Nektar Therapeutics (NKTR) Earnings Call Transcript

Ladies and gentlemen, thank you for standing by and welcome to the Nektar Therapeutics SITC Analyst Call. [Operator Instructions] Please be advised that today's conference may be recorded. [Operator Instructions] I would now like to hand the conference over to your speaker today, Ms. Jennifer Ruddock, Head of Corporate Affairs. Ma'am, you may begin.

Thank you, Krystal. Good afternoon, everyone, and thank you for joining us on today's analyst call to review data presented for Nektar's I-O pipeline at the 2020 SITC meeting. Before we start, I'll remind you that this presentation includes forward-looking statements regarding Nektar's drug candidates bempegaldesleukin, NKTR-262 and NKTR-255 and other potential drug candidates; clinical trial results; the timing of the start of and plan for ongoing or planned clinical trials with partners; the therapeutic potential of our drug candidates; the timing and outcome of regulatory decisions; and future availability of clinical trial data. Because these statements relate to the future, they are subject to inherent uncertainties and risks that are difficult to predict and many of which are outside of our control. Actual results could differ materially and these statements are subject to important risks and uncertainties, which are set forth in our Form 10-Q that we filed on November 5, 2020, and is available at sec.gov. We undertake no obligation to update any of these statements whether as a result of new information, future developments or otherwise. A webcast of this call will be available on the IR page at Nektar's website at nektar.com. On our call today are Nektar management team members, Dr. Jonathan Zalevsky, our Head of Research and Development; and Dr. Wei Lin, our Senior Vice President and Head of Development at Nektar. In addition, we are privileged to have here with us today 4 of our SITC authors and presenters. First off, I'd like to introduce Dr. Adi Diab. Dr. Diab is an Associate Professor of Melanoma Medical Oncology at the University of Texas MD Anderson Cancer Center. Adi is one of the lead investigators in PIVOT-02, the Phase I/II study of BEMPEG plus nivolumab; and also in REVEAL, the Phase I/II study of 262 and BEMPEG. He is also on the steering committees for both the BMS-sponsored Phase III registrational study in first-line metastatic melanoma and the Nektar-sponsored Phase III registrational study in adjuvant melanoma. Next, we have Dr. Brendan Curti. Dr. Curti is a Director of the Melanoma Program, Cytokine and Adoptive Immunotherapy and GU Oncology Research at Providence Cancer Institute. He also serves at the Robert W. Franz Chair for Clinic Research and member in the Earle A. Chiles Research Institute at Providence Cancer Institute. He is a senior author and clinical investigator for both the PIVOT-02 and REVEAL studies. Here to present the 255 data today, we have joining us Dr. Nina Shah, who is an Associate Professor in the Department of Medicine at the University of California San Francisco. Nina is a specialist in blood diseases with a focus on treating multiple myeloma. She is also the first author of the first-in-human Phase I presentation of 255 data from SITC today, and we're happy to have her joining us today and presenting. Finally, contributing to our discussion and serving as a panelist on the 255 study, we also have Dr. Alan Tan, Assistant Professor in the Division of Hematology, Oncology and Cell Therapy at Rush Medical College. Alan has an extensive background in hematological malignancies. He is also a contributing author of the Phase I presentation of 255 at the SITC meeting today. So here's our agenda. To start off, we will review highlights from today's PIVOT-02 data of BEMPEG with nivo in patients with metastatic melanoma from PIVOT-02. JZ will follow away with a review of highlights from the Phase I dose escalation study of 262 plus BEMPEG. Dr. Shah will then present the first-in-human 255 data and several patient case studies. Finally, we will host a Q&A session with our expert oncology panel. With that, I would like to hand the call over to Wei for a discussion on the PIVOT-02 data. Thank you, Wei.

Thank you, Jennifer. Next slide, please. As many of you know, NKTR-214, also known as bempegaldesleukin or BEMPEG, is an investigational CD122 preferential IL-2 pathway agonist that leverages the clinically validated IL-2 pathway to stimulate an antitumor immune response. In vivo, BEMPEG induces increased proliferation and infiltration of CD8 T cells and natural killer cells without expansion of unwanted regulatory T cells, or Tregs, in the tumor microenvironment. BEMPEG plus a checkpoint inhibitor treatment increases infiltration of CD8+ T cells into the tumor, and hence this tumor PD-L1 expression, providing the rationale for further exploration of this combination as we have done here in PIVOT-02 trial. Next slide, please. Here, we have listed the ongoing clinical development program for BEMPEG in a range of solid tumors. In collaboration with BMS, we have a number of registrational trials in metastatic melanoma, adjuvant melanoma, metastatic bladder cancer, muscle-invasive bladder cancer and metastatic kidney cancer. We also have the Nektar-sponsored PROPEL study in first-line non-small cell lung cancer with the combination of BEMPEG plus KEYTRUDA. In addition, we are evaluating BEMPEG in combination with NKTR-262, our toll-like receptor 7/8 agonist in relapsed/refractory melanoma in the REVEAL study as well as the combination of BEMPEG with cancer vaccine in head and neck squamous cell carcinoma in a collaboration study with Vaccibody. Next slide, please. Despite the success of checkpoint inhibitors in metastatic melanoma, there's still an unmet need for therapies that produce deeper and more durable responses in more patients. In previous presentations, we have reported that BEMPEG plus nivo has manageable safety and encouraging preliminary clinical activity in patients with metastatic melanoma with durable responses that deepened over time. Based upon these data, this combination received FDA breakthrough therapy designation in July of 2019. Today, we reported updated results from the same set of patients with approximately a 2.5-year of follow-up. Here -- next slide, please. Here is our waterfall plot with a median follow-up of 29 months for patients treated at the recommended Phase II dose of BEMPEG at 6 micrograms per kilogram combined with nivolumab. All responses were evaluated by blinded central independent radiology. We illustrate here with arrows 2 more patients with deepening of response since we last presented these data at SITC in 2019. Both patients, which achieved a 100% reduction in RECIST target lesions. Almost 50% of all patients who are 90% of patients who responded in the study achieved complete clearance of their target lesions, illustrating the depth of response achieved with this combination over time. The rate of confirmed complete responses by RECIST criteria was 34%. With this deepening of response, we reported an updated median reduction from baseline of RECIST target lesions of 79% compared to the 62% reduction we presented last year at SITC 2019. And we see that patients responded to treatment early on with a median time to response of 2 months and median time to complete response of 7.9 months. In addition, we see that even patients with poor prognostic markers, such as those with PD-L1 negative tumors, high LDH or liver metastasis, achieved clinically meaningful responses. Of note, all 5 responses in patients with liver metastases went on to become complete responses or a remarkable outcome for those poor prognosis patients. At the September 2020 data cutoff in 16 of 20 or 80% responding patients continued to have ongoing responses. The median duration of responses has still not been reached. No patients remain on treatment because the maximum treatment duration in [indiscernible] was 2 years. We see that overall, the patients in this cohort had a median of 9 cycles of therapy with a doublet, demonstrating the long-term tolerability of this regimen. Next slide, please. With the median follow-up of 29 months, I'm pleased to report that we have now reached median PFS, which was 30.9 months. The PFS rate by Kaplan-Meier analysis at 12 months was 56%, at 24 months was 53% and at 36 months was 46%. Next slide, please. Despite having a median follow-up of 29 months, the median overall survival was not reached. The OS rate at 12 months was 82%, at 24 months was 77% and at 36 months was 71%. All patients who experienced CRs, who were at 100% reduction of target lesions, are still live. We hope that -- we hope to share median overall survival at a future meeting when these data are not -- are more mature. Next slide, please. At this point, we'd like -- I would like to direct your attention to a retrospective meta analysis conducted by the FDA and presented at ASCO 2019. The analysis analyzed 4,826 melanoma patients with a total of 10 randomized trials in order to explore the relationship between depth of response and OS with various therapies used to treat previously untreated metastatic melanoma patients. Depth of response in RECIST target lesions clearly correlates with longer OS. I draw your attention to the yellow line on the right of the slide, which are the 76% to 99% decrease and the blue line, which are 100% decrease. This clearly shows that depth of response of greater than 75% is associated with a higher rate of estimated overall survival of 24 months. And their analysis clearly indicates that in these patients with melanoma treated with immunotherapies, achievement of a deep response in their target lesions early on after they started treatment with an I-O combination could be an excellent hallmark for OS. We believe this phenomenon has occurred with I-O therapy. Correlation of depth of response to OS is what we are also observing in this small cohort in metastatic melanoma patients from PIVOT-02. Next slide, please. To put these data into historical context and when looking at these results from the checkpoint -- CheckMate 067 study, we see distinctions in the PIVOT-02 data set. Median PFS with nivolumab therapy in this setting is 6.9 months at a similar time point, while at the median PFS for nivo plus ipi is about 11.5 months. Turning to the OS analysis. The landmark OS for PIVOT-02 at around 2.5 years follow-up is higher than both that of nivo monotherapy and of nivo/ipi combination at less than 2-month follow-up. Landmark survival data for nivo and ipi was 64% at 2 years and 58% at 3 years. Next slide, please. Now let's turn to our exploratory biomarker analysis that was conducted at baseline and on treatment, in the tumor and blood, looking at the relationship with response to BEMPEG plus nivo. Blood-based analyses included determination of the polyfunctional strength index, or PSI, based on the IsoPlexis technology, which enables functional phenotyping at a single-cell level. First, we will look at baseline biomarkers. On the left, we have the [indiscernible]. We look at the number of objective responses in patients by BICR with values above and below the median for each biomarker. We found that increased CD8 tumor-infiltrating lymphocytes and increased interferon gamma gene expression profile in patients at baseline were associated with a higher rate of objective response. Both of these tumor biomarkers were also found to correlate with longer PFS. Next slide, please. We next look at biomarkers in paired blood samples at day 8 of cycle 1 versus baseline and whether they correlated with response. Polyfunctional strength difference, or PSD, is the difference in polyfunctional strength index between baseline and day 8. We found that PSD in CD8+ and eosinophil full change was associated with a higher object response rate. Similarly, increased CD8+ PSD between baseline and day 8 was also associated with longer PFS. Note that a trend was also observed for eosinophils and PFS. This was not statistically significant. Next slide, please. So a reminder on the registrational study designs. PIVOT IO 001 is the BMS-sponsored Phase III randomized, open-label study of BEMPEG plus nivo versus nivo monotherapy in previously untreated, unresectable or metastatic melanoma. The study is enrolling 764 patients and stratification factors that include PD-L1 status, BRAF status and AJCC staging. Primary endpoints include overall response rate and progression-free survival by blinded independent central review as well as overall survival. This study is currently being run by BMS with first data expected in Q4 of 2021 or Q1 of 2022. Next slide, please. We also recently opened the PIVOT-12 study, which is our Phase III randomized, open-label study of BEMPEG plus nivo versus nivo as adjuvant melanoma therapy, which is sponsored by Nektar. Similarly, the patient population is reminiscent of the nivolumab monotherapy trial in a similar patient segment. Stratification factors include PD-L1 status and AJCC stage. The primary endpoint is relapse-free survival by blinded independent central review. This study is also currently recruiting. Next slide, please. We will now turn our attention to data we presented for NKTR-262, a toll-like receptor 7/8 agonist in solid tumors. With that, I'll turn the call over to JZ.

Thank you, Wei. Next slide, please. In brief, NKTR-262 is a small molecule agonist of toll-like receptor 7/8, and it's given by intratumoral injection. NKTR-262 is retained within the tumor microenvironment and it promotes an immunostimulatory milieu and tumor antigen release. BEMPEG is the CD122 preferential interleukin-2 pathway agonist, which increases proliferation and tumor infiltration of CD8+ T cells and natural killer cells. And preclinically, NKTR-262, combined with BEMPEG, resulted in targeting both the innate immune signaling and enhanced antigen presentation with sustained T cell activation, which together resulted in tumor growth inhibition of both treated and abscopal lesions. The next slide. Now this is the REVEAL study design. It is a dose-escalation and dose-expansion study of NKTR-262 combined with BEMPEG, with and without nivolumab, in patients with advanced solid tumors. And today, as noted, we are focusing on the dose escalation part. The primary endpoints were safety and tolerability, including determining the recommended Phase II dose and assessment of clinical activity by RECIST. Other endpoints included progression-free survival, overall survival, abscopal response by RECIST, correlative biomarkers, pharmacokinetics and pharmacodynamics. Next slide, please. 36 heavily pretreated patients with advanced solid tumors have been enrolled so far across 9 dose cohorts. Patients received escalating doses of NKTR-262 from 0.03 milligrams to 3.84 milligrams in combination with a fixed dose of BEMPEG at 0.006 milligrams per kilogram. The recommended Phase II dose was selected at the highest dose of NKTR-262 tested, which was 3.84 milligrams given intratumorally to 2 lesions per cycle in combination with BEMPEG. In terms of clinical activity, 29% of efficacy-evaluable patients experienced a regression in the injected lesions. 2 of 22 heavily pretreated patients with melanoma experienced an objective response. One of these patients had a 50% reduction in tumor burden and the other experienced 100% reduction in the sum of diameters in the noninjected target lesions. Further assessments of clinical activity are ongoing as is the study. Next slide, please. Now let's first take a look at safety. Overall, NKTR-262, combined with BEMPEG, was well tolerated and had a favorable safety profile with few treatment discontinuations due to adverse events. The most common treatment-related adverse events with NKTR-262, combined with BEMPEG, were similar to NKTR-262 monotherapy, and they were flu-like symptoms, fatigue and nausea. The maximum tolerated dose as defined by the protocol was not reached. Next slide, please. Let's now turn to the biomarker data. Here, I am showing the gene expression analysis. We examined sets of genes known to respond to toll-like receptor 7 and 8 agonism and tested whether they were activated in response to NKTR-262. The data shown are for patients with melanoma. In the heat map, we can see that the Type 1 interferon genes were induced as early as cohort 3 and plateaued thereafter. Next slide, please. NKTR-262 combined with BEMPEG increased proliferation of circulating CD4+, CD8+ and natural killer cells in the blood in cycle 2. In general, there was no clear change in proliferative immune cell subsets in cycle 1 with NKTR-262 monotherapy, indicating this effect was driven by BEMPEG, starting from cycle 2 onwards. This finding reflects retention of NKTR-262 in the tumor microenvironment and aligns with the mechanism of action of BEMPEG. Next slide. Next, we'll look at changes in the expression of Type 1 interferon genes by NKTR-262 and melanoma biopsies. First, the heat map shows that there was a clear dose-dependent induction of Type 1 interferon genes. The charts on the right show that induction of toll-like receptor 7 and 8 target genes significantly correlated with the baseline density of CD11c positive cells. Of note, CD11c positive cells, which include myeloid dendritic cells and monocytes, our target cells for NKTR-262. Together, these findings connect the presence of the target cells at baseline with induction of the NKTR-262 target engagement biomarkers. Next slide, please. So how do these data translate for patients with melanoma and other tumor types. Here, you can see from these dot plots that there is a significantly higher density of CD11c+ cells in melanoma baseline biopsies, and this level is higher than seen in other tumor types. The chart on the right illustrates how this observation was not biased by biopsy location. Although preliminary, these data suggest that the observed trend of higher density of CD11c+ cells in melanoma could translate to a greater antitumor effect. Next slide, please. So in conclusion, intratumoral NKTR-262 has shown early clinical activity and an acceptable safety profile in this highly relapsed/refractory melanoma patient population, both as a single agent and in combination with BEMPEG. The MTD was not reached, but the totality of safety, PK/PD and biomarker data supported the selection of NKTR-262 at the 3.84 milligrams intratumoral plus BEMPEG at the 0.006 mg per kg intravenous q3 week as the recommended Phase II dose to take forward. For NKTR-262, robust TLR7/8 engagement supported the MoA, and the minimal toxicity profile underscore the benefit of local delivery. NKTR-262 plus BEMPEG induced systemic activation of T and NK cells, demonstrating engagement of the entire immune activation cascade required for systemic tumor clearance. CD11c+ target cells were significantly more abundant in baseline melanoma biopsies versus other tumor types, and this supports further exploration in this tumor type. Our REVEAL study has been expanded at the recommended Phase II dose to explore the combination of NKTR-262 plus BEMPEG, either with or without nivolumab in patients who are heavily pretreated with I-O relapsed/refractory melanoma. Next slide, please. Last but not least, I will turn the floor over to Dr. Shah, first author of the following research and have her present the data for NKTR-255, our IL-15 agonist, which is currently being investigated in a Phase I/II study in NHL, and multiple myeloma as well as in a new solid tumor study in patients with head and neck cancer and colorectal cancer. Dr. Shah?

Thanks so much, JZ. This picture describes the ongoing Phase I open-label multicenter study of NKTR-255 in patients with relapsed or refractory multiple myeloma or non-Hodgkin lymphoma. Next slide, please. So NKTR-255 is an investigational polymer conjugated Interleukin-15, or IL-15 for short, receptor agonist that shows improved pharmacokinetics versus recombinant human IL-15. So this means it can provide sustained pharmacodynamic responses without the need for daily dosing. NKTR 255 engages with the IL-15 receptor alpha/Interleukin-2 receptor beta/gamma complex to boost the number and function of NK cells and enhance immune recovery via expansion of CD8+ T cells. By boosting NK cell number and function, we think that NKTR-255 will enhance the anticancer effects of monoclonal antibody therapy. Next slide, please. The study has 2 parts. So you can see here in the dose escalation part successive cohorts of 3 patients, each receiving escalating doses of NKTR-255 monotherapy, given the infusion every 3 weeks until the maximum tolerated dose and/or recommended Phase II dose are determined. The dose-expansion part comprises 5 cohorts, as you can see on the right, and these are patients who will be treated at the recommended Phase II dose. Eligible patients will receive NKTR-255 monotherapy or in combination with daratumumab or rituximab. Patients in cohorts B and C, who failed response to monotherapy can then cross over to receive combination therapy. This presentation today describes the first 4 patients enrolled into the dose escalation. Three patients received NKTR-255 at 1.5 micrograms per kilogram and 1 patient received NKTR-255 at 3.0 micrograms per kilogram. Next slide, please. NKTR-255, as you can see here, was well tolerated with only low-grade cytokine-related adverse events. These events were fairly transient and easy to manage. No dose-limiting toxicities or serious treatment-related AEs occurred during the DLT period. Next slide, please. We also found that NKTR-255 had a long half-life with no evidence of accumulation, as you can see on this slide. And actually, it was mirrored for cycle 1 and cycle 2 and a representative example here showing the kinetics of this particular agent. Next slide, please. Induction of NKTR-255 also showed transient upregulation and then rapid decline of cytokine to baseline levels by day 2 with no further increases, and this supports the safety of NKTR-255. No further changes were observed after day 15. You can see this on the interferon gamma, IL-6 as well as MCP-1. Next slide. NKTR-255 was shown to be biologically active and demonstrated consistent expansion of lymphocytes with durable and sustained increases in NK and CD8+ T cells in this population of highly refractory patients with myeloma or non-Hodgkin lymphoma. We found that NKTR-255 expanded NK cells by fivefold and CD8+ T cells by threefold. Moreover, proliferative capacity was maintained across multiple cycles of NKTR-255, and it peaked around 8 to 10 per cycle. Next slide, please. CD8 memory T cell expansion was also seen in all patients treated with NKTR-255, including a more than ninefold increase in one patient who is receiving NKTR-255 at 1.5 micrograms per kilogram. Next slide. Importantly, we saw no meaningful changes in CD4+ Tregs with NKTR-255 treatment, supporting further NKTR-255's biological activeness to enhance immunostimulatory properties but not increase immunosuppressive properties. Next slide. I want to take a little time to go over some of the patient clinical vignette. I think it's really important because although there are only 4 patients presented today, you can see how these drugs can be active in these very heavily pretreated patients. So here, you can see a clinical vignette of the first patient enrolled on the study of NKTR-255 at the 1.5 microgram per kilogram dose. As you can see on the left-hand side, the patient had very heavily pretreated multiple myeloma and had received all of the novel agents that we currently have available. As you can see on the right-hand side and particularly paying attention to the kappa light chain, which is a measure of disease, you can see that from baseline up until cycle 4, the patient seemed to be responding. Unfortunately, the patient did progress eventually, but I will point out that this stable disease through 9 cycles is something fairly unprecedented for a patient with heavily pretreated multiple myeloma. Next slide. Very interestingly, the data that we saw from this therapy shows that there was actually a 13-fold increase in the CD56+cells, for example, the NK cells here after administration of NKTR-255, when you look from baseline to cycle 9. This does support the idea that this drug can actually have immunostimulatory properties and specifically NK cell expansion. We know that NK cells can form a long-term memory pool and can migrate to niche tissues like bone marrow and liver. And the increase in the bone marrow may suggest that 255, the expanded NK cells may convert into memory-like T cells -- excuse me, memory-like NK cells and migrating to NK memory areas like the bone marrows. This patient actually did fairly well. As you can see, baseline was doing fine and then about 4 to 5 hours after infusion had mild rigors, grade 1, and flu-like symptoms. These are all very expected with this type of therapy. The patient did have grade 3, neutropenia, and thrombocytopenia related to study drug. But I will point out with heavily pretreated patients, this is almost always expected with immunotherapies. As you can see on the right-hand side, all of these symptoms resolved. I want to point your attention now to a different patient. This is the second patient enrolled in the 255 trial. This patient had non-Hodgkin lymphoma. And as you can see on the left-hand side, was equally very heavily pretreated, including an autologous stem cell transplant. As you can see here after receiving 7 cycles of NKTR-255 monotherapy at a dose of 1.5 micrograms per kilogram, you can see here that the index lesion in the spleen had gone down significantly. Next slide. This patient also tolerated the therapy very well, just had some grade 1 muscle tension. This is a reproducible pattern and was treated with Tylenol, but had no significant SAEs or other significant AEs. Next slide. I want to now point your attention to a third patient who was enrolled in the 255 trial. Here, this patient, interestingly, actually had previously received CD19 CAR-T cells, as you can see on the left-hand side. So again, the patient was very heavily pretreated, multiple therapies, had eventually in the fifth line received Yescarta, which is a CD19 CAR-T cell therapy. The patient subsequently progressed unfortunately and then underwent therapy with NKTR-255 at a dose of 1.5 micrograms per kilogram. Very interestingly, you can see that from baseline to cycle 2, there was actually an increase in the percentage of CAR-T cells that were detectable in the patient's blood sample. This also underscores the ability of this drug to likely expand very important population of activated T cells. Next slide. Again, this patient also tolerated the therapy very well, also had a muscle tension grade 1, which essentially was treated effectively by acetaminophen. Patient also had grade 3 fever and grade 2 chills, both of which resolved. And again, no SAEs were reported. Next slide. So in conclusion, patients with relapsed or refractory multiple myeloma or non-Hodgkin lymphoma who have previously exhausted all available therapeutic options were eligible for the dose escalation part of this study. For dose escalation, successive cohorts of 3 patients each received escalating doses of NKTR-255 monotherapy to determine the MTD. NKTR-255 thus far has been well tolerated with low-grade, cytokine-related AEs that were transient, easily managed and, I would say, very expected in this patient population and with this type of therapy. No DLTs were observed. No drug-related AEs led to treatment discontinuation, dose delay or dose modification. NKTR-255 exhibited a long half-life with no evidence of accumulation. In addition, NKTR-255 was biologically active and demonstrated consistent expansion of lymphocytes with durable and sustained increases in both NK and CD8+ T cells in this very highly refractory population of patients with myeloma and lymphoma. These data support continued dose escalation of NKTR-255 and subsequent evaluation in combination with other anticancer agents. With that, I'd like to say thank you and move on to the next part of our session.

Thank you so much, Dr. Shah. We will now move on to start with a few moderated questions that Dr. Jonathan Zalevsky will provide to our panelists. And following that, we will open it up to the queue for analysts calling in. JZ?

Thank you, Jennifer. I'd like to begin with a few questions directed to our panelist, Dr. Alan Tan. Alan, you're an investigator on the 255 study. And I know you have experience with the early emerging data. Can we begin by asking you to just share your thoughts and impressions of the early data we're seeing from the study?

Thank you. Yes. So this is, of course, our first-in-human study, and we're fortunate enough to have the first 2 patients on study as Nina nicely presented. The first patient was a myeloma patient that had a relatively aggressive disease. The free kappa/lambda light chains were climbing quite rapidly and predictably. And I assume if he got the 255 agent, the kappa/lambda ratio had seemed to halt and stabilize. And I think at such a low dose and to have single-agent activity which we usually don't see in multiple myeloma like this is quite encouraging. And also, tolerability has been seen, too, with the lower doses and the next level. Both of my patients both had incredible tolerability. Few rigors, but were mitigated by acetaminophen and a little bit of meperidine and the side effects went away completely and did not have any issues in subsequent days. I also have experienced with 214 as well, and I find it even better tolerated than the 214 drug. So -- and I think we're just excited that it's doing what it's supposed to be doing and expanding NK cells and CD8 cells. And so I think so far, in these 4 patients, we're optimistic that this agent is efficacious in heme malignancies.

Thank you, Alan. And that sort of kind of leads into the first question. And so with 255, we consider the purpose of adding cytokine support that can aid currently approved therapies with the potential to elicit deeper and prolonged antitumor responses. Can you share your thoughts on how you think NKTR-255 can be effective in this space and these kinds of addition to these regimens?

Sure. There's been multiple studies with other investigators such as Kochenderfer that had shown the association between an increased serum level IL-15 after lymphodepletion and improved clinical responses even after anti-CD19 CAR-T cell therapy. So also, there's published data available showing that the higher IL-15 serum concentrations are associated with better predictability of response and higher CAR-T cell in vivo expansion and better persistence, which may translate into more complete responses. I think that the question out there with CAR-T cells, especially in myeloma, initial data looked extremely promising. But over time, it doesn't look like we're curing multiple myeloma with cellular therapy just yet. But perhaps if we expand upon this population and increase serum IL-15 level, increase NK cell population and as we know, there's other agents such as lenalidomide and pomalidomide that enhance this as well. Elotuzumab is another one that Nina could probably also mention as well. So I think there's definitely room to grow with this.

Thanks, Alan. That actually really leads into the next question, which is that as we look at overall -- the landscape in NHL and the different tumor types such as DL, BCL or CLL, we'll see that polatuzumab and other agents like tafasitamab, MONJUVI, they continue to reinforce the additional ongoing threat potentially to CD19 CAR-T with meaningful, albeit likely noncurative therapies that enter into that space. And I'm curious what you envision the role of cytokine, especially with NKTR-255 in this space. So for example, we know that in the setting of MONJUVI, that's a combination with lenalidomide. And lenalidomide, of course, is a well-known NK modulating agent, but it also comes with some undesirable properties. Certainly, the NK cell effects of NKTR-255 could potentially be even greater both in their magnitude as well as their duration of expansion. So I'm curious if you could share your thoughts on this hypothesis.

Yes, I agree. I think once again, speaking to the tolerability of 255 and the ability to perhaps combine, I have a lot of experience with I-O agents, and we're finding it's -- the toxicity is not usually very additive. We combine TKIs all the time in GU and melanoma, et cetera. So -- but while CAR-T cell has shown a lot of promise thus far is a big splash, but many patients just can't get there. I've referred several patients for CAR-T cell therapy. And for biologic reasons or logistic reasons, the patients just are not a candidate for this therapy. And these patients are probably ideal for less toxic novel therapies out there. And it's a good time to be in oncology because we have a lot of different mechanisms here for a more tailored approach. And diffuse large B-cell lymphoma is a very heterogeneous disease, and there's several promising monoclonal antibodies such as polatuzumab, as you mentioned. Tafasitamab just recently approved as well. So I don't think this is going to pose a threat to CAR-T, but perhaps maybe complementary to a lot of these treatment strategies.

Thank you, Alan. I'd next like to ask a couple of questions to Dr. Shah. So Nina, we know that daratumumab is moving, and it has moved now into the frontline setting in combination with proteasome inhibitor and/or immunomodulatory agents. And this, in turn, would create a large population of daratumumab refractory multiple myeloma patients that eventually progress. How likely do you think NKTR-255 might overcome resistance to daratumumab based on NKTR 255's mechanism of action?

Yes. Well, I think it's a really important point because daratumumab has basically run from the back of the line to the front of the line and is being used, as you pointed out, in upfront therapy in both transplant-eligible and transplant-ineligible patients. And because of this, there is going to be a burst of patients who are daratumumab refractory within the next few years. Some of the -- there are multiple mechanisms of how daratumumab -- patients being on daratumumab refractory. Some of that is loss of CD38, which makes them less sensitive to daratumumab, meaning that they need a bigger gun of an effector cell to get the job done. And other parts of it may be that the NK cells have been exhausted by constant stimulation through daratumumab. So I'm actually very hopeful that an immunotherapy, which is not chemo-based, the true immune-based, such as NKTR-255 can actually boost the ability of inherent NK cells to have effective cytotoxicity against myeloma cells in the presence of daratumumab enhancing the ADCC.

Okay. And a second question comes to mind is, so we know that combinations of immunomodulatory drugs as well as checkpoint inhibitors, they might continue to enhance -- further expand CAR-T activity, and we see many clinical trials now of these combinations underway. Do you think that cytokines and ultimately, NKTR-255 might possibly alter the quality and the durability of CAR-T responses?

Yes. I think this is the next frontier for CAR-T responses because these are autologous cells, so they shouldn't be rejected like an allogeneic cell would be. And so the ability for cytokine -- a nonchemo cytokine-based therapy to come in there and boost the already effective output of these CAR-T cells would be something that would be a game changer for these patients, I think, particularly, for myeloma, who are progressing after CAR-T. And I think the main question is going to be timing, and I'd love to see this agent be placed sort of as a planned agent after CAR-T administration to give that extra boost and allowed to mop up whatever myeloma hasn't been mopped up by initial CAR-T administration.

Thank you, Nina. So switching gears now, I was going to ask a few questions to Dr. Curti. And Brendan, we ask a handful of questions focused on the data for PIVOT-02. So the first is, I'm wondering if you could take a moment to comment on what you see as the most notable takeaways from the updated PIVOT-02 data that we just presented in first-line melanoma. And particularly, how it relates to any differentiation in the data to the current standard of care therapy, such as, for example, checkpoint inhibitors or BRAF agents?

Sure. Well, so the thing that's most striking to me is the proportion of patients who achieved a complete response. And so although, I'll say, in the current era of immunotherapy and targeted therapy, it's great that we have a much higher response rate, but most of the patients who have partial response and certainly those who have stable disease, they end up progressing. And so this was illustrated in one of the supplemental slides that was shown. But the more complete the response is, the better those patients do. And I think this is something we've known from the Jurassic age of immunotherapy using high dose IL-2, but it's encouraging to have regimens that have a much higher proportion of response and complete response. Again, I think those patients do their very best. Another thing that [indiscernible] was also the duration of response or the -- more particularly, the progression-free survival, which in ballpark terms is a year, give or take, for checkpoint monotherapy or combinations or even BRAF-targeted therapy. And so from a patient's perspective, you get a year of therapy. And on average, there's a year until your melanoma progresses again. If we had a therapy that, well, if you got a year or so of therapy and you've got 2 or 2.5 years, that's -- I'd sign up for that. That's certainly better, although not as good as a home run response. Last but not least, these patients had -- a high proportion of them had known bad prognostic features, such as high LDH or PD-L1 negative tumors and also the presence of liver metastases. And to see response in those patient groups is certainly something that we don't get to see all that often. And we need more treatments that induce more responses in those patients we know have the worst prognosis.

Yes. Brendan, maybe if I could ask you to expand on that a little bit because one of the things that we did in our report today is that there were 5 patients in our melanoma cohort with liver metastases. And they first experienced a PR, and then they went on to experience complete responses. And so you did touch on it, but I'm wondering if you could even further expand. Is it common to see such kind of level of response, both in that tissue as well as to complete response depth for checkpoint inhibitor therapy in patients with that kind of tissue involvement. And would you expect to see that kind of outcome, say, with a single agent or even with a combination of CPI?

Yes. Although we do from time to time see responses in liver metastases with checkpoint monotherapy or CTLA-4 plus anti-PD-1 and also, of course, in the setting of targeted therapy, but yet they're low probability events. And just reflecting back on the various landmark ipi/nivo or targeted therapy papers, they all -- the various New England Journal papers describe M1a, b or c or LDH high or low, but -- or a number of metastatic sites, 1, 2 or 3 or more. But there's, I'll say, a conspicuous absence of calling out liver responses. And beyond that, if you look at a number of the scan anecdotes of before and after, there are precious few that show liver responses. And of course, we all want to brag on our patients who do the very best, but it's much, much more common to see soft tissue lung and lymph node responses compared to liver responses with any of these treatments. And so obviously, treating more patients, doing comparison studies. That's all important to validate any of these observations, but it is remarkable to have a batting average of 1,000 among 5 patients with liver mets.

Thank you, Brendan. And this is one more question. Do you think you could please shed some light on your experience for us with treating patients with ipi plus nivo versus BEMPEG plus nivo? And specifically, from a tolerability standpoint, is it more difficult, you think, for patients to tolerate treatment with ipi plus nivo? And is it potentially more challenging for you to manage these patients medically?

And I'll say that, of course, we're here for the patients, and we'll do whatever. And of course, I know all of my colleagues, the same, we'll do whatever it takes to get our patients through the side effects of their therapy. But it is challenging to manage immune-mediated toxicity with combined checkpoint therapy. And although there are some reassuring data that you're giving glucocorticoids or TNF inhibitor antibodies, all of those things can help the side effects go away, but yet the patients are pretty roughed up by that experience. And I would also observe that many of our patients, if we have to stop early because of side effects that they feel that -- it's a disappointment that they're letting their family down by not getting all of the planned treatments. But obviously, they can't because it's not safe to do so. And so treatment that can be given more routinely. And although there are side effects with anything, but those that can be easily managed and with relatively little administration of steroids or other immunosuppressives, I think, that's value added. And clearly, just in the patients that we've treated here with NKTR-214 and nivo, the -- and of course, also supported by the larger study, but there's not the same degree of grade 3 or grade 4 toxicity that we would anticipate with combined checkpoints.

Thank you, Brendan. So for the next couple of questions, I'd like to ask and turn the floor over to Dr. Diab. Adi, I'm wondering to begin -- I'm curious about your clinical experience. And wanted to get a sense of what proportion of patients are the kinds of patients whom you would target -- prescribe ipi/nivo versus what proportion are you using single-agent nivolumab or pembrolizumab? And maybe you could talk us through some of the sort of situations where you use the mono versus the combination regimen?

Sure. Yes. So the way I look at the data right now, when I look at the ipi/nivo data or any combination checkpoint inhibitor between anti-PD-1 and anti-CTLA-4, I see an additive effect. Ipi has well-documented overall survival benefit and well-characterized overall response in the first line and in the second line after PD-1 failures. And PD-1 antagonist, whether nivo or pembro also well characterized in terms of their responses. And I really look -- whether in separated trials or in the CheckMate 067 or the CheckMate 069, I see an additive effect of the ipi/nivo, which mean that you can preserve that effect if you can give in sequential therapy, by it means you start with nivolumab or pembrolizumab, and then those patients who do not benefit, they can get ipi-based therapy and get the same benefit from that effect. There are certain scenarios where you want that additive effect upfront, like patients with a brain metastasis. You may not want to wait for progression in the brain because that can be detrimental. So you want that additive effect and upfront, but otherwise -- or patients who have really progressive disease that you think that there is no time for sequential therapy. So you justify the significance of toxicity when you give those 2 agents together. I think if there is a synergism, I see that in the toxicity between ipi and nivo or ipi/nivo or any combination of CTLA-4 or anti-PD-1, if I can say synergism in toxicity. But in terms of efficacy, it's an additive effect. And to that end, that's really how I direct my therapy. I think looking at the data, and I think the data supports that, you're looking at the combination trials, you don't see an overall survival benefit. And you see that sequential therapy like the CheckMate 064, whether you start with nivo and follow-up with ipi, you get a very high response or the CheckMate 067. If you look at the ipi arm and the nivo arm separately and you add them, we get roughly the same response rate like you get with ipi/nivo. So based on that, I really treat my patients first-line with anti-PD-1-based therapy. And at MD Anderson, we do clinical trials. So these patients go for anti-PD-1-based clinical trial. And if not, they go with monotherapy, unless I think they need that upfront combination such as brain metastasis, as I mentioned. And then I move in the BRAF wild type to ipilimumab-based therapy. And in the BRAF mutation, I may consider either ipilimumab-based therapy or BRAF inhibition-based therapy. I should mention that also, if you look at the sub group analysis, maybe the BRAF-mutant population has some sort of benefit in the combination because I think they need that inflammation, but that has to do with [indiscernible]. Other than that, JZ, my practice is anti-PD-1-based therapy for the first line, anti-CTLA-4-based therapy for the second line.

Thank you, Adi. And sort of maybe sticking on to this theme, we know very recently that there was a failed trial of the combination of nivo plus ipi in the adjuvant melanoma setting. And we recently started a trial of BEMPEG plus nivo in the adjuvant setting. I'm wondering if you could take a moment to comment on what you think is the potential for BEMPEG-nivo in the adjuvant setting?

Yes. Sure. I think when we look at the PIVOT-02 trial here, we see promising responses that the BEMPEG adding to the nivo in a nonoverlapping way. There is some sort of benefit in the scenarios where BEMPEG really immunologically steer the immune response in a different way that the checkpoint inhibitors has already. And one of that effect is really the proliferation of T cells. And looking at the ASCO data that was presented, looking at the proliferation rate of the CD8 -- Ki+ -- Ki-67+ CD8 cells or the ICOS-positive CD cells. And you look what happens after the first cycle. You can see that there is a proliferation -- enhanced proliferation of these CD8 cells. But if you compare the second cycle versus the first cycle, you can see that there is effects of saturation. And that goes well with the mechanism of action of checkpoint inhibitors. They rescue a certain antigen-specific populations that was inhibited either at the PD-1 or CTLA-4 level, and then the risky that population, that population proliferate. If we compare that data, although we cannot compare trial to trial, but in terms of mechanism of actions, we've seen, again, in the monotherapy with BEMPEG and in the combination BEMPEG-nivolumab, that the proliferation rate continue. That sign assigns that every time you give the bempegaldesleukin, you see enhancing and proliferation of the T cell in the blood continuous for deep into the cycles and hard numbers of cycles that the effect of proliferation continues. That may indicate that this is a different additive effect to the benefit that we're already getting from the checkpoint inhibitors. There may be a limitation of checkpoint inhibitors, but you don't get enough proliferation cells or a large pool of proliferating cells and maybe BEMPEG increasing that pool of proliferating cells and eventually, that lead to a better response. This is the data from the Phase II trial. So we see there is -- and of course, from the biopsies, and it's not that we want to complement the study design, but the study design with the monotherapy and the combination had multiple biopsies showing that there is increased infiltration on treatment biopsy showing increased infiltration of the T cells to the tumor microenvironment without increasing of the Tregs. That's a known well-documented market that correlate positively with the responses. So this -- altogether, I think there is a potential benefit from the bempegaldesleukin independent from the already benefit we get from checkpoint inhibitors. Now ipilimumab and nivolumab, as I mentioned, it's an additive effect and limited to certain populations that's spontaneously induced by the tumors and they rescue that population. So compared to the clinical trials I mentioned, in the adjuvant setting, adding ipi/nivo and failing to have a benefit from that or even looking at the survival data -- overall survival, nivolumab versus ipilimumab, while there is benefit in relapse-free survival, there was no benefit in overall survival, again, because these patients had additive benefit. And when you fail nivolumab, you get ipilimumab, you catch up with the survival benefit. I think the fact that BEMPEG can mechanistically add in a different way immunologically to the immune response, I think that's indicative that it can work also even more in the less immunosuppressive adjuvant patient population. So I think that is a completely different mechanism of actions. And I think that open the field for BEMPEG combination, if it's positive, to be also potentially positive in the adjuvant setting.

Thank you very much, Adi. So that concludes the panel sort of prepared question part of our discussion. And with that, I'd like to now turn it over to the operator, if you could please open the floor for general questions from the audience.

[Operator Instructions] Our first question comes from Peter Lawson from Barclays.

I guess a question for the -- to one of the 2 [indiscernible] that Dr. Diab and Dr. Curti, is CheckMate 067 the best comparator here for the -- an I-O combination? Do you think BEMPEG plus nivo is kind of superior? Discontinuation rate holds up as we see more patients being added. And do you think that's also true for the CR rate, which seems significantly higher. Do you think that kind of holds up as the trial expands? Just your thoughts around that would be great.

Thanks, Peter. So maybe if I could ask first, Dr. Curti and then next, Dr. Diab to comment. Really, the question is, is CheckMate 067, which is a melanoma study comparing ipi versus nivo versus Ipi-nivo. Is that the best comparison?

Yes. So getting back to Dr. Diab's comments earlier about patients who get checkpoint monotherapy versus dual checkpoint in their initial treatment. I think I'll say based in the -- at least the Pacific Northwest and the practice here that most patients have checkpoint monotherapy. And I think that is certainly a valid comparison arm. It would be -- if there were some grand scientific experiment that we could do comparing all of the different combinations and sequences and -- that might make a fine mouse experiment, but it's not a practical one to do in the human model. And beyond that, of course, our patients experience toxicity. And so I think one of the aspects of comparing to checkpoint monotherapy versus BEMPEG plus nivolumab is that the toxicity is, you could say, more comparable and we're teasing out more about the clinical effectiveness.

Thanks, Brendan. And Adi, would you like to comment as well add additional remarks?

Yes. No, I think I totally agree with Dr. Curti's answer. But what I would add is it's very essential when you compare between trials. So you cannot compare between trials, but this is how I evaluate all the data coming, especially in the first line, what are the baseline patient characteristics? I mean -- and that can give you relevance to what you see in the Phase III trial. So I do agree that the CheckMate 067 is an acceptable comparison trial to the BEMPEG nivo combinations. And we look at the PIVOT-02 patients, and we compare the baseline characteristics of these patients, looking at the LDH population. LDH is the most -- one of the most important negative prognostic factors that independent negative prognostic factor for melanoma, including patients treated with checkpoint inhibitors. And you see how much these patients are represented it in this trial compared to the CheckMate. And you see there, and you are in the ballpark of 30%, that's what you see in most of the pivotal Phase III trial. So I think that gives you a hint that these patients' characteristics, including the patients that are having a percentage of M1c metastatic disease, and what's the responses in these patients. So as Dr. Curti presented before, he was impressed with the responses in patients with LDH, high LDH patient with liver metastasis. I think that's where the promise comes from the PIVOT-02 data that it has patient characteristics compared to the Phase III trial and the responses hold in these challenging subpopulation. So I think the comparisons of BEMPEG nivo versus nivo is fair. And I think that is where we see the promises in the PIVOT-02 when we look at the patient characteristics and the responses in these patients as well.

Our next question comes from Tyler Van Buren from Piper Sandler.

I guess it's pretty clear from the data, at least, BEMPEG plus nivo, the higher CR rates translating to improved median progression-free survival and overall survival is tracking well relative to nivo plus ipi. But historically, as you guys are well aware, there's been a lot of comparisons to IDO, even though it's now, [ the failures ] over 2 years old. And the Phase II data looks great and the effect essentially disappeared in Phase III. I guess, with this latest update at 30.9 months that appears to be significantly above the median PFS, which if I recall correctly, they showed just over 20 months. But I would like to hear you guys maybe compare and contrast what we've seen with this latest data cut with BEMPEG plus nivo relative to the Phase II IDO data set beyond maybe, well, including medium PFS, but maybe what else gives you confidence that this is going to translate into Phase III. Is it target lesion reductions, complete response rates. Curious to hear your thoughts.

Yes. Thank you, Tyler, for the question. We believe there are numerous points of comparison as well as clear distinction between BEMPEG as an agent with its mechanism of action of the cytokine versus IDO inhibition with a small molecule. I'd like to ask Dr. Diab. If you could please comment on comparing and contrasting both IDO to BEMPEG, but also comparing and contrasting our data set with PIVOT-02 relative to the data set that was available with IDO in Phase II.

Yes. Sure. I think we do that all the time because with all due respect to the Nektar folks, like Brendan, our loyalty, first and foremost, is only for our patients and what's best there. So every trial I look for it is really when I see a new combination, I want to see if there is potential because we are in need of a new agent. So when you looked at the epacadostat trials, there is our 3 different categories where I can see their comparisons. I start from, again, what I mentioned, I think it's very important when you look at Phase II trials, especially single-arm Phase II trial, is how the baseline patient characteristics compare. If I remember [ very well ] they don't have the same high LDH patient population. I think they were below 20% compared to 30% and above percent that you see in the Phase III trial. Also looking at the PD-L1 positivity, I think major -- most of the patients were PD-L1 positive. And I think that's when single agents, anti-PD-1, whether pembro nivo performed very well. So I think -- and I cannot remember, to be honest with you, the percentage of M1c. But looking at the LDH alone, which is, again, independent prognostic factor, that's the differentiation between the PIVOT-02 and epacadostat IDO trial. That's very important because these patients, these are negative prognostic factors and determine the response rate so if you don't have enough high LDH or not similar to what you see or close to what you see in Phase III trial, that may be why you see some differences, whether better or worse, depends on the percentage of these patients. In terms of mechanism of actions, you have to remember one thing, that's also important. When we talk about overlapping and non-overlapping, and that's what JZ mentioned, cytokines and we've seen that in our biopsy-proven data, in monotherapy and the combination with nivolumab, that there is independent mechanism of actions to a proliferation of T cells, increasing the enhancement of T cells into penetration in the tumor microenvironment in terms of mechanism that you don't see that the Th2, Th17 inflammatory markers, which important not to add additional immune-related adverse events. The last point I would look in the quality, that's maybe something -- again, you should not compare between a trial. But since we are asking about the comparison of these things is the observation that we see is the complete response rate that we see in the epacadostat. And I don't think that was as high in comparison to what we see in the PIVOT-02 and back just to the mechanism of actions. Remember, IDO is similar to PD-L1. It's induced by interferon gamma. So it's in the same umbrella of mechanism of actions like PD-1. And I would have loved -- the only thing that I would have seen with IDO is anti-PD-1, actually higher CR rate. I would say the PR induced by the PD-1 and then that was limited by IDO. So IDO inhibition should contribute to deeper CR in terms of theory of mechanism of action, but we haven't seen that. So again, I think -- and maybe IDO was wrong to be combined with nivolumab, and you can argue about that mechanism as well. Totality to compare the data, I think these are the 3 mechanism, which I think the PIVOT-02 is still closer to what you see in the patients with a Phase III trial. And that's why I keep a promise. I shared with you that this is a Phase I -- or Phase II single-arm trial that has its own limitation for sure. But we look at the positivity of that the patient characteristics, the mechanism of action by biopsy proven and pre and on treatment, demonstrating the mechanism of actions with that and the data, the clinical data demonstrating very impressive CR rate.

And our next question comes from Boris Peaker from Cowen.