alone in patients with metastatic non-small cell lung cancer with progression on or after platinum-based chemotherapy. 276 patients with ECOG performance status of 0 to 2 were randomized 1:1 to TTFields therapy and standard of care, which contained investigators' choice of immune checkpoint inhibitor or docetaxel versus standard of care alone. Patients were followed every 6 weeks and continued therapy until progression or intolerable toxicity. The data cutoff was November 26, 2022. The study was conducted in 124 sites in 17 countries. The primary endpoint of the LUNAR study was overall survival with TTFields plus standard of care versus standard of care alone. Key secondary endpoints include overall survival in ICI and docetaxel-treated subgroups. Other secondary endpoints include progression-free survival, overall response rate, progression-free survival and overall survival by histologic subtypes, quality of life and safety. The LUNAR study targeted a hazard ratio of less than 0.75 using a 2-sided proportional hazards testing with an alpha of 0.05 and a power of 80%, stratified by standard of care treatment and histology. Key secondary endpoints were tested hierarchically if the primary endpoint was met. In a planned interim analysis in March of 2021, the Data Monitoring Committee recommended that a reduced patient accrual of 276 and a follow-up of 2 months -- 12 months would be sufficient to evaluate endpoints of safety and efficacy while retaining statistical power. The baseline demographics and patient characteristics were similar across all subgroups. The median age was 65. The majority of patients were male. The majority of patients were white, 80%. 30% apiece were enrolled in North America, West Europe, Eastern Europe and 9% in East Asia. The majority of the patients had ECOG performance status of 0 to 1, and 84% of the patients were current or former smokers. 56% of the patients had non-squamous histology. With regards to PD-L1 expression, about 17% of the patients had PD-L1 expression less than 1%; 29%, 1% to 49%; and 13%, 50% or greater. About 45% of the patients had unknown PD-L1 status. With the PD-L1 status available, there were no differences between the subgroups. 89% of the patients had 1 prior line of therapy and about 10% of the patients had more than 1 prior line of therapy, 2 or more. 31% of the patients had prior immune checkpoint inhibitor and about 30% of the patients had a response to their prior therapy. 16% of the patients had baseline liver metastasis. The LUNAR study met its primary endpoint of overall survival. The median overall survival is 13.2 months in the TTFields plus standard of care versus 9.9 months in the standard of care arm with a hazard ratio of 0.74 and a p-value of 0.035. The curve separated early and remain separated throughout. The hazard ratio here met statistical significance for our patients. In addition, the overall survival in the ICI-treated patients was particularly prominent, with a median overall survival of 10.8 months in the ICI-treated patients to 18.5 months in the TTFields plus ICI with a hazard ratio of 0.63 and a p-value of 0.03. The 3-year survival rate is 27% in TTFields plus ICI versus 9% in the ICI alone group. The median overall survival in TTFields plus docetaxel was 11.1 months versus 8.7 months in the docetaxel with a hazard ratio of 0.81 and a p-value of 0.28. The median overall survival in the non-squamous subgroup was 12.6 months in the non-squamous group with TTFields plus standard of care versus 9.9 months in the standard of care alone with a hazard ratio of 0.8 and a p-value of 0.28. The median overall survival in the squamous subgroup was 13.9 months in TTFields plus standard of care versus 10.1 months in the standard of care alone with a hazard ratio of 0.67 and a p-value of 0.05. The median PFS was 4.8 months in TTFields plus standard of care versus 4.1 months in the standard of care with a hazard ratio of 0.85 and a p-value of 0.23. The overall response rate was 20% in TTFields plus standard of care versus 17% in the standard of care arm. The majority of patients achieved stable or response to their therapy. We observed 5 complete responses, all occurring in patients receiving an ICI, 4 with TTFields therapy and 1 with ICI alone. Analysis of patterns of progression, infield versus outfield, is ongoing. The majority of patients had at least 1 adverse event, not necessarily related to study treatment. The rate of grade 3 or higher adverse events was comparable between the 2 groups, 59% in TTFields plus standard of care versus 56% in the standard of care arm. One notable difference was dermatitis seen in the TTFields plus standard of care, 43% all grades. Other frequent adverse events were attributable to systemic therapy or underlying disease. No difference in rate of pneumonitis or other immune-related AEs were observed. Any serious AE reported was 53% in TTFields plus standard of care versus 38% in standard of care. AEs leading to discontinuation included 36% in TTFields plus standard of care versus 20% in standard of care. Any AE leading to death was 10% versus 8%, respectively. There were no notable differences in health-related quality of life when TTFields therapy was added to standard of care. Detailed analysis is ongoing. The median device usage was 15 weeks with ICI and 13 weeks with docetaxel. Any adverse device effect was seen in 73% in the TTFields plus ICI and 70% in TTFields plus docetaxel. Most device-related effects were grade 1 to dermatitis. Dermatitis resolved in 87% of the cases with a median duration of 3 weeks. There were no grade 4 toxicities and no deaths attributable to TTFields therapy. In conclusion, the pivotal Phase III LUNAR study met its primary endpoint of overall survival. TTFields therapy with standard of care provided a statistically significant and clinically meaningful 3-month improvement in median overall survival versus standard of care with no added systemic toxicities. Statistically significant 8-month increase in median overall survival was demonstrated with TTFields therapy and in ICI. There was a 2.4-month difference in median overall survival for TTFields therapy and docetaxel versus docetaxel alone. TTFields therapy should be considered part of standard of care for metastatic non-small cell lung cancer following progression after platinum-based therapy. Additional studies evaluating TTFields with current standard of care for first-line metastatic and locally advanced non-small cell lung cancer are underway. In summary, TTFields therapy is a potentially paradigm-shifting new treatment modality. I'd like to thank our participating patients, their families and clinical research teams for your commitment and contributions, and I'd like to thank our sponsor, NovoCure. Thank you very much.

Thank you, Dr. Leal, and congratulations to you and the entire lung cancer community on this study. So we're now going to shift to Q&A. It's my honor to be facilitating this session. I know many of you today are -- have questions about the data set, some things that we've already heard about and some things now that you may be thinking about as you've seen this data set presented by Dr. Leal. So I'm very excited to be facilitating this session.

So before we turn it over to the floor, though, there are a few categories of questions that have come through, and we'd like to start with that. Let's get to the heart of the matter related to this data set. When you see the clinical characteristics of any study, one of the first questions that comes up is, is there a balance in the study arms? One of the questions that's coming up around the LUNAR data set is related to the PD-L1 status and the balance of the PD-L1 status between the treatment arms and then the subgroups of the treatment arms. And I'd like to ask you this question. If you can comment on how you think about it and is the data set complete in this regard, and how do you think about the PD-L1 status? I'd like both of you to be able to address that from your respective perspectives.

Yes. With the available PD-L1 data that we have, there were no imbalances between the groups, there were no imbalances between the subgroups. So in that regard, I think we're pretty set on that. The additional thing that I also think about is within the ICI-treated subgroup, 63% had PD-L1 expression of 1% or greater, which is consistent with what we would see in real-world data.

And I know there was some speculation that the wide divergence in the ICI group might have been due to an imbalance of 50% or higher PD-L1 expression, but that was clearly not seen. And I guess the other concern, I know this has been brought up and may be asked later on, is why were so many not measured. Got to remember, this study started at a time before PD-L1 testing was standard. Certainly, it's never really been standard in the second line.

Great. Thank you very much. The second question that comes up is related to the study design itself. Now in oncology, we're used to the standard of care evolving as trials are going on, and that's certainly what we saw happen here. So can you comment on the shift in standard of care? So as you look at this data set now and as you think about your patient population in the second line setting, how will you sort of -- how will you put into context the results from the LUNAR study and the patient that's sitting in front of you that may be eligible for Tumor Treating Fields therapy, whether that's added on to an immune checkpoint inhibitor or docetaxel?

Yes. I think this study really addresses a population that has limited therapy options in second line and beyond. And so for a patient in second line and beyond, I think of patients that I'm rechallenging with an ICI. And I see this as a strategy that specifically with the ICI-treated groups that is still sensitive to immune checkpoint inhibitors without any added toxicities. I would certainly feel very comfortable in adding TTFields to immune checkpoint inhibitors. And I think also with docetaxel, when we think about our approval for docetaxel, ramucirumab in 2014 based on the REVEL study, when you think of the median OS there, the median OS for docetaxel is 9.1 months, the median with ramucirumab is 10.5 months. And here, we have a median survival that is comparable and numerically slightly better, again, without added toxicities, if you look at the toxicities for ram, that certainly is something that is not for every patient. So I think acknowledging that there is a shift in the frontline strategies as we were conducting the study, I think this data is relevant to our patient population. And I do think it really fills in a gap for patients in second line and beyond.

I can only amplify those comments and further say that this is the first positive trial we've seen in 6.5, 7 years in this setting, in the second line setting, since the advent of the checkpoint inhibitors in second line. I'm going to address the elephant in the room, which is -- Rebecca Heist brought this up during the discussion, and I know this has already been asked. Isn't the standard of care change that docetaxel is the de facto standard of care and certainly the differences in the curves was not pronounced there as it was for ICI? That standard of care is in constant evolution. Many of you may not be aware of a trial called S1800A, which is a randomized Phase II effort done through the NCTN cooperative groups that Ticiana and I are both part of, that compared checkpoint inhibitor plus ramucirumab. So essentially checkpoint inhibitor second line after prior platinum and checkpoint inhibitors, essentially the same setting versus "standard of care alone," which was docetaxel. Frankly, majority were docetaxel and ramucirumab. And that study showed that the checkpoint inhibitor in the second line after prior exposure to checkpoint inhibitor had a 3.5-, 4-month improvement in median survival, and that's laid the groundwork for a major Phase III trial that's going to compare those approaches. So the notion that docetaxel is the "standard" and is fixed as the standard, I think, is fallacious. It's a constantly evolving standard. And I really think, particularly given the results that Ticiana has shown, that this trial may actually have even further relevance as time goes on.

Great. Thank you very much for that. I'm going to stay with this topic for a little bit more and dive into a very specific patient population, a question that keeps coming up, and that's related to those patients that were treated with ICI in the first-line setting in the ICI plus Tumor Treating Fields therapy arm. There were 3% of patients that were re-treated. And in that patient population, how do you think about your patients in the second line that will present to you in the clinic? Will you consider and your peers consider Tumor Treating Fields therapy for that patient population?

Yes. And I think that's a patient population that I would certainly consider TTFields. And we have clinical trial data with that. The KEYNOTE-024 data that use pembrolizumab in frontline that establish the use of frontline pembrolizumab, in that data set, they actually have a subset of patients that were rechallenged upon progression after they completed pembrolizumab monotherapy for 2 years and then had progression. And we saw there that the rechallenge was a successful strategy and led to activity in those patients. However, that benefit the second time around was less pronounced. And here, we have the option of adding TTFields, showing that differential improvement in survival there with TTFields plus ICI. So I definitely would strongly consider that for a patient in that setting.

I've shared with you some trial data of my own personal clinical data. I would guesstimate about 1/3 of my patients continue ICIs beyond progression. They may have oligometastases, a limited number of sites or smoldering progression. So this is the perfect opportunity to graft a new modality onto the checkpoint inhibitor, which in my case is almost exclusively pembrolizumab. And Ticiana and I are both involved in multiple studies in the second line, basically looking at other immunotherapeutics, again, grafted onto the frontline checkpoint inhibitor.

Great. Thank you. I'd now like to open up the floor to the audience, if there are any questions here. I see a hand right there. Can we get the microphone over there, please?

Because this is a novel therapy, consistency and no outliers are important. So in the Phase I, Phase II trial against -- with TTF plus pemetrexed, survivorship was 57% at 1 year. And in this trial, you clearly didn't get -- and the control arm was about what you'd expect, between 30% and 40%. Why didn't the docetaxel arm work?

I don't know that it didn't work. I think the primary endpoint of the study was met. The primary endpoint of the study was overall survival in the ITT population, which included the docetaxel-treated subgroup. Clearly, it didn't meet statistical significance. I think we need to do further deep diving into the data to better understand it. But I think even within the data that we saw, I do see that there is a benefit there. However, we need to understand if there are subsets there that we're just missing.

It's a small study, the initial Phase I, Phase II. And as you're well aware, the therapeutic landscape is full of studies where the Phase I, Phase II data don't necessarily match what we see in Phase III. So I'm not terribly surprised, but we still see a numerical advantage that's in double digits. So I agree with Ticiana. I think we need further analysis. We need to look at the nature and response depending on whether it's infield or outfield and that's being looked at. I view early-stage studies really as hypothesis generating and not as definitive.

Great. There was a question up front here. We can pass the microphone again.

This is Na Sun from JPMorgan for -- in for Jessica Fye. I have a question on the median PFS data that we saw. In light of the OS benefit, similar median PFS between the arms, were patients treated with TTF beyond progression? And then as a follow-up to that, like what were the therapies used post progression and were they balanced?

Great question. So regarding -- you're asking the PFS. Can you repeat the question about the PFS?

You're talking about the lack of significance in the PFS.

So the PFS was similar between the 2 arms. That discordance with OS is something that we've seen before in other Phase III trials that have looked at immunotherapy, including CheckMate 057, KEYNOTE-010. So I think ultimately, in Phase III trials, the overall survival is the gold standard endpoint. And here, we've met the overall survival. Regarding the Tumor Treating Fields beyond progression, the answer is yes. There were some patients that did receive TTFields beyond progression that were allowed to continue on if they did not have infield progression but had outfield progression. We're still analyzing those numbers, and we'll provide more clarity once that analysis is ongoing.

And then I think you asked also about treatment beyond progression. I think that's all...

Yes. The post-treatment progression. So about 25% of the patients received treatment post progression on this study. There were no imbalances between those groups. The majority of patients actually received docetaxel or gemcitabine.

I just want to remind everyone, 057 was one of the positive Phase III studies in the early ICI era and non-squamous that compared nivolumab to docetaxel, the same general theme, PFS, no benefit; OS, clear benefit. And we've seen that not just in non-small cell, but in mesothelium where ipi/nivo seems to have an advantage over standard chemotherapy, no response, no PFS benefit, clear OS benefit. So there's nothing more definitive than survival.

Just a couple for me, Larry Biegelsen, Wells Fargo. Congratulations on the study results.

Thank you.

The squamous versus non-squamous discrepancy, everybody's asking about some of the discrepancies. I'll ask that one. Dr. Langer, from your experience, if it works on top of immunotherapy, Tumor Treating Fields in second line, how likely is it to work in the frontline setting, if it were studied there? And just lastly for NovoCure, are we -- can we get an update on your frontline non-small cell lung cancer strategy, please?

We'll start with the histology question first and then we can go to the, can the data translate into first line, and then I'll close it off with your question related to our development program.

So with regards to histology, there were no differences there. I don't know that there is a -- there was not a comparison between non-squamous and squamous. So there's -- I don't think there's a discrepancy between the groups, if that's what you were asking.

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The squamous definitely had a greater advantage.

Yes. The p-value there was 0.05. So we didn't compare the 2 groups.

I think what we ultimately need to do is suss out to what extent the squamous were intrathoracic versus metastatic. And again, we're going to have a patterns of failure analysis and look at in-treatment versus outfield -- infield versus outfield responses. And that may give us some of the hints why there may have been a difference. On the other hand, it could have been serendipity. I'm particularly enthused about combining this with checkpoint inhibitors, both in frontline and in locally advanced. Those studies are ongoing. Remember that our standard of care in treatment-naive, wild-type non-small cell, those with oncogenic drivers, is for 50% or higher pembro alone or KEYNOTE-189, pem/carbo with pembro. So here, we have data in the second line, particularly with ICI, showing a benefit I'm quite hopeful that it will translate into frontline. And then in locally advanced, basically the same principle. Our standard of care now in patients who are eligible for immune checkpoint inhibitors, concurrent chemoradiation followed by durvalumab. So we're going to be looking at the same question as well, durva plus or minus Tumor Treating Fields. So if anything, the Phase III data in the second line reinforce the leads and the hypotheses that it will be looked at ultimately probably in bigger studies, both the frontline metastatic and locally advanced.

Great. So I'm going to circle up on the histology question just to make sure nothing is left to interpretation. So when a patient is sitting in front of you in clinic, and they either have squamous histology or non-squamous histology, will you make a decision on whether to use or apply Tumor Treating Fields plus docetaxel or immune checkpoint inhibitor based on their histological status?

Both patients would be eligible for TTFields with systemic therapy. I wouldn't make a difference based on the histology. Our data doesn't support that. So it would be for all-comers.

And I will address your question. You're going to hear at the end of this session around our development program. The only thing that I will say is the strength of this data set further fuels our long-term development in lung cancer. So there are several studies that are planned, including taking this now the benefit that we see in the second-line setting and bringing it in the first-line setting in the locally advanced disease. And you'll get more information about this in moments to come.

Jason Bednar with Piper Sandler. Drs. Leal and Langer, you're both clearly supportive of TTFields and use in second-line patients, eligible second-line patients. My first question here, I guess, revolves around really the third question that Pritesh was asking. Just how do you think the clinical community will evaluate the use of TTFields plus ICI as a second-line option, given that the trial population only had 2%, 3% of patients that were treated with an immune checkpoint inhibitor in frontline, but standard of care today currently requires or often uses immune checkpoint inhibitors as the frontline? So I guess, simply, do you think the lack of ICI use in frontline for the TTFields population will matter or inhibit clinical uptake?

So I think when we think about real-world studies in second and third line and you use like claims data or you use real-world data, the studies that I've seen in second line and beyond, after chemoimmunotherapy, people are kind of all over the place in what they're selecting to use because docetaxel is ineffective and toxic. And you really see that people are really trying to switch PD-1, PD-L1, add CTLA-4. They're doing a lot of different things, and there's no, in the real world, clear standard second-line and beyond therapy. So I think the reality of it is everybody has tried as best as they can continue their patients on an ICI for as long as possible if they're benefiting from it. So in the rechallenge setting, I think in real world, I think this is a strategy that I really do think that clinicians, given how well tolerated it is, no negative impact on quality of life, would go ahead and use TTFields with ICI, given the benefits and given the lack of other really effective therapies. The duration of response to docetaxel is really short, and the toxicities are high. So my answer is yes, I think clinicians will use it. I think people are excited about new treatment modalities. And I think patients are excited about things that are going to help them and are really interested in novel therapies. So I think it's a matter of educating the clinicians as we get out there and talk about this new technology, this new treatment modality.

Particularly as a modality that does not exacerbate systemic toxicity. I think that came through loud and clear. Obviously, a patient who's treated frontline, say, with KEYNOTE-189 and has disease progression within 3 to 4 cycles with rapid systemic relapse, we're not going to expose that person to checkpoint inhibitor. It's not clear that anything works in that setting. But as they've had at least stability or response, they're out 6 months or 9 months during a year, their disease is smoldering, but clearly progressing, they're the perfect candidates.

And sorry, maybe just to follow up on the question. It's more so the lack of the use of ICI in the frontline for the TTFields population where I'm wondering if clinicians will look at this and say, we need more data, we need a follow-up study where ICI used in frontline is followed up with ICI used in rechallenge with TTFields. Is that going to be a requirement for the clinical community to drive uptake?

And of course, I'm just guessing. And I would say, given the patterns that I see in real-world data for second line and beyond, I would say no, but I do think it's important to get more data in that patient population, and I hope that we conduct more studies in that patient population.

I think what's going to happen, particularly as we see studies going forward, is that it will be -- I don't know if it will be a stratification, but it will be allowed in the context of additional trials. And you'll probably get that answer at least in part because arms of the studies will be balanced. And whether it's ICI plus some other modality versus docetaxel alone, again, it will be reinforced. I don't see how, once assuming it gets an approval, that it can be sussed out of prospective follow-up clinical trials.

Okay. All right. And then the TTFields or the trial discontinuation for the patients in the TTFields plus or in the experimental arm, I mean, that was higher than kind of the standard of care population. It looked like it was a pretty wide delta. Are you able to elaborate on maybe what drove that discontinuation in that patient population?

I think we need to do further analysis of that data.

I'm not sure I completely understood your question.

The rate of discontinuation, what drove discontinuation.

Any hypotheses, even without further analysis?

Maybe in duration, it was about 15 weeks or 13 weeks for the 2 groups. There'll be multiple analyses looking at duration as well as the daily duration. It's been done with GBM looking at the number of hours per day and the outcome. Those data are still being analyzed.

Any more questions from the audience?

Emily Bodnar from H.C. Wainwright. I was wondering if you can comment at all the compliance of actually wearing the TTFields among the different groups. And then a question for the company. When submitting the PMA, are you looking to just focus on TTFields in combination with checkpoint inhibitors? Or do you still think there's potential for approval broadly in the second-line setting?

So regarding adherence and average use of device, we're looking at that in the first 3 months and also average use during the hours. Currently, we don't have that data fully analyzed. But I do think that this will be important, given that we've seen an association into GBM with that use and then outcomes. So that is something that we're certainly very interested in looking at.

This is going to require, obviously, a fair amount of teaching and servicing of our nurses and advanced practitioners, and frankly, the families. Families can control only 2 aspects of their loved ones' lives, their dietary intake and to some extent, their environment and certainly what they wear as part of that environment. So this actually gives them a certain degree of agency that they don't have when we're giving systemic agents.

And as to your question related to the regulatory process. So the study overall, the ITT population was positive. That will guide our regulatory approach and the label that we seek.

Just two for me for the clinicians. One, is there -- have you guys done a per protocol analysis? I assume -- a per protocol analysis instead of intent to treat. I assume that would be better given the discontinuation rate was higher on Tumor Treating Fields. And second, I know you touched on this a little bit. But without it, there was no progression-free survival benefit, no overall response rate statistic. So the question that was e-mailed to me is the overall survival benefit driven by what patients got post the study?

Well, the overall survival and the discordance between the overall response rate in PFS is what we've discussed previously that we've seen that discordance before in these therapies with ICIs. I would say that given the fact that most of the patients who receive post-progression therapy was docetaxel, gemcitabine, gemcitabine actually has no survival benefit defined in non-small cell lung cancer. So I think we need to learn more about this study and these data, but gemcitabine and docetaxel is what they got after. So I don't know that the post-progression therapies necessarily are driving that survival with the information that we currently have.

What you saw today was an intent-to-treat analysis, not per protocol. Pretty much they matched. I mean there wasn't that much deviation.

And Dr. Leal, can you comment on the balance between those patients in both arms that received post-progression therapies? I think you commented on that earlier, that data point may be important.

Yes. And I think it's also important to note that it was just 1/4 of patients who got therapy post progression, which again, I think, highlights the need to incorporate new therapies as soon as we have them available so that patients can benefit. Like I definitely agree that having the frontline studies and the locally advanced studies are going to be very helpful addressing the rechallenged population. But for a patient living with lung cancer now, I think this is their time, right? And so if you see that benefit, we have a Phase III positive study, people are living with cancer, and they want a therapy that's novel and better. I mean I think that this study meets those gaps. And then we just have to follow up on all these important questions.

This is [ Kevin ] here on behalf of Vijay from Evercore. Just to the clinicians, why would the PFS and overall survival dynamics seen in IO trials be relevant here when TTF is a local therapy, given both arms had the same IO?

So I think one of the mechanisms of TTFields is, as we were talking about triggering a systemic anti-tumor immune response. So TTFields is delivered local regionally, but we think that perhaps there's systemic effects there given the potential to trigger an anti-tumor immune response. And so within that, that would be one hypothesis of driving that discrepancy.

There may be differential effects both infield and outfield that may also be describing -- driving the discrepancy. There are other effects going on here that, frankly, semi objective, really subjective [ OR ] and PFS don't necessarily catch. You've got to remember in ICI-treated patients, we actually have pseudo progression and anywhere from about 5% to 8%. And yet -- we have data, for instance, from the OAK trial, which is another one in the critical Phase III trials, comparing atezo to docetaxel that showed treatment beyond progression in that group translated into survival benefit as opposed to just switching. So there's a lot still going on that we haven't really figured out in the field of immunotherapy.

Great. Let's see. Any more questions? So we are going to wrap up. I'm going to invite Ashley Cordova, our Chief Financial Officer, to close it out today. Thank you.

All right. Thank you. And thank you, Dr. Langer. Dr. Leal, [ Tesh ]. Good afternoon, everyone, and thank you again for joining us today. I would like to start with a brief review of our commercial pathway to treating non-small cell lung cancer patients. The presentation of our LUNAR trial results earlier today marks an important step, next step in a round of engagements upcoming. We have already submitted these results for publication in a peer-reviewed journal, and our regulatory teams are preparing both the PMA and CE mark applications for submission later this year. As a reminder, the FDA's review time line for PMA submissions is 180 days, but that clock is paused for any correspondence between NovoCure and the agency. Once we have gained regulatory approval, our goal is to treat patients as soon as possible while our market access teams take the necessary steps to secure reimbursement. We expect to be treating patients in the later stages of 2024 with commercial and national reimbursement to follow in the coming years. As a part of our clinical strategy, we strive to broaden our labels and expand the eligible patient populations in solid tumors where we have proven efficacy. We have already taken these steps in GBM with our ongoing TRIDENT trial and our upcoming launch of Keynote D58 in collaboration with Merck. And we now have the chance to follow a similar path in the torso. We've been very clear that we do not plan to be one and done in lung cancer. The LUNAR results build upon years of clinical development in thoracic oncology, beginning with our Phase II EF-15 trial and our STELLAR trial in malignant pleural mesothelioma. The results from these trials, together with the profound results of the LUNAR trial, provide a strong foundation for the continued expansion of our lung cancer development program with the goal to treat patients in earlier lines of therapy and together with multiple standards of care. I am very excited to announce today that we have a number of new clinical trials in various stages of design, regulatory review and launch preparation. These trials will enable us to build upon the efficacy shown in the LUNAR trial with the goal of expanding the pool of patients who can benefit from Tumor Treating Fields. We are planning to launch 3 new trials on lung cancer, aptly named LUNAR 2, LUNAR 3 and LUNAR 4. LUNAR 2 will evaluate Tumor Treating Fields together with immune checkpoint inhibitors in chemotherapy in first-line metastatic disease. LUNAR 3 will focus on patients with locally advanced disease studying Tumor Treating Fields with immune checkpoint inhibitors following chemoradiation. LUNAR 4 will evaluate the potential of ICI retreatment in metastatic non-small cell lung using Tumor Treating Fields together with an immune checkpoint inhibitor in patients treated with an ICI in chemotherapy in the first line. In addition to these 3 new trials, we continue to enroll patients in our KEYNOTE-B36 trial, which is evaluating Tumor Treating Fields with pembrolizumab in the first line. These next series of trials represent an important pattern for NovoCure as we pursue opportunities to expand the addressable market in solid tumors where we have proven efficacy. Beyond lung, we have multiple Phase IIIs set to read out before year-end 2024. The data from these trials will inform similar opportunities to expand our clinical pipeline. As a reminder, we expect to release data from our Phase III INNOVATE trial in recurrent ovarian cancer later this year, top line data from our Phase III METIS trial in brain metastases from non-small cell lung cancer in Q1 2024 and Phase III data from our PANOVA-3 trial in unresectable locally advanced pancreatic cancer in the second half of 2024. We expect these 4 foundational trials to drive NovoCure into our next phase of growth as we look to further expand our development pipeline, launch numerous commercial franchises and new indications and continue exploring opportunities to extend the lives of patients. Building on more than 20 years of research and a strong commercial business in GBM and with the opportunity to treat tens of thousands of patients on the horizon, we have never been more excited for the future of this company. I'd like to thank you all for joining us here today, and welcome you to stop by and say hello to members of our executive team as well as Investor Relations after this event. As we often do, I would like to close today's session with our mission. Together with our patients, we strive to extend survival in some of the most aggressive forms of cancer through the use of our innovative therapy, Tumor Treating Fields. LUNAR is the first randomized trial in more than 7 years to show a significant extension in overall survival for patients with metastatic non-small cell lung cancer post platinum. The results hold the potential to make a meaningful difference in the lives of patients who are eager for new, well-tolerated, effective treatments. We look forward to the opportunity to reach these patients and many more in lung cancer and beyond in the coming years. Thank you.