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

Good day, thank you for standing by, and welcome to the Iovance SITC Update Call. [Operator Instructions] I would now like to turn the conference over to your host, Ms. Sara Pellegrino, Vice President, Investor and Public Relations of Iovance Biotherapeutics. Please go ahead, ma'am.

Thank you, operator. Good afternoon, and thank you for joining our conference call to discuss the clinical data updates for Iovance TIL cell therapy in multiple solid tumors during SITC 2021. For today's agenda, our Interim President and CEO, Fred Vogt will do a brief introduction; Dr. Friedrich Finckenstein, our Chief Medical Officer, will highlight the key takeaways for each data set in relation to our TIL development strategy. The highlight of today's call will be clinical data updates for Iovance TIL in metastatic non-small cell lung cancer and Iovance TIL in combination with pembrolizumab in early-line cervical cancer, melanoma and head and neck cancer. We are fortunate to welcome key opinion leaders and Iovance study investigators to summarize the clinical data they just presented at SITC. Dr. Adam J. Schoenfeld, Medical Oncologist at Memorial Sloan Kettering will review clinical data for Iovance TIL in patients with metastatic non-small cell lung cancer in our IOV-COM-202 study, which was featured in a poster at SITC. We also welcome Dr. David M. O'Malley, Professor of Obstetrics and Gynecology at The Ohio State University College of Medicine and Director of the Division of Gynecologic Oncology at OSUCCC - J. He will summarize the data for Iovance TIL in combination with pembro in advanced solid tumors, which he just presented an hour ago during an oral presentation at SITC. Following the clinical data presentation, Dr. Madan Jagasia, our Senior Vice President, Medical Affairs will lead a panel discussion with Dr. Schoenfeld and O'Malley as Dr. Omid Hamid, Chief Research Immuno-Oncology at The Angeles Clinic and Research Institute and Clinic -- Iovance Clinical Study Investigator. Before we start, I would like to remind everyone that statements made during this conference call will include forward-looking statements regarding Iovance's clinical trial results, goals, business focus, business plans, clinical trials and regulatory plans and results, manufacturing capabilities, regulatory feedback and guidance, collaboration, cash position and expense guidance and future updates. Forward-looking statements are subject to numerous risks and uncertainties, many of which are beyond our control, including the risks and uncertainties described from time to time in our SEC filings. Our results may differ materially from those projected during today's call. We undertake no obligation to publicly update any forward-looking statements. With that, I will turn the call over to Fred.

Thank you, Sara, and good evening, everyone. I'm pleased to host today's call to highlight our clinical updates at SITC. SITC Annual Meeting is always very important for Iovance, and we're happy to be back in-person to share our data and connect with the physician community. We are increasingly confident in the broad potential for TIL new indications in earlier treatment settings. And I believe that the clinical data at SITC is further supportive of the development strategy for TIL in non-small cell lung cancer as well as the platform potential for TIL combinations in earlier treatment settings. The Iovance team in collaboration with Dr. Schoenfeld, O'Malley, Hamid and our study investigators did a terrific job in the abstract submissions for SITC. Our Cohort 3B and TIL combination abstracts ranked within the top 100 abstracts as scored by the SITC Review Team, which was out of nearly 1,000 accepted abstracts and is a testament to the potential power of our TIL platform and the efforts of our team to publish the data. With that as a backdrop, I'd like to turn the call over to Friedrich for a high-level takeaways.

Thank you, Fred. The data we presented at SITC this week further support our ongoing TIL [Audio Gap] non-small cell lung cancer in a diverse first set of 28 heavily treated patients, including 8 patients who had best response of progressive disease on prior ICI therapy. It is also the first experience for TIL monotherapy to show clinical benefit in a multi-center study with a centralized manufacturing process. The ORR is 21.4% in the full analysis set of 28 patients and 25% in the efficacy evaluable set of 24 patients. At the time of the data cut of one CR and one PR were ongoing at 20.7 months and 3 months respectively at a median study follow-up of 9.8 months. Both of these responses are also read forward as ongoing as of today. Responses were observed following multiple prior therapies, including tumors and tumors that were resistant to anti-PD-1 and across the range of PD-L1 expression levels, clinical characteristics and molecular features. Both of the ongoing responders, for example, had best response of progressive disease on prior anti-PD-1 therapy and include the PD-L1 negative patients as well as a patient with a KRAS mutation that is associated with more difficult to treat tumors. We believe these results validate the potential for TIL in non-small cell lung cancer and support the ongoing study, IOV-LUN-202 in second-line metastatic non-small cell lung cancer patients. TIL made demonstrated responses and durability for patients with unmet medical needs, but with fewer prior lines of therapy in the LUN-202 study. Now I would like to introduce Dr. Adam Schoenfeld. Dr. Schoenfeld is a Medical Oncologist in the Thoracic Oncology Service and Cellular Therapeutic Service at Memorial Sloan Kettering Cancer Center and the Weill Cornell Medical college. Dr. Schoenfeld leads clinical and translational research efforts to develop novel immunotherapeutic and cellular treatment strategies for patients with lung cancer and other solid tumors. He is an investigator in the metastatic non-small cell lung cancer cohorts from IOV-COM-202 and IOV-LUN-202. Today, he will review the Cohort 3B [Audio Gap].

Thanks so much, and thanks for having me here with giving me this opportunity to talk. So I'll just review some of the highlights that I think we already briefly reviewed. So here you can see the first table shown is the baseline patient characteristics and it's pretty standard for non-small cell lung cancer cohort. There are a couple of things that I would like to highlight on the baseline characteristics of the patients. First, as -- as is usually the case, most patients are former or current smokers, most commonly had adenocarcinoma as the primary histologic cell type. And PD-L1 expression range from negative to greater than 50% with all patients having been in one of the categories of negative 1% to 49% and for greater than 50%. A couple of things to highlight here, I think that's important to note is that 35% or 36% of patients actually had prior brain metastases, and prior brain metastases is a poor -- can be a poor prognostic factor in lung cancer and can be as found a more aggressive disease as well. So that's just something to highlight in this cohort and that all patients received prior immune checkpoint inhibition. TILs were most commonly harvested from lung metastases. This slide shows a table of treatment-emergent adverse events that occurred in greater than or equal to 30% of the full analysis set. And safety was primarily consistent with the underlying advanced disease and known safety profiles of the lymphodepletion and IL-2. Any great tumor harvest-related AEs were reported for 41% of patients, I mean, most commonly, they had procedural pain followed by hypoxia. And the large majority of that more tumor -- of the tumor harvested related AEs were Grade 1 or 2. And I think this is an important figure to show as well that has been shown in the other Iovance cohorts is that most AEs occurred prior to or within the first 2 weeks after TIL infusion, and since this is a one-time treatment following that infusion period, patients are generally free from toxicity. And also that the median number of doses for patients receiving IL-2 was 5.5, which is similar to the 6 [ missing ] doses that patients have received with melanoma, suggesting that patients can really tolerate the IL-2 in lung cancer. Here shown is the table of the efficacy data, and I'll summarize the data both in the full analysis set and the efficacy evaluable set. So the overall response rate was 21.4%. This includes 6 partial or complete responses. We had one patient with a complete metabolic response, 5 patients with partial responses, and there were 12 patients with stable disease. And the efficacy evaluable set, the patients who were able to undergo imaging and follow-up, the overall response rate was 25% and the disease control rate was 75%. It's notable that all responders received 2 or greater prior lines of systemic therapy. The median time from resection to infusion was 35 days, and the median time from infusion to best overall response was 2.2 months. And here also highlights the best percentage change from baseline and target lesions and sum of diameters in the efficacy evaluable set. And as you can see from this figure, most patients had some degree of shrinkage in their target lesions. And here shows more granular details of time to first response, duration of response and time on efficacy assessment for confirmed responders who achieved PR, or partial response, or better. As you can see, most patients received 2 or greater -- most patients received 2 or greater lines of therapy, 3 patients had -- who had received prior checkpoint inhibition had progressive disease as their best response. PD-L1 expression ranged from 0 to greater than 50%, and 2 of our responders had PD-L1 negative, including the patient that had a response now ongoing past 20.7 months, and one patient continues to have a response -- duration of response at 3 months, which we'll talk more about on the next slide. So here tracks the patient's target lesion at each assessment, and the patient I want to highlight is patient 17, as you can see, this patient has had a deepening response over time. So technically, it wasn't called a partial response until many weeks into treatment, but has clearly had clinical benefit for 6-plus months at this point in time. So in summary, this is a signal finding study which demonstrated feasibility of tumor harvest, TIL manufacturing until treatment in patients with advanced non-small cell lung cancer, the patient's tolerated surgical resection, including pulmonary lesions, TIL manufacturing was feasible for most patients, and one-time treatment with LN-145 treatment with conditioning regimen was well tolerated. Moving forward, TIL cell therapy is the potentially viable treatment option for patients with advanced non-small cell lung cancer, and the study IOV-LUN-202 was designed to enroll patients with lung cancer with an unmet medical need, but with fewer prior lines of therapy to maximize the potential for more sustained responses.

Thank you very much, Dr. Schoenfeld. We are very encouraged by the Cohort 3B data and our advancement of TIL in non-small cell lung cancer. Right now in the IOV-LUN-202 study, the design of which is shown on this slide, we have treated patients and plan to enroll approximately 95 patients. This is a second-line patient population that has received only one prior line of therapy with immune checkpoint inhibitor plus chemotherapy, and we have excluded driver mutation. The 2 main cohorts in this study are further divided by PD-L1 high and low status prior to their first-line of therapies. And we have a third cohort that will receive TIL harvested from biopsy and manufactured our 16-day Gen 3 manufacturing process. Given this patient population has less prior treatment, we believe TIL has the potential to deliver more responses with longer durability. We also continue to enroll even earlier ICI-naive patients in our ongoing basket study to receive TIL plus pembrolizumab. Overall, we are confident and committed to advancing both TIL alone and TIL combination to address multiple non-small cell lung cancer patient population. Next, I would like to turn our attention towards clinical data for TIL plus pembro in advanced solid tumors. We believe the clinical data validates the combination of checkpoint inhibition and TIL cell therapy as a potential platform in solid tumors. We know that novel early-line combination therapies are needed for patients with solid tumors to improve rate and depth of responses with manageable long-term safety. In the ICI-naive setting, TIL and pembro produced encouraging efficacy with expected safety in patients with advanced melanoma, head and neck cancer and cervical cancer, an ORR of 57% in cervical cancer, 60% in melanoma and 39% in head and neck cancer represent a meaningful increase in responses versus pembrolizumab alone. Early-line treatment with single-agent pembro achieved an overall response rate of 33% in patients with advanced melanoma and 17% in patients with head and neck cancer. Cervical cancer patients previously treated with standard of care chemotherapy achieved an ORR of 11% to 14% with pembro monotherapy. Notably, the 30% CR rate in melanoma compares to 6% CR rate for pembro alone. We also note that one unconfirmed CR and 2 metabolic CRs have converted to 3 confirmed CRs per RECIST 1 in this data cut. Overall, these data supports continued development of TIL combinations as earlier treatment in melanoma, head and neck, cervical, non-small cell lung and other solid tumor cancers. Now I'm pleased to welcome Dr. David O'Malley to summarize the data from his oral presentation at SITC. Dr. O'Malley is a Professor of Obstetrics and Gynecology at The Ohio State University College of Medicine and the Division Director of Gynecologic Oncology within The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute. During his tenure, he has developed the gynecologic oncology division into one of the premier clinical research programs in the country. A talented surgeon and clinician, Dr. O'Malley has been a productive investigator, having published over 150 articles in the most prestigious medical and oncology-focused journals. He has served as principal investigator for multiple national and international trials, including the Iovance C-145-04 study in cervical cancer. Dr. O'Malley?

Well, thank you, and thank you for that wonderful introduction. I just look at that picture myself and remember when I used to have hair and my beard was black. But with that, we have -- I want to start with the background. So immune checkpoint inhibitors that become the standard of care for treating patients with a variety of advanced cancers, as you know, including melanoma, head and neck cancer and cervical cancer. lifileucel and LN-145 are a one-time autologous adoptive cell therapies using TIL that have demonstrated encouraging efficacy and acceptable safety as monotherapy in clinical trials of these patients in the post checkpoint inhibitor setting. Earlier-line treatment with a single-agent pembro has demonstrated about 33% objective response rate in patients with melanoma and 17% in patients with head and neck cancer. To provide an earlier-line treatment option, we explore TIL cell therapy with lifileucel or LN-145 combined with pembro on patients with checkpoint inhibitor naive advanced melanoma, head and neck cancer and cervix cancer. COM-202 and C-145-04, our ongoing Phase II multicenter, multi-cohort prospective open label studies with Iovance TIL cell therapy in patients with solid tumors. We report efficacy and safety from Cohorts 1A and 2A of studies COM-202 and Cohort 3 of Study 145-04, which are enrolling patients with melanoma, head and neck cancer and cervical cancer respectively. Patient including criteria and study endpoints are included in the slide. Both trials assessed -- both trials assess safety and efficacy. It is important to note that 1.5-centimeter resectable lesion is needed to be present in addition to the RECIST 1.1 measurable lesion. Here is the study Schema. Treatment includes tumor resection for TIL manufacturing, followed by one dose of pembro, the non-myeloablative lymphodepletion, followed by TIL infusion, up to 6 IL-2 doses given every 8 to 12 hours. After the patients recovered from side effects, the pembro has continued for up to 24 months. As we move to the baseline demographics, as you see as of September 22, 2021, 10 patients with melanoma, 18 patients with head and neck cancer and 14 patients with cervical cancer enrolled in treating these cohorts. As shown on this table, patient characteristics at baseline were consistent with the requirement of checkpoint inhibitor naive disease for patients with melanoma head and neck cancer and the requirement for only chemoradiation or surgery for local regional disease for patients with cervical cancer. Despite relatively early-line treatment, patients had a higher tumor burden at baseline and all patients in the cervical cohort had distant metastases at the time of study entry. Here we see treatment-emergent adverse events reporting greater than or equal to 30% of patients overall. Treatment-emergent adverse events were consistent with the underlying advanced disease and known safety profiles of pembro in non-myeloablative lymphodepletion as well as IL-2. 5 Grade 5 events were reported. All were assessed not related or not likely related to TIL or pembro therapy, 2 were felt to be related to lymphodepletion, and one was related to lymphodepletion and IL-2, 2 were felt to be unrelated to treatments. Here we see the frequency of adverse events over time separated by cohort. AEs were generally transient and temporally associated with pembro, lymphodepletion and IL-2 administration. Most events occurred prior to or within the first 2 weeks after the TIL infusion. The mean number of IL-2 doses was 5 or 5.5 in each cohort. In the full analysis set which consisted of all patients who received TIL therapy and pembro, the objective response rate as assessed by investigator was 60% in the melanoma cohort, 39% in the head and neck cohort, and 57% in the cervical cohort. Of note, the complete response rate in the melanoma cohort was 30%. In the efficacy evaluable set seen on the bottom 2 rows, which includes only those patients who reached the first efficacy assessment at the time of the data cut, the objective response rates were 67%, 44% and 57%, respectively. The median study follow-up was 11.5 months for melanoma, 7.8 months for head and neck and 7.6 months for cervical. The waterfall plot a best overall response by cohort demonstrates that nearly all of the efficacy evaluable patients had some degree of reduction from baseline tumor burden. The green bars represent patients achieving a complete response, hash green denotes unconfirmed complete response, blue indicates partial response and hash blue indicates unconfirmed partial response. It's important to note that these unconfirmed responses at the time of the data cut, they've not yet had their confirmatory [ CAT scan ]. In this figure, we see time to response and duration response. The timing of pembro doses are indicated with blue circles. Time to response is typically by first assessment at around week 6 after TIL infusion with several deepening over time as indicated by the blue and green triangle. Most were -- responses were ongoing at the time of the data cut off as you can see by the arrow. These spider plots show percent change from baseline and target lesions for each individual patient colored according to the best response. Patient responses were durable and deepened over time for many patients. In conclusion, the combination of lifileucel or LN-145 plus pembro produced encouraging efficacy with expected safety in patients with advanced melanoma, head and neck cancer and cervical cancer in the -- in early-line setting. Notably, nearly all efficacy evaluable patients experienced a reduction in tumor burden. Very important to note, nearly all efficacy evaluable patients experienced reduction in tumor burden with objective responses for investigator assessed RECIST 1.1 observed in 39% to 60% of patients. Rates that are similar to prior reports for the combination and that are somewhat unprecedented in some of these tumor types. This included a 30% complete response rate in the melanoma cohort. With these data, we now have support for the efficacy and safety of TIL cell therapy with lifileucel and LN-145 in multiple solid tumor types and lines of therapy, both as a monotherapy in combination with checkpoint inhibitors, strengthening the promise of this potentially best-in-class IO combination for patients with advanced cancer. The combination of TIL checkpoint inhibitor warrants continued investigation of patients with advanced cancer, the ongoing studies. Thank you for your attention.

Thank you, Dr. O'Malley. Following the data summaries from SITC, I would like to ask Madan Jagasia, our Senior Vice President of Medical Affairs, to lead the panel with Dr. Schoenfeld and O'Malley as well as Dr. Omid Hamid, who is here to offer his perspectives on melanoma. Madan?

Thank you, Friedrich. I'm pleased to moderate a brief panel today to hear further perspectives on unmet need and the potential for TIL to address some of these needs. As Friedrich mentioned, Dr. O'Malley and Schoenfeld will also be joined by Dr. Hamid. As the Director of the Melanoma Center and Phase I Immuno-Oncology Program at The Angeles Clinic and Research Institute, Dr. Hamid has been instrumental in bringing new therapies from the investigation lab to the clinic for patient benefit and building immuno-oncology therapies such as PD-1 inhibitors and other checkpoint inhibitor therapy against tumor angiogenesis and targeted agents. He has presented research done at The Angeles Clinic at major national and international meetings and published manuscripts abstract and reviews on immunotherapy, targeted therapy and melanoma care in prestigious journals. Dr. Hamid has been a principal investigator in our C-144-01 clinical study and lead author on several of the publications and presentations at medical meetings. I would first like to ask each of you what you believe are the most significant unmet needs in cervical, melanoma and non-small cell lung cancer. Dr. O'Malley?

The first unmet need is curing more patients, and particularly in those frontline patients with metastatic and recurrent disease. So the first-line setting identifying patients who are going to benefit more and are cured of their disease. Then followed by post IO treatment, for those who have been exposed and have already received IO therapy, then what are the next options for those patients.

Thank you, Dr. O'Malley. Dr. Hamid?

I will agree with what Dr. O'Malley has said. But in melanoma, we have a little bit more data to go on. I think in the refractory population, so those that don't ever respond to PD-1 were having issues in finding the appropriate therapy. And from the initial trials in melanoma, we're seeing high response rates on patients whose best responses to PD-1 therapy or progressive disease, that's where I think the bright light of this therapy shines for melanoma. Additionally, we'd like to have therapies that in the first-line bring us closer to a durable response. And what we're learning in melanoma understanding what types of therapy you get is that those patients who get a complete response or a partial response that's negative on PET, those are the ones that do the best in the long-term, and that's what we're seeing in the first-line combination trial. Additionally, we'd like to decrease toxicity. And unfortunately, the combination that's leading in melanoma, despite giving us high response rates and durability is associated again with 55% Grade 3 or 4 toxicity. That's also important in melanoma, where chemotherapy is not the major therapy and targeted agents are being pushed further and further back. If you have a toxicity in your first-line therapy that almost ensures that you are excluded from clinical trials moving forward. So what we're seeing with this PD-1 Iovance trial in the first-line is lower toxicity, higher response rate, higher complete response and the host of durability.

Thank you, Hamid. Dr. Schoenfeld?

Thank you. Yes. I agree with the other 2 speakers here. I think they were transient across tumor types. In lung cancer, if we look in the metastatic setting, immunotherapy with or without chemotherapy has really revolutionized the treatment of patients in the first-line setting, but most patients still really do not respond to treatment or they develop resistance over time. The objective response rate is less than 50%. It's worse for patients who are PD-L1 negative or PD-L1 low, and the median duration of response is less than a year. In the second and later line setting, we're assigned to single-agent, primarily single-agent chemotherapies, where they had a really poor response rate and high toxicity. So I think a great place that we need newer therapies is in the second-line setting. And there's been numerous trials of other immune modulation that unfortunately have not had success in lung cancer to-date. And so I think this is an opportune time for innovation in lung cancer in that setting.

Thank you, Adam. So given these unmet needs that you've described as well as your experience with TIL, how do you believe TIL may fit into your practice? I will note that each of you is involved with a lot of clinical studies to investigate promising agents. So for the purpose of today's call, I will ask you to speak specifically to TIL. So a question to you, Dr. O'Malley, where do you believe TIL may fit into your practice?

Yes, yes. There's a lot of the discussion after the oral today with some of the most recent data with KEYNOTE-826 and looking at the combination of platinum doublets with IO, plus or minus bev, and it's important to note that, that indication was in only on those PD-L1 positive patients. So clearly, the first-line setting in PD-L1 negative, but also is the chronicity of therapy which is required is quite challenging, particularly in cervix cancer patients that are really under resourced. So in some ways, a more intensive therapy which could -- that could be completed sooner maybe quite beneficial to patients. Obviously, as I said earlier, the post IO exposure, you look at the -- those patients who go on to require systemic therapy that about 80% of them had local regional disease to begin with. And so those patients if one of these several trials which are ongoing are positive for local regional disease will all be exposed to IO therapy. So once again that post IO exposure is going to be so important, as Adam was saying in that second-line and greater to offer options. Omid, I think really eloquently said with regards to our patients who don't have response, we all see those in our practice across our solid tumors.

Omid, back to you. So how do you believe TIL may fit into your practice?

Well, it's not a belief, I've been told by my patients that TIL is fitting into my practice. They are voting with their treatment is the durability of response, the high response rate post failure of a PD-1 containing regimen and the indications from our initial trials in patients who have seen anti-CTLA-4, anti-PD-1 and the targeted agent makes this a very viable option for patients and one they are looking for every day. Where it will fit in our research program is that it will push other agents aside as we work together to find the optimal therapeutic regimens and combinations that will increase benefit and durability for patients. And I love what Dr. O'Malley said, the ability to get a dose-dense regimen in and be done with it. And the concern for our patients is that they will continue to have decremented performance status, and they understand that this type of therapy should be moved earlier in their therapeutic regimen, that's what they're telling us.

Excellent. Thank you. Adam, where do you think that TIL fits into your practice in lung cancer?

Thanks. Yes. I think the most obvious place to start in lung cancer would be after treatment with immunotherapy with or without chemotherapy. So in the second-line setting where our treatment options are incredibly limited, and so I think that would be a great place to start. But I honestly think there are multiple places that TIL therapy could be used. Lung cancer is a very heterogeneous disease and there's multiple different subtypes. There's groups of lung cancer patients who have oncogene drivers such as EGFR, ALK mutations, who traditionally do not respond to checkpoint inhibition. There's also patients who are PD-L1 negative who traditionally do not respond to checkpoint inhibition. So I think those are also great places to explore the use of TIL therapy. And I think the early data really suggests that the traditional biomarkers of response to checkpoint inhibition may not be -- may not translate to TIL therapy. So I think all of those places are good places to start.

Excellent. Thank you. So we'll turn it over to the operator to read the Q&A instruction.

[Operator Instructions] And your first question comes from the line of Mark Breidenbach from Oppenheimer.

Just a couple of quick ones for me. First of all, to Dr. O'Malley, I'm wondering in the cervical trial, did the responses you saw depend on PD-L1 expression, you mentioned PD-L1 negativity as an area of potential unmet need given recent changes in the landscape? Second question for me is with regard to the lung cohort. There was a fairly high fraction of patients screened for enrollment, but does not meet eligibility criteria, and then there was another drop-off in patients who had tumor resected versus those who actually received treatment, perhaps you -- Iovance or the panel can comment on the main reasons for screening failures as well as dropouts from the intent to treat population, and how this level of attrition compares to what you've seen in other TIL trials, trying to get a sense of it's very indication specific or not?

I'll start, it's Dave O'Malley. So I think as we look at this in a cervical cancer cohort in the first-line setting, there's only 14 patients. So at this point, we -- I -- we have not reported with regards to PD-L1 positive negative and response rates, as you -- you did see that there were patients included, but to sub -- to break those down right now, I think would be premature with such small numbers in this initial cohort. Obviously, in time, we'll report those in the larger cohorts and look forward to look at that data in the future.

All right. Any comments from you, Friedrich?

Go ahead, Adam?

Great. Yes. So I can go through both the screen failures and then the patients, the 11 patients who do not receive treatment. So the screen failures to me is not surprising. It shows there's a demand for the study and the need for -- when we're first exploring TIL therapy in a new patient population, the need to abide by our inclusion and exclusion criteria, so patients didn't meet inclusion or exclusion criteria weren't -- did not move forward with the study. And I think that is totally appropriate in this case and it doesn't seem surprising to me. The -- in terms of the 11 patients that did not receive TIL therapy among the 39, so I think breaking it into separate categories is helpful. So there were 5 patients, only give patients who do not have TIL available. Among those patients, 3 had potentially low or very low TIL infiltrate, one was contaminated and one wasn't a product per the site, but the manufacturing was attempted and no TIL was present. And then there were 6 other patients that did not receive TIL, 2 had progressive disease, 1 passed away, and 2 decided for other reasons to not take part, and 1 patient had an universe of that. So I think it's helpful to break it into those 2 separate kind of sub cohorts of patients who didn't go on to TIL.

And is that sort of representative or typical of other TIL therapy trials?

I think -- typically, I think the manufacturing rate has been 90% or 90%, and this is 87.5%, which in lung cancer I think is really good. I think it will be interesting to see in IOV-LUN-202, if you have an earlier patients who are earlier on in their treatment, whether you might have a higher manufacturing success rate, I think exploring if there are any sites of disease that potentially could be associated with manufacturing failure, but what we really saw is that you can manufacture from lung sites in most patients. And so I think the success -- the manufacturing success rate was very high in my opinion and on par with other studies. And then -- yes, and then the other question that you had was just other classes. And some patients are going to progress between the time of TIL resection and treatment. And so there were a few patients that, that happened, too.

And your next question comes from the line of Boris Peaker from Cowen.

Great. I have 2 questions, and let's start with maybe Dr. O'Malley. Dr. O'Malley, in melanoma in Cohort 1A, we saw a response rate of 86% or 6 out of 7 responders that was back at ASCO, and so now we're up to 10 patients, and there's still only 6 responses, which is why the response rate declined to 60%. I'm just curious, can you say whether the newly added patients had enough follow-up to confirm whether there are responses or not or there was just not enough follow-up to make that assessment?

Go ahead.

Yes. I think I -- this is Friedrich, thanks, and maybe I can answer that. So you're rightly pointing out what has changed from last time when we presented these data, and you're right, we added 3 patients to the study. In the meantime, with these 3 patients, we had reported an abstract at which we reported one additional responder with one added patient that additional responder did not confirm. So that's one of the stable disease patients, and then the other 2 patients that we added also have stable disease. But you rightly point out, these are most recently added as of between the last time we presented at the time we published the abstract in now this presentation. So there is room. We do see responders that happen over time. So we do need more follow-up here.

Great. And my next question is maybe broadly, we always talk about partial responses and complete responses and understandably those are very meaningful results. But there's a lot of patients that are getting stable disease here. And I know chemotherapy stable disease maybe as not counted for a lot, but I'm just curious, in TIL therapy or immunotherapy in general, how valuable is the stable disease patients, how durable are these stable disease across various tumor types, I'm not focused on any particular malignancy?

Yes. This is one thing that we struggle with all the time is what to make a stable disease, and there's probably a group that biologically is responding and a group that is biologically slowly progressing and how do you distinguish those 2, and what is the best criteria really to use in immunotherapy for measuring response. I think in lung cancer, I can say that stable disease that over a long periods of time is clinical benefit, and patients who have tumors, some degree of tumor shrinkage and stability and maintain their performance status, I consider that valuable clinical benefits that patients are having. And so I think it's really tricky in some of these cases to use duration of response as a surrogate for clinical benefit because as you -- as we saw with some of the patients in lung cancer, the patient -- the responses can deepen over time. And so your duration of response is going to be more limited too.

So I would just like to point out that in the melanoma experience, we have extensive reviews to evaluate what stable disease postural response and complete response mean based on the KEYNOTE trials with anti-PD-1 that has been published and in the CheckMate trials with combination with anti-PD-1 CTLA-4. And it really shows that those patients who have confirmed stability ongoing do worse in the long-term than patients who have a good partial response, and again, the best are patients who have a complete response. And what we have now are turning to is trying to get our patients even though we're on a therapy with a stability of disease into a deeper response and that may translate into greater benefits. So the 30% CR rate here is important. The ability to bring in TIL in heavily pretreated patients to get them to CRs that we've seen that in our trial is important. And additionally, this trial initially looked at those patients who didn't achieve a radiographic CR and had a PET CR, in our experience, a PET CR is equivalent to a radiographic CR. So that speaks to the benefit of this regimen and this combination therapy.

The only thing I'd add to my esteemed colleagues is that question, and one of the things I drew the attention to the waterfall plot that the stability of disease the patient with disease regression clearly is a clinical benefit. Ultimately, the duration and potentially impact on survival will be the gold standard factor. So when you're seeing regression disease, you're seeing symptomatic improvement and improvement in the quality of life that we know that if we shrink disease, patients have better quality of life, even though it doesn't meet that bar of 30% that the agency holds us to on the PR. So it's a very good point. Ultimately, the clinical benefit in that continued sustained stable disease can be important getting back.

Well, Friedrich has a comment on this as well. Friedrich?

Yes, I just wanted to point out 2 observations in our programs, where I just wanted to pick up on something that Dr. Hamid said about metabolic CRs. We are now seeing examples where patients with initial metabolic CRs are converting to complete radiographic CRs as well. So I think that is important to know, obviously, one of the values of PET imaging and looking at metabolic responses that we're seeing things a little earlier. I think that's an important background as you're looking at some of the data that we're generating with that modality too.

Excellent. Thank you.

And your next question comes from the line of Michael Yee from Jefferies.

Question on lung cancer and then a question on melanoma. In lung cancer, maybe it's for Dr. Schoenfeld, could you comment about your thoughts around the second-line data in the context of, for example, other alternatives, such as chemo? How do you expect second-line to play out ultimately here if this data went to a pivotal study? And then what is your read through to first-line, which is ongoing with PD-1, given all the data to-date, how are you thinking about first-line and the results in PD-1 combo? And I have a follow-up on that.

Yes, yes, this to me is really a proof of principal signal finding study in a really heavily appreciated patient population. I can speak for my personal experience that I had patients that were extremely heavily pretreated and barely met the inclusion criteria and progressing quite quickly. And one patient has an ongoing response for many months now off of any treatments with the patient that's had the deepening response. And then another patient who had a partial response for -- or PFS for essentially 6 months continues to have benefit. And that's just not the type of benefit we see with chemotherapy. So I'm really excited to see what will happen when we go into the second-line study, the IOV-LUN-202. And if we have a healthier patient population combined with a TIL product that's probably less exhausted and more of a stammer memory like phenotype that maybe will get a higher response rate and more durable responses. But honestly with 6 patients and to see this durable response greater than -- close to 2 years and another one that's ongoing patient now for 9 to 10 months is really exciting to me. And it's on par with what Ben Creelan saw in his Nature Medicine paper where he saw 2 complete responses as well for greater than a year. So I'm very excited about the second-line space here, and I think it could be a huge contribution to patients. For the first-line setting, it's a totally different story. I'm just interested to really see the dynamics of combination with PD-1 blockade similar to what they've shown here in melanoma cervical cancer is potentially, it can be synergistic and add benefit. So and you're additionally getting patients who are earlier on our treatment regimen unless treatment exposed, and Ben Creelan's data in Nature Medicine, these are patients who have not PD-1 experience. So you're getting that type of data as well. So it will be interesting to compare and look forward.

And my question for the -- for melanoma, and maybe it's for the company. Can you just remind us about the ongoing pivotal Cohort 4, what have you said about timing guidance of finally releasing those results? I know you had disclosure back in the past. I know there's been some comments in the 10-Q filings as well about Cohort 4 versus Cohort 2. So -- because investors ask questions about it, could you just remind us how you think about Cohort 4 and when the data would come?

Sure, Michael. This is Fred, I can answer that one. So that's tied to our IRC reads in the process of filing up BLA. The plan there is to basically commence that work, and then at some point, we'll have the IRC read Cohort 4 data set in a condition that we could put it out, and of course, that will be also the [indiscernible] for the BLA. That's time to our BLA timings, which are first half of next year. And all we can say right now is stay tuned and we'll hopefully have more information pretty soon on that.

And your next question comes from the line of Reni Benjamin.

And congratulations on the data. A couple for me. Can you -- you have several unconfirmed CRs and PRs as of the data cutoff. I just wanted to know have they subsequently been confirmed? Number one. And then I know that you had talked to the panel about where TILs might ultimately find their way in each indication. I'm just kind of curious how the physicians might ultimately choose between either mono or combo as they evaluate kind of both within their each therapeutic indication? And then kind of finally, can you talk a little bit about the Grade 5 events, what is happening there, and is there any learnings there that you might be able to -- anything you might be able to implement to mitigate that?

All right. So we, I think in that 3 questions, the first is the unconfirmed PR, unconfirmed CR, so I'm going to give that to Friedrich to try and tackle that.

Yes. We haven't cut the data. We haven't cut the data yet again, so I don't think that I can comment on this. But again, what you have to keep in mind as we are presenting data like this, we're cutting a live database, these patients are on their observation. They are sometimes in for like in the first assessment we are following them. Many of these patients are confirming, but I can't comment on the data as we have them right now.

The second question that was posed is and I'll probably pass that over to Dr. Hamid for melanoma is TIL monotherapy versus TIL as single therapy, how do you sort of compare and contrast, how would you be using that?

So I think at this point, TIL availability is how you will compare and contrast that, so -- and a discussion with patients. But we're open to a clinical protocol that would allow us to do upfront TIL therapy after an extensive discussion about options with patients. As you'll know, in melanoma, there are approved first-line therapies and multiple clinical trials. So it's an extensive discussion with patients and also in patients who are willing to have the resection and wait for that to begin. We've shown that we can turn it around within 3 weeks. We've shown that you can harvest from any site and get viable TIL, and it is something that is in the forefront of their thoughts. So I would say that it's only limited by the availability of the clinical protocols and the slots on trial.

Thank you, Hamid. And I can take, Michael, the Grade 5 event. So I think that your question is probably at the presentation on the TIL plus pembro. So we had a total of 5 Grade 5 events, one Grade 5 event was in Cohort 1A, where it was attributed to sepsis, it was felt to be related to cyclophosphamide, fludarabine and IL-2 and not attributed to TIL all or pembro. The 4 patients were in the head and neck cohort, Cohort 2A, and these patients actually fall and sort of 2 sort of teams. There are 2 patients which have progressed beyond. And so let me sort of back up a little bit, our definition of treatment-emergent adverse event varies by the protocol. So in the single therapy arm, the definition of treatment-emergent adverse event is from TIL infusion until day-30 post TIL. But in the combination arm, since the intervention starts with the pembro after harvest, the clock starts there, and so these patients continue on pembro after the TIL infusion, the time horizon continues. So you've got more opportunities to "be classified as a treatment-emergent adverse event." So keeping that sort of context in mind, I think it's important to kind of keep that. So in head and neck, there were 2 events that were deemed related to cy/flu, but not TIL pembro or IL-2. And there were 2 events that were unrelated to any study therapy that basically happened one at day-62 and the other at day-212. So these were late events not attributed to the regimen at all and attributed just to the disease.

Yes. So the only thing I would add to that is that last point is important, which is 2 of the 5 were seemed to be clearly related to disease, but with the way they reported, they look like they're treatment related. So that really leaves the 3 patients as we said, and we continue to move forward with supportive care in this technology, particularly on the IL-2. So as we look at these patients, that is the -- often where we have the toxicities. And so additional knowledge as we move forward will be very important with regards to management toxicity with the IL-2.

Got it. And just in the non-small cell lung cancer study, just a quick one. I think during the presentation, you mentioned that some of the patients had brain metastases coming into the study, do you have any sort of analysis or any thoughts regarding TIL's impact on brain metastases?

Yes, this is Madan. I don't think we have the data currently in non-small cell lung cancer, but actually at the presentation, Stephanie Goff presented just prior to Dr. David O'Malley and actually showed data that in melanoma, there is documented in literature that brain metastases can regress after TIL therapy. So we know that the TILs actually cross the blood-brain barrier and can "effect responses in -- parenchymally in the brain."

Actually that's been reported, that was really interesting because, obviously, that's a concern for us with regards to the crossing the blood-brain barriers. So that's from a proof of principal standpoint is extremely important as we move forward.

And your next question comes from the line of Peter Lawson from Barclays.

I guess a couple of questions on lung data. Just your thoughts on the initial durability and what you think could be impacting durability, if that's kind of the exact reason in late-stage patients. And I've got another follow-up?

Yes. So let me restate the question, Peter, I make sure I got this right. So the question is, what are the factors that may impact durability? Adam, would you like to answer that?

Yes, yes. So I think one thing that potentially will impact durability is the number of prior lines of therapy the patient has had. Unlike in melanoma, these patients are -- typically are treated with multiple chemotherapy regimens in addition to immunotherapy. And by the time they were enrolled on the trial, their performance status could have been quite limited, and I think that also could potentially affect the phenotype of the TIL product as well. So I think earlier TIL resections could potentially have a more active TIL product as well. Additionally, still with that, I thought -- I heard about the durability is actually quite impressive in some of the patients. So they're looking at the patient with the complete metabolic response, who has had a response ongoing for 20-plus months, the other patients had the deepening response that's ongoing. And then if you really look at, I think better thing to look at and even the duration of response, the progression-free survival at the time to the next treatment regimen. And I think those are definitely better than what you would see with chemotherapy regimens.

And I just will add to that, the same question could be asked in the data which I presented, and it's really important to keep in mind this is that our median follow-up is quite short with melanoma, 11.5 and 7.5 months -- about 7.5 months on the head and neck and cervix. So very preliminary data with regards to this earlier lines of therapy. And we -- as you can see in the swimmers plot with the arrows, most patients with the PR or CR are ongoing at the time of this data cut.

Great. And just I guess a follow-up just around tumor heterogeneity and the location of the tumor, and if that impacts the TIL efficacy? And if you think that's worse in whether that's lung or head, neck or melanoma? Any comments about that would be great.

Yes, Peter, I can take that. So as we had reported at ASCO '21, when we looked at Cohort 266 patients, we classified the anatomic side of resections to skin subcutaneous lymph node and visceral organ and the site of anatomic resection did not influence either the TIL dose and the TIL dose did not affect the sum of diameter change. So at least in that limited data set of melanoma, where we've looked at this very systematically, we could not see an impact of the anatomic location on the TIL dose or efficacy.

So, obviously, important question moving forward across -- especially across tumor types, and we'll be able to learn from each other with regards to heterogeneity as well as the best areas for resection moving forward.

And do you think that site of anatomic on location is also important for lung cancers?

I think it's definitely possible. It could be -- I think it's something worth looking into more deeply in the lung 202 Cohort. My feeling though is probably more exposure to prior therapy is a bigger component that was at play here. Omid has comment?

Yes, I would agree with that anyway. We at Angeles harvested from multiple sites and had no issues, and actually reinduced an patient after progression on melanoma and reharvested a site after multiple immuno-oncological and chemotherapeutic treatments. But I have no doubt that we'll find more and more of that as the patients are more heavily treated that their T-cells will be more exhausted, and it would be a difficult T-cell expansion.

And your next question comes from the line of Ben Burnett from Stifel.

I had a question for Dr. O'Malley on cervical cancer. Can you talk about the standard of care? And I think you kind of alluded to this a little bit before the Q&A, but just the extent to which you use or plan to use chemo plus pembro? And then also for the company, is there an appetite to maybe look at a triplet of pembro, chemo and TIL in cervical cancer?

Well, I mean, the landscape in cervix cancer is changing rapidly, particularly the KEYNOTE 826 recent, both leading to approval as well as the recent reporting New England Journal of Medicine article, so the upfront therapy with pembro is clearly going to be impactful in moving forward into where TIL therapy will fit, that, that will fit to as an adjunct versus replace or an after IO therapy. So that's obviously extremely important moving forward for positioning and patient selection.

And Friedrich's got a comment.

Yes, I can maybe comment on your question around the combination triplets. So that would mean having to identify a rational sequence and rational timing of the TIL regimen versus chemotherapy, that's something that we have not done yet. We would have to think about how to line this up, but I do think there are options that we could consider. Keep in mind, what we have to do, thinking about the ability to harvest tumor having T-cells around that are not impacted by the chemotherapy. So it's something that we're considering and thinking about.

Okay, very helpful. And then just one quick question Dr. -- for Dr. Schoenfeld. I think this question was asked in regards to cervical cancer, but were there any trends in response or durability in the lung cancer go forward with PD-L1 status?

So there were responses across PD-L1 status. So there were 2 responses that were PD-L1 negative, there's responses that were PD-L1 low and there's responses that were PD-L1 high. And I think the biology of TIL therapy that makes sense to me. The PD-L1 expression may not be a good marker -- a predictive marker like it is for checkpoint inhibition.

And that would be consistent with our observations in melanoma, right. So we have, I think now a very healthy data set there in which we show that PD-L1 status is, in a way, predictive for benefit from TIL therapy, which speaks to TIL therapy being a differentiated immunotherapy mechanism of action. It works differently, and it doesn't have the same tendency as immune checkpoint inhibition.

I would say it also speaks to the fact that these are going to -- there are going to be biomarkers that will identify patients who are going to be resistant, primarily resistant, and that will move TIL into the first-line for patients with melanoma.

It is somewhat the rationale for the study design of LUN-202, where we have divided the cohorts by PD-L1 status prior to their first-line regimen. So we are not expecting impact on the ability -- on the activity of TIL directly, but rather indirectly possibly by determining the cause of the disease and the response to first-line chemoimmunotherapy.

And your next question comes from the line of Colleen Kusy from Baird.

Thanks for taking our questions and all the updates today. Looking at the TCR repertoire data from the waterline lung update, do you mean TCR clones look to be a little bit lower in lung than what you reported in melanoma and cervical. Just curious if you have any thoughts on what might be driving that and what kind of impact do you think that might be having? And then I have a follow-up.

Yes. I wouldn't make much of that to be honest. I think TCR repertoire data is interesting to look at. And this clearly shows there's polyclonal population of cells that are -- there's 4,000 plus. When I think TCR repertoire data and diversity data gets particularly interesting is when you monitor it over time and you see changes in diversity and whether there's clonal expansion. So I think this is a good place to start just to show the polyclonal repertoire as we've seen at other tumor types, but really there's a lot more translational work and analysis that can be done from there.

And Colleen, this is Madan. So statistically, they are actually -- they are overlapping. So even if you look at the clonality and the entropy index and the median number of clones, and I think we put out with the footnote over there in the poster, we benchmark it against the cervical and the melanoma data on TCR that we published a couple of years ago. So it's completely overlapping. So I wouldn't make a statement that, that is lower in lung cancer.

Okay, great. That's really helpful. And then I think it was reported that there was an average day of 35 for the manufacturing from resection to infusion in the later-line lung. Just curious as to kind of the difference there between the 22 days expected for Gen 2?

Yes, so 22 days, right, is the time line, not including what operational workflow the institution has. So whether there's a bed available, when they can admit the patient, if they're allowing for lymphodepletion prior or after receipt of the product. So it involves every component up until the treatment with TIL. So to me, 35 days, it sounds pretty good and pretty short with the 22-day manufacturing process.

And your next question comes from the line of Madhu Kumar from Goldman Sachs.

I have a couple of bookkeeping questions to start out with and then a couple of bigger picture questions. So bookkeeping questions for the company, what fraction of the head and neck cancer responders had prior platinum chemotherapy?

Friedrich, do you want to take that?

We can move on this slide. Yes. I think it's in the slide set over here. So let me just kind of rewind back and keep going by Gen -- back, back, right there, okay. So Madhu, for head and neck, I don't have specifically for the platinum assuming most of them on platinum-based chemotherapy. So 12 out of the 18 patients, 66.7% got chemotherapy, 9 out of 18, 50% got radiotherapy. Does that help?

No, I'm asking is how many of the responders had prior chemotherapy, this is the number of patients who had prior chemotherapy?

Got it.

How many of the responders had prior chemo?

I do not have that information, but we can certainly get back to you.

Okay, awesome. Next question, how many of the cervical cancer responders had prior chemo rad therapy?

We didn't break down the cohorts with a very small number. You're talking about 14 patients here, so with regards to breaking it down the responders, we did not do that at this point.

Okay, cool. So then bigger picture questions. The first one is, so it seems like a common theme among the physicians' commentary earlier on in this call was about the desire for a limited duration therapy, where you give a treatment, then you can discontinue treatment. So is there a thought kind of following that about running kind of on the forward, a PD-1 plus TIL combination trial would kind of define stopping rules for the PD-1 therapy, and kind of where do you think that a regulator might sit on that type of a combination trial?

All right. So that's I think -- Hamid, do you want to answer that?

Yes, I'll take that. I mean I think most of our clinical trials in melanoma are looking at 2 years, so it's the first tumor that has a stop time, and then there's multiple trials going through looking at complete metabolic response if you could stop at one-year, KEYNOTE 1 allows you to stop after 2, one or 2 imaging if you had a complete response, so there's indication there. Unfortunately, melanoma is a highly immunogenic tumor, you can't really translate that to other tumor types. I think the question you asked is a field question. As we can -- as we find more durable responders, we will be able to start to think about holding therapy there and amending the trial to do that. In order to do that, you would require a trial that have high CR rates, and this is what we're looking for in these components, such as the combo PD-1 and TIL.

And when I think about in our cervix cancer patients, it's a great question with regards to impacting resource management, but I have to be honest, when I think about single-agent immune therapy, I don't think that -- of that as a regimen, I think of that as a maintenance. And so in that regards, when we're giving triplet therapy -- cytotoxic triple therapy and prolonged exposure on that, the toxicity and the quality of life impact is real. So no, it's a dichotomy and thought, I probably should really think about the impact of our patients every 3 to 6 weeks coming in for immune therapy. So it's a great question.

A lot of the comfort will come from evaluating patients who've come off for toxicity and have durability. So the patients like that in your melanoma cohort, who has been treated, but is still having a durable response. Once we see more of those in the PR/CR setting, there will be a comfort level.

Okay. And then last bigger picture question is thinking about the cervical cohort, is there a plan to try to focus future patients into the kind of PD-L1 negative population on the forward?

At this point, those decisions have now been made, obviously, with the changing landscape, bringing that information in from an investigator standpoint, I'll let the company speak on that. But I think as we see these patients, particularly post IO both PD-L1 positive and PD-L1 negative patients are going to be very important to continue to evaluate this exciting technology investigational agent moving forward. So I hope they don't. I hope they continue to evaluate in the PD-L1 positive population, especially in the post IO exposure.

Yes. I don't think we know that, and I think the landscape is changing. Patients are going to go into different available standard of care therapies, and that as well, to a certain extent, also going to determine the population enrolling into clinical trials. So I think we're going to have to follow that, but at this point, we don't know how that's going to turn out.

And your last question comes from the line of Joe Catanzaro from Piper Sandler.

I'll try and keep it pretty brief here, one for the company. Just following up on this idea of number of prior lines of therapy and impact on T-cell exhaustion and quality of final TIL product. So the lung cohort had a range of prior therapies as few as one, as many as 6, recognized numbers are small, but do you see any indication that one prior line has a better phenotype than 2 prior lines? And maybe you could take that question across your entire experience, not just considering lung?

Yes, I can take that, Joe. So I think the translational studies in lung are currently ongoing. Basically on our melanoma experience, we have not seen any specific phenotypes that correlate with prior lines of therapy that that's not to say that we won't see that in lung, because the prior lines of therapy in melanoma are not cytotoxic agents versus in lung, they are predominantly cytotoxic agents. So I think stay tuned, those translational efforts are ongoing.

We also shouldn't disregard the fact that prior lines of therapy are not just affecting characteristics and capabilities of the product, but also the patients' tumor microenvironment, right. Once we put themselves back into the patient, they are going to encounter the tumor microenvironment, which is very likely to have been shaped by prior therapies. So it's difficult to really unravel this, but that is an important factor as well. So we might not be able to pick the impact -- pick up the impact of prior lines of therapy just in our product.

Okay, got it. That's helpful. Appreciate you guys squeezing me in.

And these are all the questions we have for today. I would now like to turn the conference back to Mr. Fred Vogt. Please go ahead sir.

Thank you again for joining this Iovance Biotherapeutics SITC update call. I want to give special thanks to Dr. Hamid; Dr. O'Malley; and Dr. Schoenfeld for joining us and congratulations to the Iovance team on putting together the abstracts, poster and presentation for this year's SITC. Please feel free to reach out to our Investor Relations team if you wish to follow up. Thanks, everyone, and have a good evening.

And this concludes today's conference call. Thank you all for your participation. You may now all disconnect. Have a great day.