Welcome. I'm Omid Hamid, a medical oncologist at the Angeles Lincoln Research Institute in Los Angeles, CA, and also Co-Director of the TIL Working Group. Today, we have a very special, experienced, and informative guest to take us through the role of TIL and what's going on. My name is Friederich Finckenstein. I'm the chief medical officer at Iovance Biotherapeutics. I joined IOVANCE in mid-2019, and in my role as the Chief Medical Officer, I'm responsible for working with all the teams that are involved with designing and executing our IOVANCE-sponsored clinical trials and clinical development efforts. Congratulations on the approval of TIL and the IOVANCE product. Can you let us know a little bit about how it's going? What has been the uptake, the benefits at this point? It's been going great.

We are super happy about having achieved this milestone together with our collaborators and the patients that helped us during the clinical development of Lifileucel and then culminating in the approval of Antagvi. Obviously, this is important because Antagvi is now the only FDA-approved treatment option for patients with advanced melanoma after anti-PD1 and targeted therapy. And that's a big deal because so far, there have just been no FDA-approved treatment options in that setting. It's also significant that Antagvi is the first and the only one-time individualized T-cell therapy to receive FDA approval for the treatment of solid tumor cancer. So, that's always been a big barrier for cell therapy, to get a step into solid tumor treatment. And for us, this is the first step. Around like how is it going specifically with Antagvi?

The, we're in the midst of the launch as you know, it's going extremely well with strong patient demand that continues to increase that we're seeing thanks to the urgency among our authorized treatment centers, the eagerness of additional centers to become an ATC and mobilizing the referral networks to drive patients to be treated at the ATC's. We have about 50 ATC's today which is really an unprecedented number for an early self-therapy launch. Many of these centers were motivated well in advance to be ready at the time of the approval and this early until the launch. Also thanks to some of the work that's been done in preparing sites and experts with educational efforts like the ones that are driven by the chill working groups. Earlier in May, we disclosed that we had more than 100 patients enrolled for treatment with Antigua. As of today, the number obviously has grown well, quite,

quite well north of that number of 100. What are the obstacles that you've seen so far? Getting the right patients selected and tumors sected? And they are key, the key factors in a, in a, in successful outcomes. And again, talking about the educational efforts by the working group that's well underway and we're working alongside the ATC's on, on, on optimization of this reimbursement needs to be mentioned here. It, it, it takes a little longer in the beginning to get coverage, but so far that's going really, really well and is accelerating. Also based on the published NCCN guidelines, manufacturing is running on track with ample capacity to fulfill the demand. We are having more capacity available for treatment centers than any other cell therapy at launch in the past. We are optimizing the capacity utilization, matching the

overall demand and working with the ATCS on using the capacity across the entire time that we have slots available. That often times requires some coordination, but it's not a problem. Where do you see this therapy going in the next few years for Melanoma? What's really important for us is to build on the current approval on the second line advanced Melanoma indication. Next steps here is to bring this therapy to patients with that indication in additional geographies and countries. So we are, we've talked about that we are submitting for review and approval to the EU fairly soon. Next plans are submissions in the UK, Canada, and Australia where we are then going to extend the launch. We are working on broader use of TIL cell therapy beyond this approval including treatment settings. And here we can talk a little more about our randomized phase three trial TILVANCE for the use of antaggy and for the

treatment of frontline indications. And then additional solid tumor indications, including non-small cell lung cancer, where we have an ongoing registrational program, and other ongoing indications building on previous experience, such as cervical cancer and head and neck cancer. Give us a little bit about TILVANCE. What are the major points here, and when do you expect to be able to present more? The data that we showed at ASCO were from a melanoma core within a larger combination effort. These were the involved patients, who were patients with checkpoint inhibitor-naive melanoma, and they were treated with a combination of TIL with added pembrolizumab. We showed results in 1/4 of 23 patients, where we saw a very encouraging rate of depth and durability of responses, with 2/3 of the patients having a confirmed response by RESIST, about 1/3 of the patients with confirmed complete response.

And that's important in the context of this setting and the context of previous data with TIL with deepening responses over time. Tumor shrinkage basically developed in all patients that were evaluated here, and nearly all responses ongoing. So it really, really encouraging, particularly knowing that we are now comparing this combination with Pembrolizumab monotherapy and the ongoing TILVANCE trial. Just going to TILVANCE, this is the ongoing phase three trial comparing the TIL plus pembro combination with pembro monotherapy. Important here, it's a randomized trial. It has dual endpoints of ORR and progression-free survival, which allow us to do an early interim analysis of the ORR results that could support an accelerated approval, as well as conversion of the current accelerated approval form tag via in the post-PD1 setting. Then the PFS endpoint could then support a full approval in the

in the front line setting. So, a really important trial for the field, for patients, and for IOVANCE. As you've succeeded in bringing TIL to approval and to many centers, you're also working on improving the product itself and have some ongoing studies there. Can you describe those and what you think they'll bring to the field? We are pursuing genetic modifications of TIL cell therapy products, not by modifying the target specificity of this. So, we're not taking a step back into approaches that would be comparable to TCR, CAR T cell therapy. But what we're doing is, by bringing in modifications of immune modulatory mechanisms, and we do that either by taking out inhibitors by knockout approaches. And IOB 4001, which is a TIL cell therapy product with a PD1 knockout, is an example for that. And we can pursue this with other checkpoints that we might

be knocking out or combinations of checkpoints. We're knocking out or we're bringing in enhancers. And we've just recently announced that we will be pursuing a TIL cell therapy part that's genetically modified to express a tethered IL12, which is obviously a really, really important cytokine. Where is the next tumor type or tumor types that you would feel you're close to getting into some approval mechanism? I mentioned before that we have pursued and are pursuing additional indications and tumor types. I think we're a lot of effort is within IOVANCE right now bringing TIL cell therapy to patients with non-small cell lung cancer. We have an ongoing single-arm registrational trial of Lifileucel in advanced non-small cell lung cancer patients that have been previously treated with standard of care frontline therapy. So that's checked benefitors plus chemotherapy. We are targeting enrollment of about 120 patients in this trial.

and are planning to have that data set support a potential supplemental BLA with the FDA initially. We have also announced that we're planning to start a phase two trial this year to investigate Lifileucel for the treatment of patients with endometrial cancers. And it's a tumor type that's relevant here because it's one of the immunosensitive tumor types where checkpoint inhibitors have been integrated as standard of care. But also because a large portion of patients in this tumor type have microsatellite instable tumors that might very well have a different component of cancer and neoantigens. So I think that's important in the context of TIL cell therapy for the field of TIL therapy. What do you see as the major obstacles that we'll have to overcome together? Having good control over the product. That's been what we have been working on for a long, long

time and where IOVANCE has now accumulated a lot of expertise, experience, but also experts working with us. I think building that out and producing products of high quality that pass the requirements that regulators have as well is really important. I think that's what we're going to continue working on: a full control and ability to manufacture and meet the demand out there. That's going to be important. That all takes time to build and then to maintain and build out, and that's what we're working on right now. I think that's important for the field across the cell therapy space, to be honest. I'm going to give you a free reign for any concluding remarks and parting thoughts. We're committed to remaining the leader in this field. And what we're working more on is innovating, developing, and delivering TIL cell therapy, right. These three pieces are really, really important.

We have shown that TIL cell therapy is an important player, an important mode of action for cancer treatment in general. We want to take it to the next level, and we talked about some of the approaches here. Developing obviously now means bringing this therapy to more patients, which means going into other cell therapy and into other tumor types and indications. And delivering is what we covered last, which is making sure that there's access. We want to continue working with our collaborators out there on our clinical trial efforts, but also with experts on the educational efforts around this. And again there, the TIL Working Group is really an important partner. So thanks for that partnership.

TIL Working Group - Dr. Friedrich Finckenstein and Dr. Omid Hamid

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