Iovance Biotherapeutics, Inc. (IOVA) Earnings Call Transcript & Summary

The next company at our conference is Iovance Biotherapeutics. And it's my pleasure to host Fred, the Interim CEO; and Friedrich, the Chief Medical Officer. Thanks both of you for joining us.

Thanks, Boris.

So I'd like to discuss the issue that I think is at the top of all investors' mind, and that's the regulatory assay. Can you just walk us through the assay development issues that arose during the regulatory review and kind of what stage of validation work you currently are in for this assay?

Sure. So during the prior regulatory process that we're in or we're currently still in, FDA had comments on our potency assays, which are assays designed to determine whether the T cell products is sub potent or is potent and capable of achieving a clinical effect. We went back and forth with FDA on some assays over the period of 2020. In late 2020, we announced that we had been delayed by ongoing regulatory discussions with FDA over the potency assays. And then more recently, in May of this year, we announced a further delay as a result of potency assay discussions. Since then, we've been involved with FDA discussing in great detail potency assays, their mechanisms and how they work. We've developed new assays and new assay technologies that we think will address FDA's concern. And we've been working very hard in the laboratory and other facilities to complete these assays, including qualifying and validating them. We haven't disclosed exactly where we are in that process, but it's coming along quite well. And we anticipate being able to file our BLA in the first half of 2022 on the time line that we have right now with the regulatory process that's ongoing.

Got it. Can you comment on what kind of parameters were the initial assay and the new assay you measuring specifically?

Yes. So the initial assay typically utilize bead-based stimulation of the T cell product, in this case, a TIL product. So the TILs are being stimulated by beads. The beads have antibodies on them that stimulate TILs to activate and then the TILs give off protein -- one or more proteins that we can detect. The first protein that we worked on was one called interferon-gamma; second one was called granzyme B. And we discussed both of those assays with FDA, and they had questions about the mechanism of action of these assays and how they work with respect to TIL therapy and the mechanism of action in TIL therapy in vivo. The interferon-gamma assay was truly the gold standard when we brought it to FDA initially and that assay, we spent a lot of time and effort on with FDA. Since then, we've made more progress with more advanced assays that we think will further delineate the mechanism of action in TIL therapy more specifically in a way that is consistent with FDA's guidance industry in this area. And that's what we've been discussing with FDA now. Now we haven't disclosed exactly what those new assays are yet, but that's -- it's in advance over the prior bead-based assays.

Got it. So one other question as it frequently comes up is whether or not you would have to reanalyze the melanoma and cervical data in the BLA filing using this new assay? And if so, do you have the required samples to do that?

Yes. We have the samples to do that. FDA has been -- we've discussed this with FDA, they're open to that, and they understand that, that's something we have to do. And so yes, you could -- that's the plan, it's basically to go back and retrospectively analyze, for example, the melanoma Cohort 4 samples with the new assay once it's agreed with FDA or its part of the BLA review process.

Got it. So for the BLA filing time line, you have a fairly wide window of the first half of next year. Can you comment on some scenarios that can maybe [ land ] in the earlier part of that window or the latter part of the window?

Sure. There's a lot of things that have to happen with the assay as we develop it. And there's also a lot of other things we have to do with our clinical development program to finish off Cohort 4, including doing IRC reads and writing clinical study reports and finishing the entire process. So some things that might put us in the earlier window would be if stuff goes very well and very quickly. Later part of that window might be if things are a bit delayed or FDA takes some time, to get FDA to give us the right feedback or there's some other delays as we finish off our work, for example, type of delays.

Got it. Are you going to provide any kind of more incremental update? Or is the next thing we're going to hear is just announcement of your BLA filing?

We don't know yet. It's possible we can provide an update depending on what FDA says to us. We certainly would want to provide an update. That's certainly something we would like to do. But we can't say for sure, because you never know what the regulator is going to say and how they're going to say, and whether that update would be something we can actually speak about or be better -- or be too confusing or unsupported by what FDA said for us to be able to put that out there.

Got it. Maybe a question that arose just recently. I mean, can you discuss the logistics to the utilizing TILs and specifically the investor question has been around -- the novel manufacturing method that you have to take just a little over 3 weeks, it's 22 days, right? But if we look at the recent update, just presented on Saturday, the average time for harvesting [indiscernible] infusion was 35 days. So I'm just curious, what is adding that it's almost another 2 weeks of time frame.

Yes. With that particular poster, we did disclose the entire end-to-end process there, but there's additional time there for product release shipping, lipid depletion and other tests that goes on before you actually infuse the TIL product. Process still takes 22 days at the manufacturing facility. And 35 days happens to be the time that occurred in that study, but that doesn't mean that -- that's what would occur commercially or in other studies. Some sites decide -- don't push to lymphodeplete until the product is on site. Others are willing to go ahead without that. There's all sorts of factors that are baked into that analysis.

There is some research -- like clinical site logistics involvement here as well, right? So you need to schedule for the patient to be admitted. So there's an additional impact just from sites that add some variability. This is the average, right, it [ implies ]. It can also go faster than 35 days. And that's really where that comes from.

Remember, this is an early long study. So we're working with doctors that had not -- again, Friedrich can comment more on this, but this particular physician community doesn't have a lot of experience with cell therapy. So there was a lot of learning that goes on. This is the first time this has been done in a multicenter study like this. And so things can speed up and get a lot faster once the community gets comfortable with it, for example, like in melanoma.

So realistically, I understand this is kind of a very unusual environment, obviously, given these stills. But realistically, what do you think kind of the [ pain ] could be in the community setting or in the academic settings for commercial product?

It would be somewhere between 22 and 35 days. I mean, I would put it probably in the middle of that ballpark, vein-to-vein, but we don't know for sure, we'd have to see how it goes. I mean, it's going to depend. Individual hospitals, treatment centers, that would eventually have TIL therapy, commercially available to their patients, might do it differently, depending on how they work, what their internal processes are.

Got it. And in terms of IL-2 dosing, are these facilities -- and do you see significant pushback on 6 doses of IL-2, maybe step back to how you came to the 6-dose number to begin with? And is that a limiting concern in terms of patient enrollment and tolerability?

So yes, let me ask one of the middle questions first. So really, the rationale for choosing 6 is based on a large data set coming out of the NCI. We basically looked at the NCI experience and with doctors there. Is there a plateau of a number of doses from which, if you are adding doses, you're not gaining efficacy. That's actually -- there's a paper by [ Stephanie Gulf ] that is picking that as far where really you saw that if you add more doses beyond 6, it doesn't really add activity. Up until then, it seemed to add. We are -- for sites where -- that we are including in our clinical trials, we do training. So these sites are being trained, being educated. They have the infrastructure to do this. And we are not necessarily getting pushback from site in our clinical trials to lower that dose. As we've presented on the 3B Cohort data, the median dose that was -- that we were able to administer in this [ board ] was 5.5, which really means that a good proportion of these patients did receive either 5 or 6 doses. So this is feasible. And that's what enabled this data.

And very sick, [ not just ] lung patent, too. So not the easiest patients to deal with, with IL-2 and with physicians that are relatively new IL-2 would still be able to do that. Now Boris, we are developing new IL-2 analogs. We're developing different approaches. We just -- we had to pick something to run our trials with. And as Friedrich mentioned, we just pick what was the optimal dose. And over time, we can further optimize that for the community setting and beyond.

Got it. So let's pivot over to the clinical data in melanoma and cervical cancer. When are we going to see the final result? And can you comment in terms of the bar for efficacy that the FDA needs to see for approval in both of these indications?

Yes. So I think in order for us to have clinical -- to have the final data, we do need to read -- we [ don't ] need to IRC read these cohorts. We're going to time that somewhat in respective to resolution of the potency assay question, right? So there is some dependency there in having clarity on that, having read the IRC data and then being able to communicate the data. Around the bar, I think for melanoma, it's fairly clear what provides the bar is the experience with chemo monotherapy in -- where that has been used that gives you response rates between 4% and 10%, very short overall survival. That is the benchmark. And that is what this data was -- what this study was designed to demonstrate benefit over. In cervical, we're planning on engaging with the FDA to really understand what the expectations are. So that's going to be a discussion that will also address the changing landscape that they're looking at and indication overall.

And also, are you seeing significant difference in efficacy reported through investigator review versus centrally reviewed data? Just curious if there's a delta and if there is, why that is the case?

Yes. So number one, I think, to be clear, we are collecting both, right? So we're doing most the investigator reads in them, we're doing the IRC reads. What we can go off in actual experience with the data would be based on the comparison of IRC and investigator reads in Cohort 2. that's actually data that we published in -- at SATC 2019 where we saw really good concordance between the 2 different reads.

Got it. Maybe let's touch base on the recent lung cancer data, so I'm referring to the Cohort 3B where we saw the median durability of about 3.5 months. Now the question, I think, coming up is certainly in melanoma, we're out 33-plus months and median has not been reached. Here, we're reaching the median in 3.5 months. Can you comment why that might be the case? Is there a likely -- is it a kind of pretreatment for these patients? Is it just the nature of the tumor itself, the nature tells? Help us understand the big disconnects between the 2 tumor types?

Yes. To be honest, I don't see the -- as an oncologist and clinician, I don't see the disconnect because. I don't compare what you are achieving in melanoma patients with what you're achieving in non-small cell lung cancer. These are different diseases based on what we know about the natural course of the disease, based on what we know about sensitivity or benefit from therapies, right? Remember, in melanoma with standard of care for first-line treatment is very different for standard of care in lung cancer. Lung cancer is still using a lot of chemotherapy. So I don't really think that not seeing complete overlap in response rates or durabilities saying anything about the potential of these therapies to make a difference for the populations. The second point that you mentioned, which is the pretreatment, I think that does play a role here as well. This study, the Cohort 3B study was designed as a feasibility and proof-of-concept signal-generating studies and a fairly #1 heterogeneous but also heavily pretreated population. These patients have received a median number of 2 prior lines of therapy with a range of 1 to 6, with only very few of these patients having received only 1 line of therapy. I am not surprised that we are seeing limited durability in a population like this. This population was never intended to be population that would support an indication or a label that is really what we're doing in the next step, right? So what the study has shown us is demonstrated feasibility, demonstrated a proof of concept for efficacy and showing more than 20% response rate in a heavily pretreated population, which I personally find very encouraging. And together with the data from the [indiscernible] study that was conducted at the Moffitt that was -- that also showed very comparable response rate also showed long durable responders and a patient -- I believe, there was a patient who was PD-L1 negative. The other one had an EGFR-activating mutation. Our long responder, long complete responders was also PD-L1 negative shows the potential of what we can accomplish in the context of the PREVENT study that was run in patients that were less heavily pretreated. I think the design of the LUN-202 study, which is really the study where we are generating data in a homogeneous population that defines a high unmet medical need population of patients with less prior treatment is validated. That is really the real experiment that will be informative of the real benefit profile of TIL therapy and lung cancer.

And what's the time line for seeing that data to really understand TILs in that setting?

Yes. So the study is ongoing. We're enrolling and treating patients, and we're going to provide updates when we have a meaningful data center.

Got it. One other question comes up, and this is a theoretical question. It is, how does the TCR between melanoma, cervical and non-small cell lung cancer compare? And is there kind of a correlation between the TCR repertoire and response? Or should there even be one?

Yes, that's a good -- both questions are really good. And we very intentionally added the TCR data to the poster for the Cohort 3B because we wanted to show that really, there's no meaningful difference in what we're getting in regards to the number of unique clones, diversity and clonality, which are [indiscernible] a measure of polyclonality compared to melanoma and cervical. I think we even provided the comparator numbers in the footnote to that table. Statistically, there is no difference. Right now, this data set is too small to do any association analysis between the number of the unique loans and response status. So we're going to have to generate more data for that. What's important, though, is that this data supports that we can produce TIL products that are comparable in their profile to what we are generating in cervical and melanoma patients.

Got it. So it's that -- over the weekend, you presented data on the TIL combo study in several indications. Can you comment on what the combo strategy is? And when will we have to make some of these combo investigation decisions?

Yes. I mean just to kind of recap on the data. And these were checkpoint of the naive patients that were treated with TIL plus pembro where we saw really encouraging efficacy with expected safety profile. So again, it shows the feasibility of the combination. And we saw efficacy data that compared really positively to what their logical benchmark is, which is pembro monotherapy, right? We saw a response rate of 57% in cervical cancer; 60% of melanoma; and 39% in head and neck cancer. What you would compare that with is, in melanoma, single-agent pembro achieves overall response rate of mid-30%, 33%. In head and neck cancer in the similar setting, you see 17% response rates. And since there is no single agent first-line data in cervical probably the best competitor is what you would be getting in checkpoint-naive patients in second line you accomplish between 11% to 14% response rate in cervical cancer patients. So what you're seeing here is we're achieving at least double the response rates when we're combining TIL with pembrolizumab. Particularly important is that in the melanoma cohort, we saw 3 of 10 patients with CRs, and these CRs had converted to confirmed CRs per RECIST from what we had presented in the previous presentation where we saw one unconfirmed CR to metabolic CRs. So that's -- I find that very encouraging. These continue to deepen, continue to disappear and that supports that they are real. Overall, this supports continued development of TIL plus pembro combinations in these melanoma, head and neck, cervical and also non-small cell lung cancer. We do have an ongoing cohort in non-small cell lung cancer with the combination trial.

And as we develop the plans for these [ 4 ], we have to interact with the regulators. You can see we recently announced our Fast Track designation in melanoma and their frontline indication now. We'll hopefully be able to talk more about what we want to develop here based on this data and how we want to develop it. It's a little premature right now as the data is still coming out, but that's something we're thinking about deeply internally.

Great. Well, thank you very much for that. We're just out of time. So I'd like to thank both Fred and Friedrich for joining us, and we look forward to the updates from the FDA assay.

Thanks.

Thanks, everyone. Bye-bye.

Thank you. Bye-bye.