Morning, welcome everyone to the BeyondSpring R&D Day. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. As a reminder, this call is being recorded and a replay will be made available on the BeyondSpring website following the conclusion of the event. Before we begin, I would like to remind you of the company's forward-looking statements found here and in their filings with the SEC. I would like to advise listeners that comments made on today's call may reflect forward-looking statements that are related to such matters as BeyondSpring's clinical and pre-clinical research and development activities and results, regulatory and commercial plans, industry trends, market potential, collaborative initiatives, and financial projections, among others. While management believes that its assumptions, expectations and projections are reasonable in the view of the currently available information, you are cautioned not to place undue reliance on these forward-looking statements. The company's actual results may differ materially from those discussed during this call for a variety of reasons, including those described in the forward-looking statements and risk factors sections of the Company's Form 20-F and other filings with the SEC, which are available on the investor sections of BeyondSpring's website. Today's presentation will begin first with an introduction from Dr. Lan Huang, BeyondSpring Co-founder, Chairman, and Chief Executive Officer. Dr. Ramon Mohanlal, Executive Vice President, Research Development, will follow with an overview of the company's development program. We will then turn the call over to our esteemed key opinion leaders, Dr. Stephen Lin and Dr. Trevor Feinstein. After the presentation and company remarks, we will open the call for a question- and- answer session. It is now my pleasure to turn the call over to Dr. Lan Huang, Co-founder, Chairman, and Chief Executive Officer of BeyondSpring. Lan, please go ahead. Thank you. Thank you everyone for joining our R&D day. It's such early morning. Thank you for your continued support. We're very honored and privileged to have two of the leading experts to come with us and discuss plinabulin clinical development with you. First, Dr. Lin, who is a very well-respected radiation oncologist from MD Anderson. He has been working on plinabulin's immune mechanism for the last almost four years, and also is a PI for the triple IO combo in seven different cancers, which has started at MD Anderson. In addition, Dr. Feinstein has been with us for the last five years in the DUBLIN-3 study as a PI for the study. He is a board-certified medical oncologist from Piedmont Cancer Institute. Thank you, Dr. Lin and Feinstein for joining us. The next slide, please. Next slide. BeyondSpring is committed to raising the standard of care for cancer patients with first-in-class treatments that improves lives and clinical outcomes for millions of patients in life. We have a very robust pipeline with lead asset plinabulin currently in two near-term NDAs and also three pre-clinical IO agents. We also have a targeted protein degradation molecular glue discovery platform, which was recently validated with a recent $800 million R&D collaboration with Eli Lilly, that's in our subsidiary SEED Therapeutics. Next slide, please. We are developing plinabulin as a pipeline in the drug. As you have already seen, CIN has been proven in six clinical trials in over 1,200 patients. We just received priority review from U.S. FDA with a PDUFA date November 30th, 2021, this indication also received breakthrough designation last fall. In addition, plinabulin has potent immune anticancer activities. We are expanding plinabulin into other anticancer indications, including the DUBLIN-3 study in non-small cell lung cancer and also in a few different cancers in triple IO combo, which will be transforming opportunity for plinabulin and potentially making plinabulin a cornerstone therapy in the IO treatment landscape for cancer. Next slide. Now let me give you the journey of plinabulin, which we are developing as a pipeline drug. Plinabulin is a first-in-class selective immunomodulating microtubule-binding agent. We call it SIMBA. Next slide. We have been developing plinabulin from the treatment of chemotherapy-induced side effects to the direct anticancer therapeutic effect. Let me give you a brief overview where we are in the CIN prevention indication. Next slide, please. Chemotherapy kills fast-dividing cells, including neutrophil in the bone marrow. Therefore, CIN is a problem for bone marrow independent of chemotherapy type or cancer type. We believe that the data and the mode of action of plinabulin support the broad use of plinabulin for protection against CIN in Week 1 when G-CSF are not effective. We call the Week 1 as the neutropenia vulnerability gap. G-CSF approved for the broad label is effective in Week 2 and provides the base protection for CIN for the combination regime. As such, our proposed label for the plinabulin and G-CSF combination is for all solid tumor and all chemo for prevention of CIN. Next slide, please. Here is a detailed description of the favorable benefit risk profile of plinabulin and G-CSF combination, which elevates standard care in CIN prevention in 30 years. In short, compared to G-CSF alone, plinabulin and G-CSF combination has improved efficacy in AEC-based endpoint and in clinically meaningful endpoint, such as reduction of incidence and severity of febrile neutropenia and hospitalization, and very importantly, also with improved safety, including reduction in bone pain. Next slide. As such, we have filed NDA for the CIN indication using sx clinical studies in over 1,200 patients, and we are very honored and also grateful to FDA's support to give us priority review, and the PDUFA date is end of November. Next slide, please. As you see that plinabulin and G-CSF combination is elevating standard of care in the last 30 years, and we have very targeted approach to marketing. As you see, the current U.S. is very focused in 360 multi-centers, accounts to 81% of G-CSF use, and just 150 sites on the networks actually accounts for $2.1 billion of G-CSF sales. Just in four cancers, that accounts to 79% of the G-CSF use. Our go-to-market strategy is very targeted. We let the disease awareness to be the champion, really educating the market on the neutropenia vulnerability gap and positioning plinabulin in the right manner, and also with a very targeted market access program. With that said, I'm going to turn the baton to Ramon. Next slide, please. Ramon is our head of R&D, and he really have been developing plinabulin as his brainchild for the last five years. Let him take you through our strategies and all the thinking behind developing plinabulin as a pipeline drug. Ramon. Thank you, Lan. As we are continuing to work with both the U.S. FDA and the China FDA in getting the CIN application approved, we will increasingly now also direct our attention to the anti-cancer development program of plinabulin. This here is an overview of our plans how to develop the plinabulin as a triple IO combination. As a start, a brief summary about plinabulin. Plinabulin is a small molecule. It is a simple manufacturing process, three-step synthesis. Plinabulin is given by IV infusion on the same day of chemotherapy. Regarding the mechanism of action, plinabulin acts primarily through immune enhancement for the anti-cancer application. I will show you, in the next slide, more detail about how plinabulin helps to activate and maturate the dendritic cell. In addition to being an immune-enhancing agent, plinabulin also has direct anti-cancer activity in a number of cancers that you see listed here. On the top, you see small cell lung cancer. That is the reason why we initiated the triple combination, with nivolumab and ipilimumab in small cell lung cancer. In the box on the right at the top, you can see that plinabulin currently through all clinical trials, has been exposed to more than 700 patients and is demonstrating a favorable safety and tolerability profile. Next slide, please. Regarding the mechanism of action, on the left at the top, you can see in a box plinabulin, which essentially binds to tubulin. Tubulin is depicted by those blue lines, the light and the dark blue lines. Upon binding to tubulin, plinabulin releases a signaling protein called GEF-H1, depicted in orange, in that orange oval. GEF-H1 next triggers an intracellular cascade of signaling through the Rho pathway and the JNK pathway. An important target cell for plinabulin for its activity is a dendritic cell, which is depicted at the bottom in the middle, as a purple star type of cell. That is a dendritic cell, and that is where plinabulin primarily acts. It maturates and activates dendritic cells, which, as you will be aware, are critical to present tumor antigen to T- cells. The T- cells are depicted as that orange cell at the bottom. Upon activation of the T -cell, they are then next primed and enabled to target and kill cancer cells, which you can see at the left. On the right, what we show is a mechanism of action for the prevention of chemo-induced neutropenia. Essentially, what plinabulin does is it protects bone marrow progenitor stem cells against the insult of chemotherapy, of myelo-specific chemotherapy. By doing that, it preserves bone marrow stem cells so that they can produce neutrophils. You will be aware that plinabulin has a very fast onset mechanism of action for CAM protection, and this is the basis of that protection. That's why plinabulin is a very good addition to G-CSF, which, as we know, has a late onset of mechanism of action. Next slide, please. The immune mechanism, as you will be aware, is a cascade of events. It is not a single-step process but a cascade. On the far right, depicted as a Number 3, you see the step with checkpoint inhibitors, and checkpoint inhibitors in fact optimize T-cell responses after they are primed and activated. With the immune response, it always starts with Step 1 at the bottom, which is the generation of antigens, which are also called immunogens, if they are capable to stimulate the immune system. It always starts there in immunology, the generation of antigens. Antigens can be generated in many ways, through radiation therapy, through chemotherapy. I mentioned there are occasions that plinabulin also has a direct anti-cancer effect. Of course, there are tumors that naturally have a higher level of immunogens, such as melanoma and renal cell carcinoma. It always starts here. Generation of antigens that then need to be presented to the T cells, in order to make the T- cells active against these antigens. The presentation of these antigens to the T- cells occurs in Step 2 on the left, that is principally where plinabulin acts. Antigen presentation is done by dendritic cells, which are sometimes also called antigen-presenting cells, APCs. Plinabulin enables dendritic cells to effectively present the tumor antigens to the T- cells in order to get T-cell specific activation against those antigens. Based on this cascade, it is clear to us that Steps number 1, 2, and 3 are very critical components to obtain an optimal immuno-oncology response. This has become the basis for our development strategy in immunotherapy, because we mimic with our immunotherapy strategies exactly these three steps. Number one, antigen presentation. Number two, presenting these antigens through dendritic cells to the T- cells. Number three, optimization of T-cell responses. Next slide, please. With cancers, we know that we have what we call hot tumors on the right, which essentially are cancers that intrinsically harbor a large number of mutations, and therefore have a higher probability to have antigens and immunogens that are capable to stimulate the immune system. Generally, we call them hot tumors because they are able to stimulate the immune system. On the left, you can see that in that much larger box, these are tumors that we call cold tumors because naturally, they do not express antigens or immunogens to the extent that they can effectively activate the immune system. You can see this is a much bigger box than the box on the right. In our opinion, this is where the future lies with IO therapy strategies that we must make an inroad, and also access these cold tumors with IO therapy. Therefore, they will also become a candidate for the classical checkpoint inhibitors, PD-1 inhibitors, and CTLA-4 inhibitors. You can see at the bottom the notion that here at BeyondSpring, we have started to work on this exciting field that we believe will be an important next wave in the overall IO strategy. Next slide, please. In the next few slides, I will focus a little more on the hot tumor development strategies that we are currently employing because they are already clinical stage. Here again, to summarize what I just said, hot tumors essentially are immune responsive. They are intrinsically immunogens and antigens and are currently candidate for checkpoint inhibitors. The cold tumors at the bottom are not immune responsive or not very immune responsive, and they happen to be the majority of human cancers and currently not candidate for classical PD-1, PD-L1, and CTLA-4 inhibitors. Therefore, an important aim has to be to convert these cold cancers into hot cancers so that therefore they become candidate for immunotherapy. Next slide, please. As I mentioned, our hot tumor development strategy is clinical-stage, and that is why I will focus a little more on this program. I mentioned that the core foundation of our approach is a triple IO combo that is comprised of those three elements, something that generates antigens, Plinabulin that helps dendritic cells to present the antigens to the T- cells to activate the T- cells, and something that optimizes T -cell responses. This is the principle that we are employing, the triple therapy principle that we are employing in a number of different scenarios, because different pharma companies, they have different approaches in their checkpoint inhibition strategy. On the top, you see the combination of plinabulin, radiotherapy, plus PD-1/PD-L1 inhibitor. Dr. Stephen Lin will talk in more detail about this combination. This combination is employed by certain pharmaceutical companies, and of course, this is something that we will strongly develop further. Dr. Stephen Lin will also point out that we have proof of concept of this triple that I described, something that generates antigen, dendritic cell, mediate the presentation to T-cell, and optimizing T-cell responses. We have the proof of principle that if we have these three components in the mix, we have the best possible immune responses, better than other combinations with PD-1 inhibitors. I'll say that's what Stephen Lin. Number two is the combination plinabulin with chemotherapy, which is employed by Vir and other companies, and checkpoint inhibitors, PD-1s. We have a number of studies here also that we are currently preparing, and we will announce that very shortly. At the bottom, you see yet another type of triple combination that is being employed here specifically by BMS, who likes the concept of chemo-free IO strategies with PD-1 inhibitor and CTLA-4 inhibitor. Here we add plinabulin to the mix. Plinabulin here has a dual role, but not only is it capable in this select number of cancers that you see listed here to be the drug that generates the antigen, but it is also the same drug that helps the dendritic cells to be activated and present these antigens to the T- cell repertoire. This trial now has finished phase I, was recently presented at ASCO, and we will present some of that data here for you. This trial now has progressed into phase II. Next slide, please. Where do we see plinabulin positioned, moving ahead and looking forward, looking actually many steps forward? The way we see plinabulin is that it is the perfect candidate for us to become a universal add-on to any kind of cancer therapy. Plinabulin is very unique that not only does it have anti-cancer properties activity, it helps the dendritic cells to present antigens better and make checkpoint inhibitors work better. Plinabulin, as you know, is also an agent that prevents chemo-induced neutropenia. If it's added on to a chemotherapy backbone, it will not only help the chemotherapy to work more effective because the antigens generated by the chemotherapy will be presented in a more effective manner to our innate and adaptive immune system, but it also will prevent the chemotherapy-induced neutropenia that comes from that chemotherapy. If the backbone is immunotherapy and we add plinabulin to that, what we expect is that plinabulin will not only enhance the anti-cancer activity, but also, as I will show you in the next few slides, help to prevent the classical side effects with immunotherapy, which are immune-related AEs. Plinabulin being an anti-cancer agent, an agent that helps dendritic cells, and also an agent that prevents chemo-induced neutropenia and immune-related AEs. We see that as a perfect add-on to any given backbone moving forward. With that profile, it is hard to imagine why we shouldn't add plinabulin to any given cancer regimen. Next slide, please. With immune-related AEs, we are aware that these are the most commonly occurring adverse events with immuno-oncology. What CIN is for chemotherapy, the equivalent for IO, immunotherapy, is immune-related AEs. Immune-related AEs, when they happen to be Grade 3 or 4, they lead to permanent discontinuation of immuno-oncology treatment. With nivolumab and ipilimumab, that is around 40% in the case of small cell lung cancer and other cancer types, which means that 40% of patients will be taken off this treatment forever. If there is a tool, if there is a way that we could prevent this immune-related AEs, that would be a tremendous advancement in the field of immunotherapy, and we have initial evidence that plinabulin is able to prevent immune-related AEs due to the inhibition of an inflammatory pathway called PDE4 inhibitor. Next slide, please. In terms of development strategy in BeyondSpring, we typically avoid doing large head-to-head comparison trial because typically they require large sample sizes and the signal-to-noise ratio typically is not that favorable. Instead, we prefer to have an approach that you see at the bottom, where the patient serves as their own control in a concept that is called reversal of resistance of PD-1/P D-L1 therapy. A number of patients who receive PD-1/ PD-L1 therapy, they become resistant over time, and an important objective for us, therefore, is to convert that and to make the patient again responsive to these checkpoint inhibitors. This is an important strategy that we are employing also in the trial of Dr. Stephen Lin, and the small cell lung cancer trial. These are typically small trials because the patient serves as their own control. The next slide, please. These are the current studies that we are conducting, and Dr. Trevor Feinstein will talk about DUBLIN-3. I will talk a little more about the Big Ten study. Dr. Stephen Lin will talk about the Anderson, and the Anderson triple combination, we have an additional number of studies in preparation. Next slide, please. Regarding the Big Ten study, Dr. Jyoti Malhotra was not able to attend this meeting, therefore I will present the data to you. This poster was presented at ASCO several weeks ago, as you will be aware. Next slide, please. On the top, you can see that with this small cell lung cancer trial, the phase I has been completed, now we have advanced the trial, you can see that in that middle row, into phase II. At the bottom, we also have employed another triple combo, that is the combo that Dr. Stephen Lin will talk about. Next slide, please. Briefly about the design of this trial. This was a phase I trial. Of course, because this was the first time we put these agents together, plinabulin, nivolumab, ipilimumab, the objective therefore always has to be safety first, which was the primary objective, to determine the safe dose to go into phase II, which we determined to be the 30 mg/m2 dose, which is exactly the same dose that we are using in the anti-cancer trial, DUBLIN-3. Secondary endpoints included efficacy measures, ORR, PFS, but also a predefined secondary endpoint was the frequency of immune-related AEs. Next slide, please. This is a summary of the efficacy analysis that has been shared with you. The waterfall plot you can see on the right. The orange bars, those are PD-1/ PD-L1 resistant patients who received the triple combination of plinabulin, nivolumab, ipilimumab. The blue bars are the PD-1/ PD-L1 naive patients who then next received this triple combination. You can see that although this is a small phase I trial, that we have a highly promising overall profile of efficacy, which is summarized in the table at the top, where in the middle you can see the summary for the PD-1/ PD-L1 therapy naive patients. There we observed a response rate of around 50%. In the patients who became PD-1/ PD-L1 resistant, and that's the column on the right, who were resistant, and what that means is that they started to have disease progression on the checkpoint inhibition. When we gave plinabulin, nivolumab, and ipilimumab, we flipped that. We made them back responsive to immunotherapy in 43% of cases. Next slide, please. This is in brief, a summary. Efficacy summary on the right in green, the combination plinabulin, nivolumab, ipilimumab, the numbers are close to 50% in terms of response rates. Nivolumab and ipilimumab, you will be aware it has been withdrawn from the market because the pivotal phase III trial didn't meet its primary endpoint for efficacy. You can see that here, if we add plinabulin to that same nivo and ipi combination, we more than double response rates. At the bottom, you see the immune-related AEs summary. Typically, it's around 37% of subjects, of patients who have Grade 3 and 4 immune-related AEs at the left in blue. Here in this trial, with adding plinabulin to nivolumab and ipilimumab, we had 12.5% of patients with Grade 3/4 immune-related AEs. This is early data. We hope to confirm this data in phase II. Next slide, please. In short, I showed you the data about the triple, and on the right you can see the conclusions, that with adding plinabulin to immune therapy, we can resynthesize the immune system. We can help to increase antigen presentation to enable more effective T-cell activation. Also, we have cases here with very long treatment response, 18 months and longer, by adding plinabulin to nivolumab and ipilimumab. At the bottom, you can see that where we start here is with small cell lung cancer. It is our belief that if it works here, it will work in many other cancer types, that is listed at the very bottom, where plinabulin has demonstrated to also have direct anti-cancer activity. Next slide, please. That concludes my presentation, and I would like to invite Dr. Stephen Lin to give his presentation. Thank you. Thank you, Ramon. Next slide, please. It gives me great pleasure to introduce this AFQT early phase study here at MD Anderson that was activated recently. Just for the interest of time, I'll be quite brief in the preclinical rationale as well as the summary of the clinical trial. The PI is Vivek Subbiah, who is actually an associate professor in investigative therapeutics, and I'm from radiation oncology. Next slide. The reason for this, and the scientific rationale for this trial is that there is a significant interplay of cytotoxic agents with dendritic cell maturation. In this case, we were specifically focused on radiation therapy. Radiation is well known to actually not only stimulate pro-inflammatory cytokines within the tumor microenvironment, but also on the tumor cells, it can release tumor antigens as well as actually damage-associated molecular patterns that can activate dendritic cells and in combination with blockers like anti-PD-1/ PD-L1 agents, can actually also reverse the immune suppression within the tumor microenvironment and synergize with dendritic cell maturation in order to enhance systemic immune responses. Of course, we're interested in plinabulin because plinabulin is a dendritic cell maturation agent that can play a role and also synergize with radiation and other cytotoxic agents. Next slide. The key question is actually, is there a role for the sequencing of radiation or cytotoxic agents with a plinabulin potentiator effect? Is it necessary for pre-activating dendritic cells with plinabulin to enhance RT response, or is RT priming in terms of conducting radiation prior to stimulation and activating with plinabulin needed to actually enhance the response? Next. To answer this question, Next slide, please. To answer this question, we conducted experiments to actually examine the optimal sequencing with radiation with plinabulin to elicit dendritic cell activation. Either pre-treating the cells with plinabulin, and followed by radiation, or to actually add radiation for several time points prior to plinabulin treatment. What we found is that it's really the pretreatment of radiation, actually adding radiation to prime the system before dendritic cell activation. This is where we see the optimal dendritic cell activation, particularly within this window of three to six hours, before plinabulin treatment would be optimal to stimulate dendritic cell maturation and activation. Next slide. We've also found that in vitro, that this type of sequencing also enhances T-cell proliferation in a mixed lymphocyte reaction that you don't see, particularly with either radiation alone or plinabulin treatment alone. Next slide. Besides actually dendritic cell activation, which is actually based on we use the marker CD86. There are other costimulatory as well as actually inhibitory molecules that are also stimulated upon dendritic cell activation. We examine a number of these other molecules as well with plinabulin treatment. Next slide. In addition to what's expected, of course, is the CD40 and other MHC class molecules that's associated with dendritic cell activation. We also found actually PD-L1 is also co-activated and co-stimulated with plinabulin treatment. Radiation does also somewhat enhances and increases PD-L1 expression, but actually the greatest stimulation is also from plinabulin itself. Next slide. The previous slide was actually on mouse dendritic cells. We actually went on to validate this in human-derived PBMCs, and these are differentiated cells in vitro from peripheral blood mononuclear cells. What we found is that plinabulin also in a dose-dependent manner, also stimulated not only dendritic cell maturation, which we see here, from between 1 uM and 10 uM of plinabulin. Next slide. We also saw that with the same concentration, PD-L1 is also stimulated with these in vitro stimulated and differentiated dendritic cells. Next slide. This is important because it's actually well known that the induced PD-L1 activation on dendritic cells, not only by cytotoxic agents, but in this case, but possibly by plinabulin, may necessitate the need of a concomitant anti-PD-1/ PD-L1 blockade. This type of research was recently discovered in a couple of high-impact journal articles demonstrating that the PD-L1 expression on dendritic cells is really important, and it plays a key role as a regulator of T-cell immunity in cancer. Therefore, the rationale for the triple combination concept, which is adding an IO, an anti-PD-L1 agent, along with cytotoxic agents like radiation, along with plinabulin to optimize the immune stimulation effect. Next slide. We tested this in the lab, in vivo, in animals, in a syngeneic tumor model. What we found that in comparison to single agents or double agents with either anti-PD-L1 with radiation or plinabulin radiation, you see some local tumor response. However, you do not see as great a systemic immune response. However, it's only in the triple combination approach that you see the effective systemic response. Not only an excellent local tumor response, but also a systemic immune response. Next slide. This is further actually replicated in other experiments. This again shows that the antitumor response, the local tumor response, is significantly enhanced with the triple combination approach. Also even in an untreated, unirradiated tumor, what we call the abscopal tumor, contralateral to the side that's irradiated, you see actually a kind of an induced antitumor response only in the triple combination approach. Next slide. What we found is actually when we dissociated and did single-cell analysis of the intratumoral cells, only in the triple combination do we see an enhanced T-cell infiltration and immune stimulation in the triple combination approach that did not seem with double agent or single agents. Next slide. This is a working hypothesis for this clinical trial, is that the RT priming followed by plinabulin as well as concomitant anti-PD-L1 agents will have a synergistic effect of stimulating the immune response, what we call the triple combination concept. Next slide. This is a phase I-B/II study to evaluate the safety of adding plinabulin with RT and IO agents in IO-progressing solid tumors. The primary objective for this phase I study in a basket trial is to assess the safety and tolerability of combining plinabulin with our radiation and IO, and as well as to assess the overall response rate. There's also secondary objectives to look at disease control, to determine the progression-free survival time, as well as overall survival. There's a number of exploratory objectives that we incorporate into the study, which I will go over in the next few slides. Next slide. We are targeting seven cancer types, what's special about these seven cancer types is that these are all cancer types that currently have as a first-line status, a first-line indication to incorporating IO agent, either as a single agent or in combination with systemic chemotherapy. Next slide. This is the trial schema. Up to five lesions will be treated with radiation. However, what's important is that there's at least one or more lesions that would not be targeted by radiation, where we will use to assess the overall response rate. plinabulin will be added, of course, after radiation, this will be optimized based on our preclinical data, will be administered three to six hours after completing the days of radiation therapy. Anti-PD-1 agent or PD-L1 agent will be administered at the same time. There will be an option to administer radiation again at the next cycle of plinabulin with anti-PD-L1 agents, as well as subsequent cycles until progression or toxicity. Next slide. Here are the inclusion criteria. The seven histologic and cytologically confirmed neoplasms that progressed on previous immunotherapies, now anti-PD-L1, but also anti-CTLA-4 agent. At least, like I said, at least one lesion will be amenable for radiation, and then for at least one additional non-continuous lesion will be amenable for radiographic evaluation. We also collect tissues to conduct translational studies. Next slide. We will administer 3 to 5 fractions of radiation along with the combination plinabulin with IO agents. As I alluded to the schema, this will continue with plinabulin and PD-L1 in subsequent cycles. There will be an optional sequential RT for other untreated lesions as well. Next slide. We'll start with a starting dose of 30 mg/m2 per the other studies that actually the BeyondSpring has conducted in other cancer patients. Plinabulin again will be dosed three to six hours after radiation therapy. Next slide. I won't go into detail, however, this is based on a novel statistical design using Bayesian optimal interval design to re-identify the MTD for all comers. Next slide. The phase II will be conducted after completing the phase I in this basket trial of seven tumors, and based on the response rate, we will expand that cohort to an additional possibly 102 patients that we randomized per the control arm, which will be anti-PD-L1 with radiation versus a triple combination approach. Next slide. We'll conduct a number of translational study, including intra-tumor TCR sequencing, single cell RNA sequencing, as well as a number of objectives and translational endpoints looking at the whole blood samples to look at now immune profiling TCR sequencing, T-cell activation, Luminex cytotoxic, a cytokine assay, as well as ctDNA analysis. Next slide. This is my last slide. This activated a couple of months ago. We have now consented five patients, four non-small cell cancer patients, one renal cell carcinoma, and two patients have already received their first cycle of triple combination therapy without any adverse events. We're very happy for the activation of this study, and we're very optimistic to proceed forward to see exciting results in the future. Hopefully, we report in a subsequent meeting. Thank you very much for your attention. Actually, at this time, next slide, I'll be happy to introduce Dr. Trevor Feinstein, who will introduce to us the DUBLIN-3 results. Thank you. Hello, I'm Trevor Feinstein with Piedmont Cancer Institute, and I want to present from the clinical data of plinabulin and non-small cell lung cancer. Next slide. As a medical oncologist, when I see a patient with advanced non-small cell lung cancer, we need to look at the histology. We assess for driver mutation and always assess PD-L1 status. Simply, when we look at, we differentiate between squamous and non-squamous histology. This talk is going to focus on patients without driver mutations, but a patient with high PD-L expression, we tend to treat with a checkpoint inhibitor, although some will use a combination of chemotherapy with a checkpoint inhibitor or an IO therapy with nivolumab and ipilimumab. Lower expression of PD-L tends to enroll a backbone of chemotherapy plus a checkpoint inhibitor, with the chemotherapy being a bit different, platinum-based. In the adenocarcinomas, we tend to use pemetrexed for first-line, and squamous, we tend to use a taxane. Next slide. When we look at non-small cell lung cancer, excitingly, we see a decline in mortality, and this is probably from reduced incidence of lung cancer from decreased tobacco. We've seen that some of our novel treatments are extending survival. Unfortunately, lung cancer remains a leading cause of cancer-related death. Most of this is because most patients present with very advanced state and about a quarter of patients who present with advanced non-small cell lung cancer do not receive treatment. Older data seems to suggest only about 30% of patients will receive second-line treatment, although I do feel that with more modern treatments, more patients will receive treatment and more patients will be receiving second-line treatment. Let's advance. As a medical oncologist, where we're stuck at is after our patients have exhausted platinum-based therapy and immunotherapy, we're left with some challenging options in tumor treatments. In non-squamous, approved drugs are pemetrexed or docetaxel or docetaxel plus ramucirumab. Most patients have received pemetrexed first line with the platinum-based treatment. It leaves mostly docetaxel-based treatments. In our squamous cell histology, it's mostly docetaxel. Next slide. Docetaxel was approved as standard care based off of trials in the 1990s. The trial that led to approval was a prospective trial, which was patients were randomized to best supportive care or docetaxel. Patients were excluded from going on this trial if they had a prior taxane. At that time, we were trying to figure out the right dose of docetaxel. Half the patients randomized to docetaxel had a very high dose at 100 mg/m2, and the other half had 75 mg/m2. In the trial, only six patients, so about 7%, had a partial response, and they were split evenly between the two doses of docetaxel. Comment on that time to progression that led to approval versus best supportive care was 6.7 weeks-10.6 weeks. You're talking about a less than a one month's PFS benefit. When you look at median overall survival, it went from 4.6 months-7 months. What was noted is that the docetaxel at 100 mg/m2 was too toxic, and this has panned out in other disease types, too. Next slide. More recently, I was looking at ramucirumab, which is a monoclonal antibody against VEGFR-2, and this large trial looked at over 1,200 patients, and patients here were randomized. This is after failure of a platinum, but there was not immunotherapy given in this trial. Patients were randomized to docetaxel alone at 75 mg/m2, plus placebo, or docetaxel plus ramucirumab. In here, you did see a survival benefit increasing from nine months to 10.5 months with the combination, and you saw a slight benefit of progression-free survival from 3 - 4.5 months. With ramucirumab, there was significant increase in toxicity. There was increased bleeding, hypertension. There was increased intestinal perforation, arterial thrombus, and most medical oncologists do not use this combination therapy, maybe in an exceptional patient with a high-performance status. Next slide. Here's a heat map if you're not familiar with looking at the warmer the color, the greater the benefit is compared, and the cooler the color, the less benefit. Here, what you see is that despite spending 20 years of trying different combinations, nothing has really shown to be any better in after platinum failure than docetaxel. Next slide. Here we are now in the 21st century, and we're still treating after platinum failure, still with docetaxel. We've not made any improvement, and when we're talking about second or third-line treatment as medical oncologists and as patients alike, we want to increase their survival. We want to find a drug that's safe and most importantly, improve their quality of life, as we see that most of these patients don't usually have a long life expectancy. Next slide. I just want to highlight Study 101, which is just looking at plinabulin, at that time it was called NPI-2358. Here was in patients with advanced non-small cell lung cancer who had progressed on one prior line of therapy or two prior lines of therapy. Patients did not have to have measurable disease to go on the study and had to have an ECOG performance status of one or better. Patients were randomized to docetaxel or docetaxel plus plinabulin. In the study, there was two different dosings of plinabulin at 20 mg or 30 mg/m2, given on Days 1 and 8. Docetaxel was given standard of care at 75 mg/m2 every 21 days. Next slide. In the study, the primary was to compare overall survival to see if plinabulin had a benefit in survival. Secondary endpoints were looking at duration of response, progression-free survival, overall response. At that time, the PD-L1 expression was not analyzed. Next slide. What we had noticed is that the 30 mg dose of plinabulin was more effective than the 20 mg as an anticancer agent. A post hoc analysis in patients who had measurable disease, which turned out to be about a little bit more than 70% of the patients, and you looked at them with measurable lung disease, I'm sorry, the response data is presented below in the table. When you look at plinabulin plus docetaxel, the median overall survival was over 11 months compared to docetaxel alone of 6.7 months. Slight benefit in progression-free survival, but what you do see here is a significant improvement in overall response from 10% to 18.4%, which compared back to the old docetaxel data, which was around 7%. Next slide. Here's looking at your survival curve, where you can clearly see that in those who had measurable disease in the lung, the curves do separate, suggesting that there is a benefit of this combination. Next slide. When it was looked at incidence of neutropenia in the docetaxel arm alone, 28.8% of patients had significant neutropenia, versus when we look at the plinabulin dose at 20 mg/m2, only 5% of patients had neutropenia. Next slide. What was also interesting is that you saw a reduced rate of patients becoming septic and severe infections with plinabulin. You also saw that there was significantly less dose reductions of docetaxel, meaning that in the plinabulin arm, only 6% of patients had to have dose reductions of their docetaxel versus in docetaxel alone, 19% of patients had to have their docetaxel reduced. Next slide. This leads to the DUBLIN-3. DUBLIN-3 had both squamous and non-squamous histology. Patients had to have an ECOG performance of 2 or less. If you're not familiar with ECOG, that means that someone is unable to perform a job, even a light desk job, but is able to perform their activities of daily living. Patients had to progress on at least one line of therapy, although you were able to progress on two lines of therapy. Patients needed to have measurable disease in the lung and was okay for prior checkpoint inhibitor therapy. This is a more modern treatment regimen. This is a randomized trial. It was global, and it was stratified per region, Asia versus non-Asia, and second versus third line. What was needed was a single blind. As physicians, we got to know what the patient was receiving, but patients were blinded with getting a placebo. Next slide. The design of the study was a 1-to-1 randomization. It is fully enrolled. 559 patients have enrolled in the study. The final outlook is anticipated soon, but I want to highlight what were our endpoints. The primary endpoint was overall survival. Secondary endpoints were response for PFS, percent of patients without neutropenia on Day 8, and then looking at cutoff rates at overall survival at 24 and 36 months, duration of response, and then quality of life characteristics. At the bottom is proportion of patients, how many patients were able to receive 8, 10, 12 cycles of docetaxel. Next slide. Treatment design was docetaxel was given at 75 mg/m2 on Days 1 every 21 days, and plinabulin was given on Days 1 and 8 at 30 mg/m2. It was given one hour after docetaxel was completed. Next slide. Unfortunately, the data is not out to present outcomes, but hopefully, that'll be out soon, and I'll be able to present that in the near future. I want to highlight two case studies of patients that I treated on the DUBLIN-3 study. As you know, this was not blinded to me, a physician. The first one is a 75-year-old man with heavy tobacco consumption, who had a history of severe mitral regurgitation. In 2015, he presented with cervical lymphadenopathy, lymph nodes enlarged in the neck. They were biopsied, it was consistent with adenocarcinoma of the lung. He was treated with carboplatin and pemetrexed, it was after four cycles, he was placed on maintenance pemetrexed with disease progression. At that time, he received second-line treatment with nivolumab. During his treatment with nivolumab, within about six months, he developed brain metastases. The disease below the brain was stable, he received whole brain radiation therapy and was kept on nivolumab. In May of 2017, or actually probably April 2017, he developed progression in the lung, at that time, he enrolled in DUBLIN-3 and received docetaxel plus plinabulin. He had stable disease and was able to receive 13 cycles of still stable disease. At that time, unfortunately, his mitral valve regurgitation became significantly worse. He was recommended by cardiac surgery to repair his mitral valve, and he declined at that time and enrolled into hospice. Next slide. What we can see here is that after a year of treatment, his cancer had not progressed, and he had very stable disease, which is excellent to say, and there was no signs of any progression at the time of him coming off the study. Next case. Next, I have a 78-year-old man, and this gentleman was a little bit worse performance status with an ECOG of 2, but presented with squamous cell lung cancer and had a history of significant GERD reflux. In September 2016, it was thought to be a very local disease and was planned for a right upper lobectomy. Unfortunately, the disease was more advanced, and he had to undergo a pneumonectomy, and he had lymph node-positive disease. Normally, you would treat this with adjuvant chemotherapy, but he had significant complications after his pneumonectomy and adjuvant therapy was not given. Within three months after undergoing his pneumonectomy, he relapsed in the right bronchial stump, biopsy-proven squamous cell. There was no driver mutation and low PD-L1 expression. At that time, disease was not found outside of the lung, and he was treated with concurrent chemoradiation utilizing carboplatin and paclitaxel, and actually progressed during radiation. He was treated with avelumab with progression after nine cycles, and then in October 2017, received docetaxel and plinabulin. He had two cycles, and then unfortunately, he had a gastric ulcer which perforated, unrelated really to his treatment. After his perforation, he became very ill and went into atrial fibrillation. He was recommended to undergo surgery. He declined to undergo surgery and went into hospice at that point. He did better in hospice without treatment and came out of hospice, and at that time, we decided to just watch him, and he did not go back on any treatment. What I find fascinating is that his last treatment of plinabulin was in November of 2017, and it was not until September of 2018 that I saw there was any evidence of disease progression. You had someone who had almost stabilization for a year after two cycles of treatment. Go to the next slide. Here you can see just part of his disease and how extensive that was in the lung without really any signs of progression. Next. I want to highlight next Study 105, which is designed for chemotherapy-induced neutropenia, non-small cell lung cancer. I want to really focus on what are some of the supportive data shown here. Next slide. In Study 105, this was a phase II to phase III randomized double-blind study of plinabulin versus pegfilgrastim in patients receiving docetaxel after progression after platinum-based therapy. This is a four-arm study. One arm received docetaxel as standard care plus pegfilgrastim, and then there were three arms with three different doses of plinabulin plus standard of care docetaxel. In this, we assessed for absolute neutrophil count with multiple days during the first cycle. Next slide. I want to highlight some things besides just chemotherapy-induced neutropenia when you look at the study. What's interesting is that in the arm of patients who received plinabulin, no patients had any thrombocytopenia, low end of the platelets, but 35% of patients who received pegfilgrastim had thrombocytopenia. Thrombocytopenia is not a benign condition. Most patients with advanced non-small cell lung cancer suffer from things like hemoptysis, coughing up blood, and you lower those platelets, that can increase. Next slide. When we look at neutropenia, when we look at Study 105, with docetaxel, you saw that 31% of patients had Grade 4 neutropenia on Day 8, and in the arms receiving plinabulin at the 20 and 30 mg, it was only 2.6% of patients had Grade 4 neutropenia. In Study 105, when you look at comparing plinabulin versus pegfilgrastim, you basically find that there's similar benefits in prevention of significant neutropenia. Next slide. Now, we know that pegfilgrastim, one of the challenging side effects is bone pain. In this study, no patients were allowed to have bone pain at the time of entry. When you look at the pegfilgrastim, 35% of patients reported bone pain, and bone pain can be severe. Our own practice, we prophylactically put all patients on Claritin to reduce their bone pain because it's significant. The bone pain is not short. In this study here, you find that bone pain first became present about three days after receiving pegfilgrastim and peaked on Day 7, but did still continue after day seven. When we look at the plinabulin arm, no patients had any bone pain after Day 3. Next slide. Other important factors, realize that this is all palliative treatment that we're giving patients, is that patients who received plinabulin had significantly less fatigue, had significantly less pain, and had significantly less insomnia compared to pegfilgrastim. Next slide. Just to highlight here, docetaxel alone has a modest benefit. We've seen that in some of our trials that there seems to be a survival benefit. Some of these patients who respond can have very durable responses. In the last study I just presented, there was one patient who had a complete response that was durable. When we look at safety concerns, docetaxel is not a benign drug. It can be challenging. It causes 10%-20% of patients will have neutropenic infections. There can be nausea, there can be thrombocytopenia with it. When we look at the combination, we find some hints that there's no increased toxicity. We see that there's reduction in thrombocytopenia. We definitely see that there's reduction in neutropenia, less infections. We find that there's less dose reductions of the important chemotherapy drug. It's convenient in that it's a same-day treatment versus pegfilgrastim, where a patient will have to come back to the office the next day to receive it, or they have to go home with an antibody injector. It's frustrating as a doctor when your patient calls you the next day and says, "My antibody injector failed to deploy" then you have to bring them in for treatment. Importantly is quality of life. I commend them to be looking at quality of life, but we see that there's superior quality of life with this combination. There's less bone pain, and that patients complain of less fatigue, less insomnia, and these are important things at end of life. Well, this concludes my part of the talk. Let's go to the next slide, and I want to welcome Elizabeth to finish up the talk here. Thank you, Dr. Feinstein. Well, we've just heard an awful lot of specifics about why we believe plinabulin truly can realize its potential as a portfolio and a product. What I'd like to try to do now is to summarize the value of BeyondSpring and the value proposition that we offer. BeyondSpring is committed to... Next slide, please. BeyondSpring is committed to raising the standard of care for cancer patients in the largest global markets with first-in-class treatments that improve lives and clinical outcomes for millions of patients in need. Our value proposition includes de-risked late-stage assets with the potential launch of plinabulin and CIN in early 2022, with phase III data in non-small cell lung cancer coming out in mid-2021, and with our triple combo IO trials, which are underway. We target large markets, including CIN, solid tumors, and IO combinations. We have two important advantages with our cost of goods, as plinabulin is a small molecule with a simple manufacturing process, where we work with top CMOs and our broad and long IP coverage, with coverage through 2036 in 36 jurisdictions. We have global capabilities with the U.S. and China representing the two largest pharmaceutical markets. Finally, our cash position at March 31st, 2021, was $90.6 million, which is sufficient for our clinical and pre-launch costs. Next slide, please. Plinabulin has value in CIN, where it targets a broad range of cancer and chemotherapy and can elevate the standard of care. It also has value in anticancer, specifically in non-small cell lung cancer and in other cancers, with an opportunity to establish plinabulin as a cornerstone in IO regimens. Finally, I would like to remind you of our upcoming milestones, which include that we expect to report top-line phase III data in non-small cell lung cancer in mid-2021. We have our PDUFA date of November 30th, which has been set by FDA for plinabulin and CIN. We expect to maybe have early clinical data already in our IO combo in fourth quarter 2021. The big thing we're, of course, looking forward to is also our potential launch of plinabulin and CIN in early 2022. We have a lot to look forward to, and I think at this point, I'll turn it back to the operator so that we can have our Q&A sessions. Thank you. Thank you, Elizabeth. At this time, we'll be conducting a question- and- answer session. If you would like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. To our analysts, we invite you to join via Zoom now. Please hold while we poll for questions. Our first question comes from Jason Gerberry from Bank of America. Please go ahead, Jason. Jason, I think you might still be on mute. Okay, our next question comes from Fong Chi from Bank of America. Fong, please go ahead. Hi, this is Chi for Jason Gerberry at BofA. Thanks for taking my questions. Can you hear me? I just want to make sure that I'm not on mute and you hear me properly. Yes, we can hear you. Okay, awesome. Thanks so much. I guess, the first question may be for the KOLs. Curious, if DUBLIN-3 is able to replicate the data that we have seen from phase II with plinabulin chemo combination, do you expect the combination to become the standard of care if approved in the U.S.? I have a couple of follow-ups after that. This is for Dr. Feinstein? Yeah, sure. If I understand your question correctly, if we find similar survival benefits in the DUBLIN-3 compared to Study 101, will this become standard of care? Yes. In your practice, yeah. Yeah. Okay It would only become standard of care at that point because you've now kind of got the home run. You've increased survival, and you've reduced toxicity compared to, you look at other combinations with minimal improvement of any overall survival and significantly increased toxicity. Yes, it would quickly become standard of care. Sure. Maybe the same question for you as well, Dr. Feinstein. You talked about two case studies. There was a patient with mitral valve insufficiency and heart failure and other patients with gastric perforation and gastric ulcer and atrial fibrillation. Did these patients continue with these adverse events? Can you confirm whether these adverse events are adjudicated to be treatment-related? I don't believe they are treatment-related. The patient with mitral valve regurgitation had preexisting mitral valve regurgitation before the diagnosis of lung cancer. I mean, there was an echo showing that it was severe before going on any treatment. I just think this is what happens to his mitral valve over time, talking with his cardiologist. It's not felt to be disease-related or treatment-related. In regard to the gastric perforation, I don't think this was treatment-related either. The gentleman had an underlying gastric ulcer that just happened to perforate. I think it was just unfortunate timing of those two. I don't believe they were treatment-related. Okay. Thank you very much for the clarification. I guess one last question from me for management. You talked about exploring plinabulin triplet with IO therapies in other tumor settings beyond small cell lung cancer, and one of them is CNS tumor, which is a PD-1 approved therapy. I'm curious, can you talk about the scientific rationale for studying the triplet in CNS tumors? In particular, what considerations we should be aware of as it pertains to ability for each individual component to cross the blood-brain barrier. Thank you. Yes. This is Ramon. I'll take that question. We have evidence also that plinabulin is active as a single agent in GBM. We also know that plinabulin crosses the blood-brain barrier. GBM is an area of focus to us as will be other CNS cancers and will be subject for future trials. Okay. Thank you very much. Thank you, Chi. Our next question comes from Maury Raycroft from Jefferies. Maury, please go ahead. Hi. Good morning, everyone, and thanks for taking my questions and thanks for the event today. I had a question for Dr. Feinstein. I was wondering if you expect there to be differences in the checkpoint inhibitor-naive versus experienced patients in phase III DUBLIN-3, and what would you be looking for based on the stratification of these patients? Wish I could answer that question without the data yet, but when you look at the preclinical, my suspicion is there might be some benefit of those who had prior checkpoint inhibitor therapy. My example is both those patients have very durable responses. In other patients I treated on the study, I seem to find that same sort of response. Our standard in the U.S. will be is almost every patient will have received a checkpoint inhibitor prior to going on any docetaxel, although in other countries, that's not quite standard, although I think that's becoming standard of care. Got it. That's helpful. I also had a question, just when thinking about the total data for plinabulin in the context of the phase III DUBLIN-3 study, how do you think about the contribution of plinabulin's benefit on CIN versus the anticancer benefit? I guess if you took out the anticancer benefit, would you still expect DUBLIN-3 to succeed based on just the CIN contribution alone? If I may start, and then I'll have Dr. Feinstein to also add his thoughts. Through interim analysis, we did discuss this topic. One way to address this question is to look at patients who have the full dose of docetaxel in both arms. Because obviously with CIN, the consequence will be that docetaxel dose will be reduced, and that is the basis of your question, if that is the reason why in plinabulin arm we have better results. If we only look at patients with full dose docetaxel in both arms, so that is constant, the chemo dose, and you add plinabulin to that, we continue to see the benefit. We know that it is plinabulin That is causing the anti-cancer benefit and not strictly through its prevention of CIN. Dr. Feinstein, I don't know if you have something to add to that. A little bit. I could add in that when you look at docetaxel alone, if you follow the NCCN guidelines, your risk of febrile neutropenia goes into an intermediate risk of 10%-20%. Most of these patients have more than one risk factor, over age 65, prior treatment, which would fall into a criteria where you should be using or considering growth factors. We know the inherent toxicity with pegfilgrastim, just the inconvenience, and the bone pain associated with it. If you have something that can be given on the same day, and has less toxicity and similar benefits in reducing of chemotherapy-induced neutropenia, I think that is a benefit there. The Day 8 infusion is not usually a big deal because most of these patients, we do follow up with them the next week anyways to make sure that they're doing okay. That's all helpful. I had one last question. When you were talking about the mechanism of action for CIN, you talked about the fast onset of benefit there. I was just wondering how you reconcile that fast onset with the bone pain improvement, how the mechanism works. Maybe if you can talk a little bit more about that. Yes. I can take that question. We indeed analyzed the neutropenia data from Study 106 further, and you're absolutely right in the basis of your question, in that the bone pain benefit with plinabulin indeed is coupled to the fast onset protection of CIN. We have the evidence through looking at the timing of when the peak of the bone pain occurs and the fast onset protection that kicks in. We do have reason to believe indeed that the bone pain benefit that we see with plinabulin is a direct consequence of its added CIN benefit and its fast onset mechanism of action. Okay. Thank you for taking my questions. Thank you, Maury. I'll now turn it over to Monique Kosse of LifeSci Advisors to read any questions that may have come over the webcast. Thank you, Tara. First question here comes from Josh Schimmer of Evercore. Says, "Great overview. Based on the data and literature, which solid tumors would you expect to be most responsive to plinabulin anti-tumor effect? Any plans to combine the SEED platform with plinabulin? Can you discuss the commercial opportunity for plinabulin in China? Yes. I'll start with the question, which tumor types? What we conveyed in this presentation is that plinabulin would be a candidate virtually in any given solid tumor types. With the cold tumors, it's important to convert them to hot. With the hot tumors, we have different strategies employed here, that would enable to, in an individual manner, target each solid tumor types, either through combination with de novo epi, with combination with radiation, with combination with chemo. That is where we would like to go with plinabulin in the concept of a universal add-on to any given anti-cancer regimen. I'll go next to the commercial question, and I'll ask Rich Daly to address that question. Yeah. Probably for the China question, I can take it first and then, of course, for Rich to add more. China is a huge market. For new cancer patients each year is over four million new cancer patients, and over 60% of them would use therapy. That's the candidate and also patient we need to help. That's why currently the biosimilar G-CSF in China market is already $1 billion, and it's growing over 30% a year. That's for the CIN market, right? As you know, plinabulin added to G-CSF is elevating the standard of care, so we could capture a large portion of this market and also helping patient with even good care. Secondly, for the non-small cell lung cancer, in China, almost one million new lung cancer patients each year, and those are additional patients we can help. That's the China question. Rich, you have anything more to add? Lan, I think you covered it really well. I also think that the U.S. opportunity, as we've talked about extensively with the NCCN guidelines changing and increasing the addressable population by more than 100%, and with the opportunity to combine with G-CSF, I think it's a pretty significant opportunity. The base business of G-CSF is in fact growing in the U.S. We're really excited about the data and the opportunity we have before us. I think the combined opportunity of China and the U.S., I think, presents a really robust commercial opportunity for CIN and then obviously for the non-small cell and all solid tumors, as Ramon pointed out. Yes, thank you, Rich. I know, Josh, you also had another question regarding SEED pipeline combination with plinabulin. SEED pipeline currently is still in very early preclinical studies, but as we move them forward, if in the cancer indications there is a complementary mechanism, we will, of course, have the opportunity to combine, which will potentially elevate standard of care. Thank you. Thank you, Elizabeth. I'll move to our next question from Andy Hsieh at William Blair. I have a multi-part question here, so several questions here. Just curious if there are plans to explore alternative ipi dosing or schedule in small cell lung cancer. Second question he has is, how would you objectively choose tumor sites to irradiate? His last question here is, Dr. Feinstein, do you re-challenge your non-small cell lung cancer patients with checkpoint inhibitors in practice? Thank you. Perhaps we should start with Dr. Feinstein first and then address the other two questions. Dr. Feinstein, this is about re-challenge. Sorry. Do I re-challenge? My standard of care answer is no, outside of a clinical trial. Have I done it before? Yeah, I have in a patient who might have had an early checkpoint inhibitor that was not approved and now with approval of one or sometimes where a patient had a very durable response and then went on chemotherapy, progressed, and sometimes we'll go back. Standardly, no, I would look for a clinical trial outside of re-challenging. Thank you. Next, I would like to ask Dr. Stephen Lin to comment on the question, which cancers are candidates for radiotherapy? Yeah. How do we choose the sites? I believe that was the question, if I understood correctly. Yes. We specifically know from other studies we've done, we have a number of trials that really try to look at the abscopal effect, just PD-1 and radiation alone in combination. We have a number of patients, or actually many patients treated, hundreds of patients actually by this point that started about four or five years ago. We know that certain sites, particularly the soft tissue sites or actually visceral sites, are actually quite antigenic, and we actually see the greatest response. We actually excluded bone mets actually as sites of antigen presentation or sites we'll irradiate for in terms of this enhancing immunogenicity. All the patients right now, what we examine is that they usually have one soft tissue site, either liver, adrenal gland, lung, et cetera. Those sites are actually preferentially irradiated. However, other sites, including bone, will be used to assess for treatment response, to assess overall response rate. Also, it's also safety. Of course, we want to make sure the sites we irradiate are safe for the patient, and that's how we usually choose when the phase I group send out the patient to say, and they always send it to me to evaluate. I will look at the patient based on the number of sites, the sites of metastases, to determine the sites to irradiate. I'll either, if I'm seeing the patient or one of my colleagues will be seeing the patient, we'll actually kind of decide and determine the sites to irradiate and the sites to evaluate. Thank you. There was the last question about the alternative dosing regimens for small cell lung cancer. Today in this trial, we follow the nivo/ipi schedule and adapt plinabulin to that. Obviously, if the trial continues to be positive and that confirmation we hope to see in phase II, we would like to continue with its schedule. Certainly, we will be open to explore other schedules. Does this answer your question, Andy? This was a written question. Okay. I believe it does. Okay. We'll move on here. Joe Pantginis at H.C. Wainwright & Co. has a question. He asks, "Can you please discuss your preclinical and/or mechanistic support for PDE4 inhibition in reducing IRAEs?" Thank you. Yes, I'll take that question. PDE4 stands for phosphodiesterase 4, which is a proven target today to treat inflammatory disorders. There are several drugs on the market that treat inflammatory skin disorders, but also pulmonary disorders through PDE4 inhibition. Immune-related AEs, in fact, are autoimmune responses. They mimic inflammatory disorders, as you know, and they are caused by the enhanced activity of the immune response induced by the combo nivo and ipi. The way we look at this, and the way we also discuss this with BMS, who is contributing to this trial, is that immune enhancement follows a different path of mechanism of action, as compared to inflammation. Those two are separate paths that have some extent of crosstalk, but they can be considered separate. We can have immune enhancement, and hence the anticancer efficacy with this combination, while with the PDE4 inhibition with plinabulin, we can reduce inflammation and therefore prevent immune-related AEs. This is a concept. This was a predefined secondary endpoint in this trial, in the BIG BANG trial, and we hope to confirm what we saw in phase I, which is a marked reduction of the Grade 3 and 4 immune-related events to occur. If that would hold, we believe this will be a tremendous advantage for plinabulin to be added to the nivolumab, ipilimumab, or PD-1/CTLA-4 inhibition combination because we expect it will not only enhance anticancer effect but also prevent the most common side effect, which are the immune-related AEs. Thank you, Ramon. The next question is on the DUBLIN-3 trial versus Study 101. Can you comment on the patient demographics differences between the two studies? What signal activity should we expect in the control arm? What are the main similarities and differences between the patient demographics of the DUBLIN-3 trial and the Study 101? Yes. I can start with maybe a response and perhaps Dr. Feinstein can add to that. With Study 101, the majority of the patients were recruited outside China. In fact, we had no patients from China. We did have Asian patients, but not from China. The majority was Caucasian. In DUBLIN-3, the majority of the patients were of Chinese origin, but we do have Caucasian patients as well. We do not expect that we will have regional differences that would impact outcome, and we expect what we saw in phase II with Study 101, that we would largely confirm that in DUBLIN-3. I would like to point out that the trial was stratified for region, so that therefore we ensure that the two treatment arms are balanced for the contribution of each region to each arm. We do not expect there is a basis for difference of the drug efficacy between Asians and non-Asians. An important part to confirm that is that we take intensive pharmacokinetic sampling, and we compare if the plinabulin pharmacokinetics are different between the regions. Thus far, we have no evidence that there is a difference. We do not expect that the two trials will have intrinsic differences, and as pointed out, the way the trials are designed is that they are stratified for region, and in this case, also for the number of lines. We expect the 101 data to be highly translatable to DUBLIN-3. Dr. Feinstein, you have anything that you would like to add? There's a few things, little differences, but you're right that most of it is fairly comparable between the two. The difference is in DUBLIN-3, you allow checkpoint inhibitors to be given. Also in the DUBLIN-3, you've taken a more kind of realistic patient population. You have ECOG 2 patients versus in Study 101 with just ECOG 0 and 1. You're taking a more true third-line patient population, people being a little bit sicker. The other sort of thing to highlight is the eligibility for the DUBLIN-3, a patient had to have measurable disease in the lung. In Study 101, patients didn't have to have measurable disease in the lung. There's a couple small differences. The other sort of thing is in Study 101, you had two different doses of plinabulin, versus in DUBLIN-3, you had one dose of plinabulin. Yes. Thank you, Dr. Feinstein, and thank you for bringing up the topic of the measurable lung lesion. The data that we showed here was in the subset with patients with a measurable lung lesion with a 4.6-month survival benefit. It is that subset design that we employed in DUBLIN-3. I just wanted to clarify the point. Thank you. Perhaps we can go to the next question if there's time. Yes. We'll take a couple more questions here. From the Study 101, what patients had a better benefit from the combo arm following what lines of treatment? Was the question for the Study 101? Yes. The Study 101 was obviously relatively small. It was phase II. It will be difficult to split that data up in different segments, and draw meaningful conclusions. That study was also conducted in second and third line in EGFR wild type patients. Obviously, at that time, checkpoint inhibitors were not yet approved, those patients were not in the mix. In terms of the key notion is that the type of patient population, in terms of second and third line EGFR wild type, we expect that will be comparable in Study 101 comparing with Study 103. With Study 101, I would say it was a relatively small study, and it probably would not be advisable to divide the data up in further segments. The one segment that we did employ is to select patients with a measurable lung lesion, which represented 70% of the data set in Study 101. The reason we selected this type of patient is because we can argue that these are the patients that are likely still immune responsive, because they still have a relatively earlier stage in the overall phase III, IV spectrum of disease. I hope that answers the question. It's phrased carefully because Study 101 is a small study, to further subdivide that in segments will always be somewhat challenging. Thank you, Ramon. Next question here is on the triplet rationale with XRT. Can you please comment on the direct effect of XRT plus plinabulin in cancer cells in preclinical studies? Does plinabulin plus XRT increase the tumor-killing effects of XRT regardless of immune activations? This question is for Dr. Stephen Lin. Yeah. Thank you for that question, actually. The direct effect that we know, of course, plinabulin has in some subset of tumors, it actually has a direct cytotoxic effect. Of course, your radiation, it also has, of course, a direct killing effect. The combination, however, I think just to be frank, we have not looked at specifically using clonogenic survival assays to see if actually plinabulin itself will be radiation enhancing directly on the tumor effects, tumor cells themselves. Most of our focus has been on looking at the dendritic size or dendritic cell stimulation effect of plinabulin, and therefore it requires a tumor microenvironment in vitro assays to really, specifically study that kind of question, but then also in vivo studies to look at the combination effect. The direct effect, radiation sensitizing effect, is something that actually would be very interesting to look at whether there would be a direct role for that. Thank you. Okay. Thank you. In interest of time, this is going to be the last question here. What level of response would be needed in the Dublin study to be of use in the medical community? How quickly or slowly could the oncology profession begin to use plinabulin as an anticancer therapy, should there be improvement? With how much of a response was the first question, and the adoption is the second question. I wonder, Dr. Feinstein, if you would be comfortable to make a start. I'll try my best at this question here. I guess the question is, one has to ask, is improvement in what? I think if you find that the DUBLIN-3 met its primary endpoint of overall survival benefit, it'll be rapidly employed and quickly accepted throughout the community. If it fails to meet its primary endpoint, when we look at some of the secondary endpoints, it depends on how many of them are positive. I think that would kind of lead to how quickly it is accepted in the community. If it's CIN, it will be, but it's going to be a slower, I believe, kind of adoption in the community. Just kind of having to convince someone that with a new agent that there are differences and there are some benefits, but they're changing a habit. If we do meet the primary endpoint, I think that would be rapidly accepted. Thank you, Dr. Feinstein. To add to that very quickly. The profile that we are developing in DUBLIN-3 with the combination of plinabulin plus docetaxel, is not only to have a survival benefit, but also the reduced safety concerns and importantly, improved quality of life. We have the Q-TWiST measure incorporated as a predefined secondary endpoint, which is a highly relevant endpoint for this population, which tends to be very sick. To have a proposition here that we not only have a survival benefit, but a longer survival at a high comfort level, at a high quality of life and minimized toxicity, we believe is a very attractive proposition here that would enable rapid adoption. Of course, we all have to wait and see what the final data results will show. Here, I think the key point is that we look at that profile, in terms of a survival benefit, but also importantly, to demonstrate the quality of life Q-TWiST endpoint, and that reduced toxicity. Thank you. Thank you, Ramon. That does conclude our question and answer session. I will turn it over to Lan for closing remarks. Thank you, Monique. Thank you everyone for spending your precious morning time with us, and really appreciate your support. As you see, we have a few very exciting months coming up with a few very important milestones to be released. Stay tuned, and I hope you have a nice day and nice weekend.