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

Well, welcome, everyone, to Jefferies Cell Therapy Summit. We're about almost done here on day 2. We've got Iovance Biotherapeutics, which has had, I guess, a news-filled last 12 hours. And so we've got CEO Maria Fardis to give us an overview of Iovance and I'm sure you'll give us the latest update. So Maria, please take it away.

Excellent. Thank you so much. Good afternoon. Thank you, Biren, for hosting us. I will be talking about investigating the power of tumor-infiltrating lymphocytes for treatment of cancers today. We're a public company. I draw your attention to our forward-looking statements. In terms of recent updates, maybe I'll start with saying what information we have talked about in 2020 and then the latest update that we have provided to The Street yesterday. We've been talking about providing data in terms of -- we presented our melanoma data at ASCO as an oral presentation. We also released top line of 68 patients from cohort 4 as part of a press release in May in 2020. We also showed some of our data, which is generated through a collaboration with Moffitt Cancer Center at AACR for non-small cell lung cancer in terms of TIL and addressing patients that are post-anti-PD-1 therapy. We have been addressing that we have over 90% manufacturing success rate. Over 300 patients have been dosed. Now what we released yesterday was an update from our regulatory interactions with FDA. We had requested a Type B meeting and as part of that Type B meeting, we received 2 sets of feedback. One was feedback regarding our clinical cohort 4 amount of follow-up that the agency would like to see, which is 6 months from initial response as assessed by IRC. They also commented on cohort 2, can be a supportive cohort as part of our BLA. They also requested that we provide them additional potency assay data. In addition, we -- the company is planning on providing additional assays to be used as potential potency assay. This has led to a revision of our BLA submission time frame from 2020 to 2021. In terms of TIL therapy, this is really our own body's natural immune system at its best. When a tumor is detected or cells that are unhealthy are detected in our body, usually the immune system kicks in. The TILs come to the site of tumor. They recognize that the tumor and the -- in a normal setting when the patient -- the individual is healthy, they remove that tumor. In the cases where a disease actually persists and forms, either because we have genetic predisposition or because of environmental factors, melanoma is a great example of that because of extended exposure to UV light, for example, TILs still come to the site of tumor and they launch an attack. However, what happens is due to the hostile microenvironment of the tumor or other factors, they're not able to be successful. So the process of TIL therapy is removing the tumor about 1.5 centimeters or so from the patient, from the patient's body, sending it to our manufacturing location, expanding those TILs, rejuvenating them and then putting the patient -- those TILs back into the patient after having removed the hostile microenvironment that exists in the patient. The process itself is shown here. The top of this image is showing the tumor journey and the bottom is showing the patient journey -- sorry, the opposite. The top is showing the patient journey, the bottom is showing the tumor journey. The patient comes in, gets resected, the tumor is taken away from various lesions, either skin, lymph node, liver, lung or otherwise. The patient recovers and goes home. And then the tumor is shipped to our manufacturing facility, where it's fragmented, it's placed in media, and it's grown over the course of a 22-day Gen 2 manufacturing process. And at the end of 22 days, it's harvested, it's placed in infusion bags, and we cryopreserve that product and Iovance is ready for infusion. When the patient and the hospital are ready, the patient comes back to the site and a lymphodepletion procedure of 7 days is initiated. This process is a chemotherapy for 7 days, cyclophosphamide and fludarabine. The idea is to remove that hostile microenvironment that did not allow the TIL to do its job to begin with. And once that 7-day course is completed, the patient is infused with TIL therapy and followed by up to 6 doses of IL-2, which takes about 2 to 3 days. And once adverse events are resolved, the patient's discharged from the hospital. This is a onetime treatment, and this is the entire regimen as shown here. In terms of what is the mechanism of action, once we infuse a patient with TIL, the TIL starts circulation in the blood. They ultimately reach the tumor side because they recognize chemokines that are produced by the tumor. They leave the circulation and they come to the side of the tumor. Once the TIL recognizes the tumor cell through interaction of T cell receptor with the MHC of the tumor cell, a full fight sort of develops where TIL produce interferon gamma, granzyme B and perforins and start the process of killing the tumor cells. So this is the understanding of the mechanism of action of TIL therapy. The company has -- Iovance has been around, although we were named by a different name earlier on. In 2011, the company had taken a license for this technology from Steve Rosenberg at NCI, who was the developer of the concept. Steve Rosenberg, over the course of a few decades actually, optimized the regimen. So we are taking advantage of the deep knowledge around the product. He also had administered the product to multiple melanoma patients and has seen a response rate of 56% back then when the patients were PD-1 naive and 24% CR rate, and these CRs were incredibly durable. So many of them lasted 7 to 10 years post-follow-up. In the melanoma landscape, we started our development program in 2015, where we received a orphan drug designation from FDA. In 2016, the first patient was dosed in the melanoma program. I had joined the company, and we were using a Gen 1 manufacturing, which is very similar to what Steve Rosenberg had developed, so based on the license we had taken. We embarked on developing a Gen 2 manufacturing, which is a 22-day manufacturing process, in order to shorten the process and make sure we address today's patients. Today's patients have now been treated with anti-PD-1s and typically upon progression, they're progressing very quickly and are in need of therapy. In 2017, we received the Fast Track Designation for melanoma, and we continued expanding the program into cervical and head and neck indications. In 2018, we had received an RMAT designation from the agency. As part of our cohort 2 administration with Gen 2, we held an end of Phase II meeting with FDA, where they agreed that the existing study could house a cohort that could be registrational. And at that point, we were thinking about starting at cohort 4. Just continuing with the melanoma thought process, in 2019, we started patient dosing in this cohort 4, which is the pivotal cohort and are -- we dosed our last patient into cohort 4, which is a pivotal cohort, in January of 2020, and we are in follow-up. At the same time, we have been discussing with FDA regarding our other indications, including cervical cancer. We spoke with them regarding our cervical data and we had presented that data at ASCO 2019. We had received a Fast Track and a breakthrough designation for cervical cancer, and we continue with the pivotal program in cervical indication as well. And we have enrolled our last patient in the cervical pivotal cohort already, as we announced at quarter end this past quarter in 2020. Our registration program is now planned for a submission around 2021 with the FDA. To remind us what the data in melanoma looks like, we had presented in 2019 at SITC that our melanoma cohort 2 data for patients that are heavily pretreated is 36.4% ORR. We then proceeded to report the data that was based on independent review committee or IRC at 34.8%. The concordance was quite high. We were very pleased to see a high concordance between investigator and IRC review. In 2020, we provided an update from this cohort 2 data where median DOR had not been reached at 18.7 months of median study follow-up. And we were very pleased for these patients to continue in response after 18.7 months of study follow-up. As a highlight, we are going after a very large market opportunity. In general, we think about solid tumors. And our leading indication, of course, is metastatic melanoma and behind that, we are using cervical cancer as our next indication that we are pursuing. We had focused on patients that are highly unmet medical need, which are post-ICIs or immune checkpoint inhibitors. Given the ICIs have been very well adopted in the treatment of melanoma as well as a number of other solid tumor settings, we are looking at patients subsequent to progression on ICIs. We expect to be the first cell therapy possibly approved in solid tumor landscape. As I noted, we are targeting melanoma as our first indication and cervical as the second one. The BLA submission time frame is expected around 2021. For melanoma, we have an RMAT designation, orphan drug as well as fast track. And for cervical, we have breakthrough designation, orphan drug and fast track. We feel that we have a very efficient and scalable proprietary Gen 2 manufacturing process. The product is still autologous. So it is -- every patient is a batch and every batch is a patient. We also are building our facility, our manufacturing facility, in Philadelphia, 136,000 square foot facility that is under construction, and I will show you a picture as to where it is in terms of manufacturing and getting ready for actual production. And then we work very closely with a number of different academic institutions for new indications. So we collaborate with Moffitt Cancer Center, as I noted before, for example, in non-small cell lung cancer. We collaborate with NCI, still very actively, the innovator of the idea, Steve Rosenberg. We work with MD Anderson, Yale and as well as other institutions in developing TIL for new indications as well as potentially having access to their intellectual property for new methods of TIL manufacturing. Now to kind of step back for a second and talk about what is TIL, how do we define this product. It is a polyclonal mixture of cells. These are the T cells that had recognized the tumor, and they came to the site of tumor. They're effective in addressing a very heterogeneous solid tumor, and that's been the holy grail in addressing solid tumors in general. This is highly individualized, as I've been talking about it. 100% of TIL from a patient can persist all the way to day 42, and we have recently disclosed data that many of the TIL can persist maybe all the way to 6 months or beyond. The TIL can develop immunological memory. Many of these cells are because they are basically the same thing as our immune cells, they are able to reactivate and sort of reexpress and become a larger amount of the cells as they circulate. And so there, from a pharmacological perspective, they're able to last through the immunological memory development and possibly lead to a durable response. We have been, of course, seeing data in melanoma, cervical and now non-small cell through a collaboration with Moffitt Cancer Center. In terms of comparison of TIL, CAR-Ts, other available therapies for solid tumors, checkpoints are antibodies, of course, that they have been approved, and they're widely used for treatment of many solid tumors. TCRs are another type of T cell therapy, which I believe are still a little bit further away from approval. CAR-Ts have been approved. They have been approved in liquid tumor settings and there are similarities and differences between TIL. TIL are in the setting of solid tumor. Mainly, they are both onetime treatment, available data in TIL is in solid tumor and melanoma, cervical, head and neck and lung. The safety profile is expected to be different, given that we don't have a genetically modified product for TIL, while CAR-T products are genetically modified. We heavily protect intellectual property around our product. The manufacturing method has been heavily protected. 12 granted U.S. patents have been allowed to date for composition and method of treatment. We also protect our advanced technologies, including methods of making TIL, methods of making them, for marrow infiltrating lymphocytes or PBLs, peripheral blood lymphocytes, manufacturing methods, use of co-stimulatory agents or otherwise. This is a picture of our manufacturing facility, Iovance Cell Therapy Center, or iCTC. As I noted earlier, it's 136,000 square feet. A significant investment by the company is being made to build this facility to support commercialization of TIL. It is expected to have its clean rooms ready by latter part of this year, 2020, and we expect to be able to use the clean rooms for our clinical manufacturing in 2021 and for commercial in 2022. The reason we embarked on building our own facility is to reduce the cost of goods, of course, having access to our own facility. In terms of indications we are pursuing, unfortunately, cancer still remains a significant unmet medical need. 1.6 million patients get diagnosed annually in U.S. and 90% of them are still solid tumors. Some of the statistics are shown on this graph for you. New cases in melanoma is actually on the rise at 96,000 cases in 2020 expected and 7,000 patients still are expected to die. And you can see that some of the indications that we're pursuing are quite large, including non-small cell lung cancer, for example. The incidence of lung in U.S. remains very high at 228,000. And unfortunately, approximately more than half of these patients still die on an annual basis. So still, quite an unmet medical need remains for these patients. Our pipeline is shown here. Our melanoma program has completed its pivotal cohorts. Our cervical is expected to complete dosing pivotal patients in cohort 1. Our head and neck program continues with multiple cohorts. We also have a basket study where we are enrolling patients in melanoma, head and neck and non-small cell, either a single agent or as combination with pembrolizumab. We have a program that is going after CLL. It's a PBL product, peripheral blood lymphocytes. And on the bottom, we are showing the studies that -- some of the studies that we are conducting in collaboration with academic institutions such as MD Anderson as well as Moffitt. Going into a little bit more data on metastatic melanoma. Just to remind ourselves, what is available care for the patient population that we are targeting. The patients in U.S., as I noted, 96,000 get diagnosed. Typically, they get a first line of therapy. They receive an immunotherapy. If -- if and when they progress, they would either receive a BRAF/MEK if they have a BRAF mutation. If they do not have a BRAF mutation, they may receive other approved therapies or considered -- be considered for clinical trials. They can be considered unmet medical need. The incidence of the disease, unfortunately, globally still remains quite high. And once the patients progress through immunotherapies and/or BRAF/MEK if they qualified, really the only available care for them is chemotherapy. And chemotherapy for better patients than we see offers a 4% to 10% response rate and an OS of 7 to 8 months. So unfortunately, once the patients progress through an available care, they're significant unmet medical need and they don't have a lot of time for various other options. They have very short life expectancy. Our clinical study C-144-01 is shown here. The patient population is unresectable or metastatic melanoma treated with one prior systemic therapy, which could be an anti-PD-1, and if they have a BRAF mutation, BRAF/MEK. Our cohort 1 was using Gen 1 manufacturing method, which is similar to Dr. Rosenberg's original manufacturing. Cohorts 2 and 4 both use Gen 2 manufacturing, which is identical in both cohorts with identical patient population. And cohort 2 data is what I'm going to show to you today. We have a nice lung follow-up on that. And cohort 4 is the pivotal cohort, which has not fully read out. As of now, 68 patients were reported in May of 2020. The patient population is shown here. These patients, as an average, maybe I'll focus on just a few of their sort of descriptions, had a mean prior number of therapies of 3.3. They all had received anti-PD-1 and 99% had progressed on anti-PD-1. 80% of them had received anti-CTLA-4 and 77% of those had progressed on anti-CTLA-4. If they had a BRAF/MEK mutation, they had received their BRAF therapy. And as a whole, we're a pretty late-line patient population from a description perspective. If we think about LDH levels, which unfortunately is a market for poor survival, approximately 40% of these patients had an elevated LDH level. From a sort of a tumor burden perspective, they had approximately 10 centimeters of target lesion mass, which is a summary of diameters. And more than about 77% of them had more than 3 lesions. So highly metastatic patient population with fairly high tumor burden at baseline and many of them with unfavorable survival markers. On this slide, we are showing you treatment-emergent adverse events and adverse events over time. On the left-hand side, you can see the adverse events over time. As it is typical to onetime treatment, you can see that adverse events are sort of glued together on the left-hand side, and bulk of them seem to be resolved by around day 14. We have a continuation of follow-up out to 20 months. And you can see that very little is happening beyond earlier time points. On the right-hand side, we're showing you treatment-emergent adverse events that are happening and as Dr. -- these are highly consistent across TIL regimens. And Dr. Rosenberg had published noting that many of them are well associated with chemotherapy and IL-2 that is part of the regimen for administration of TIL. In terms of response, we had 66 patients that were dosed at this cohort. 24 of them had an objective response, of which 2 were CR and 22 were PR. That puts our overall response rate at 36%. It's also noteworthy to think about disease control rate, which was 80%. And the reason it's noteworthy to think about that is all the patients entering the study were in progression. So a stable disease could be a clinically meaningful event for a patient who was progressing. Median duration of response had not been reached at 18.7 months of study follow-up. We are quite excited to see this continuing and patients benefiting from a longer follow-up and in response. The mean number of TILs that were infused was 27 billion, and median number of IL-2 doses was 5.5 doses. And this shows that up to 6 doses of IL-2 is fairly well tolerated by almost all the patients. On this slide, we are showing you a swim lane of response. What you can note on the right-hand side from the graphic piece is time to response is fairly short. Many of the patients see their original response at the first assessment, although response may mature over time and we can have patients that go out all the way to 4.5 or 6 months before they're seen as a PR. And the response can deepen even further from a PR to a CR over time. We were highly encouraged to see only 6 patients progressing at this 18.7 months of median follow-up, study follow-up data cut. On the left-hand side of this slide, we are showing patients' prior response on the prior anti-PD-1. And you can see that all the patients had received prior anti-PD-1. Many of them had received prior anti-CTLA-4. The best overall response to anti-PD-1 is shown here. And many of these patients are, in fact, what we call primary progressors. In other words, their best response to prior anti-PD-1 was a PD. And this is a significant unmet medical need because the patient is not able to benefit from ICI therapy or some combination of ICI therapies. A waterfall of the response is shown on this slide. And what it shows is -- maybe 2 factors are important here. One, the depth of the response is quite nice and deep. Many of the patients benefit from a deeper response than 30%, which is defined by RECIST as a PR. And then the second point to make here is the stars are showing patients who had a BRAF mutation. So regardless of a BRAF prior therapy or regardless of a BRAF mutation, the patients can benefit from TIL. We had also presented some sensitivity data. I will speed up a little bit. On the sensitivity data, we concluded that there's -- the patients seem to be able to benefit almost regardless of their prior therapies or stage of the disease. Some factors, such as, of course, LDH levels of over 2x upper limit of normal, may play a role, but the rest of them, TIL seems to be able to generate response regardless of the patient's prior therapy. So this is a summary of what we had in cohort 2. We were very excited to see the data, and we are certainly excited to see the additional follow-up with these patients. And the fact that we have not reached a median DOR is certainly noteworthy for this patient population. The competitive landscape is shown on this slide. I think there, I will only highlight one item. Lenvatinib plus pembrolizumab data was presented, I believe it was at ESMO, with a 21% ORR, median DOR of 6.3% and a median OS of 13.9 months. On the cervical cancer side, this remains a significant unmet medical need. This was data that we presented at ASCO 2019. Really, available care for these patients is -- at best, is still another round of chemotherapy with 5% to 13% of response is all that we can basically offer to them at this point. Recently, a checkpoint therapy was approved. KEYTRUDA was approved in patients that have a PD-L1 high expression with an ORR of 14.3%. Our current study design is shown here on -- cohort 1 is our pivotal program. As I noted, we had enrolled our last patient into the program. From a dosing perspective, we are still waiting to dose our last patient. From a patient population perspective, at the time of ASCO 2019, we had 27 patients. Mean number of prior therapies was 2.4. The patients had received, in fact, all chemotherapy as prior therapy. They had a fairly bulky disease at baseline for this patient population. And many of them had over -- 60% of them had over 3 lesions, which is, again, a highly metastatic setting for this patient population. The treatment-emergent adverse event and the AE over time is quite consistent between cervical and melanoma. The response rate was a 44% response rate. Many of them were CRs. 3 out of the 12 responders were CRs. So we were excited to see that. Disease control rate was 85% and median number of IL-2 doses was 6. A swim lane shows a very consistent signature in terms of response for this patient population from time to response as well as depth of response. I'm going to speed up a little bit, and maybe I'll skip in on non-small cell data from Moffitt. We'll just go through Iovance's basket study where we are looking at melanoma, head and neck, non-small cell and a basket program. Our study -- this basket study started about a year ago, and we continue enrollment into various cohorts. The patients that are treatment naive, they're receiving PD-1 combination with TIL and the patients that are relapsed/refractory are receiving a new therapy that has been developed at Iovance, LN-145-S1. In terms of our next steps for our next generation of products, we are thinking about, of course, selecting more potent TIL and genetic modification. The selected TIL is now in clinic, and we will have some data, hopefully, that we can, at some point in time, share with the public. And the genetic modification work is in collaboration with Cellectis using their TALEN technology, and we continue exploring building additional genetic modifications into our TIL program. Maybe from a location perspective, I'll just remind you, we are -- corporate headquarter is in California. We have other locations. Philadelphia is where our manufacturing facility is. Tampa is where our R&D facility is. And we have a subsidiary in EU, given that our programs are also active in EU. As of our last quarter, we had $777 million cash in hand with 0 debt, and we expect to close the year with over $630 million cash in hand. I'll share with you our 2020 and 2021 milestones. A number have been completed. We still continue working very closely on initiating a non-small cell lung cancer registration-directed study as well as expected to submit our BLA in 2021. With that, I will stop, and I think I'll turn it back to Biren. Thank you.

Great. Thanks, Maria, for the overview. I guess if anyone has questions, they can reach out to you or Sara with any follow-ups. Thanks for participating.

Thank you.