Good morning, welcome to BeyondSpring's ESMO Data Conference Call. At this time, all participants are in a listen-only mode. Following management's prepared remarks, we will hold a brief question and answer session. As a reminder, this call is being recorded today, September 20th, 2021. I'd 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, amongst others. While management believes that its assumptions, expectations, and projections are reasonable in 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 section of BeyondSpring's website. Joining us on today's call are Dr. Lan Huang, BeyondSpring Co-Founder, Chairman, and Chief Executive Officer, Dr. Ramon Mohanlal, Executive Vice President, Research and Development, and Chief Medical Officer, and Dr. Trevor Feinstein, MD of the Piedmont Cancer Institute, and the Principal Investigator for the DUBLIN-3 trial. It is now my pleasure to turn the call over to Dr. Lan Huang. Huang? Thank you very much, Darren. Hello, everyone, and thank you for joining today's call. We are very pleased to be here today discussing the DUBLIN-3 study, a global phase III trial with the plinabulin and docetaxel combination versus docetaxel in second-line and third-line non-small cell lung cancer patients with EGFR wild type, progressing on a prior platinum-based regimen. This data was presented earlier today at the 2021 ESMO Congress. Before we begin, here are our disclaimers. Let's start with the company highlights. Our lead asset, plinabulin, is being developed as a pipeline immunodrug and has shown promise in three separate indications: CIN prevention, non-small cell lung cancer, and IO combination therapies. We are currently seeking FDA approval with a PDUFA date of November 30th this year for plinabulin in combination with G-CSF for the prevention of CIN. We're here today to talk more about our exciting results of plinabulin tested as a direct anticancer agent in the non-small cell lung cancer indication. Our regulatory teams are in high gear preparing for our NDA filing in non-small cell lung cancer, which we anticipate in the first half of 2022. We believe that the success of DUBLIN-3 is a proof-of-concept study which showcased plinabulin's durable immune anticancer benefit and is a gateway into developing plinabulin in various cancer indications in combination with IO therapy. We have begun these IO combo studies in IIT studies, first in small cell lung cancer in U.S. sites, which was presented at ASCO this year, and in seven different cancers at MD Anderson Cancer Center. If these studies are successful, they will transform plinabulin into a potential cornerstone therapy in IO combos in the current cancer treatment landscape. We also have established great clinical partnerships and recently announced the co-development and commercialization partnership with Hengrui in Greater China. We, as a company, are committed to raising the standard of care and improving the lives of cancer patients in need using our first-in-class treatments. I will now turn the call over to Dr. Feinstein, our investigator of DUBLIN-3, for an overview of the DUBLIN-3 data. As you know, Dr. Feinstein currently is in Paris and just gave a talk on the DUBLIN-3 study at ESMO. Dr. Feinstein is a U.S. board-certified medical oncologist. He joined Piedmont Cancer Institute in 2011 and is a certified member of MD Anderson Cancer Network. I will now turn the call to Dr. Feinstein. Dr. Feinstein? Thank you, Lan. Here's a brief summary of the plinabulin clinical program in non-small cell lung cancer. It's important to remember that there is an unmet need in second and third-line treatment for EGFR wild type non-small cell lung cancer. With immunotherapies moved to first line, docetaxel-based therapies are the mainstay therapy for platinum-resistant non-small cell lung cancer. Docetaxel-based therapy has limited efficacy with a risk of severe neutropenia, and this context served as the basis for this clinical program. plinabulin was first studied in 2006 in a phase IA dose escalation study on days one, eight, 15 in a 28-day cycle with a 30 mg/m² dose of plinabulin was selected. In 2008, plinabulin was studied in second- and third- line non-small cell lung cancer, Study 101, in a phase IB study, which expanded into phase II. In the phase IB dose escalation Study 101, plinabulin was dosed on days one and eight, plus docetaxel 75 mg/m² dosed on days one of every 21-day treatment cycle. In the phase II part of the study, two dose levels of plinabulin were evaluated, 20 mg/ m² and 30 mg/ m², which were given on days one and eight, plus docetaxel 75 mg / m² dosed on day one versus docetaxel 75 mg / m² dosed on day one of every 21-day treatment cycle in second and third-line non-small cell lung cancer. Plinabulin plus docetaxel demonstrated a superior duration of response compared to docetaxel alone. The 30 mg / m² dose of plinabulin demonstrated better efficacy than a 20 mg/ m² dose. plinabulin is a first-in-class selective immunomodulating microtubule binding agent, SIMBA. When plinabulin binds to tubulin, an immune defense protein, GEF-H1 is released from microtubules. GEF-H1 is critical for dendritic cell maturation. Dendritic cell maturation is a key step in optimizing an immune oncology response. Here you see an overview of the phase III trial design. DUBLIN-3 was a global randomized active controlled phase III study evaluating the clinical efficacy and safety of plinabulin in combination with docetaxel on second and third- line therapy for non-small cell lung cancer with EGFR wild type. Inclusion criteria included ECOG performance status two or less, platinum resistance, and measurable disease in lung. Prior checkpoint inhibitor therapy was allowed. Patients were randomized to docetaxel at 75 mg per m² on days one, plus or minus plinabulin. plinabulin was dosed at 30 mg per m² on days one and eight. Treatment was continued until progression. The primary endpoint was overall survival. Secondary endpoints included overall response, progression-free survival, percent of patients with grade 4 neutropenia on cycle one, day eight, month 24 and 36, overall survival, Q-TWiST, and quality of life. The primary endpoint was overall survival from randomized based on intention-to-treat population. The planned sample size was based on 439 death events with approximately 554 patients to be enrolled, which provided 85% power to detect a treatment difference at a two-sided significant level of 0.05. Final analysis occurred after 439 death events reached. Log-rank two-sided nominal P value based on Kaplan-Meier overall survival curve of less than 0.046 was to be statistically significant taken into account to interim analysis. Restricted mean survival time method used a two-sided nominal P value of less than 0.05 to be statistically significant. The patient's baseline characteristics were similar between the two arms, with a median age of 61, slight male predominance, along with more patients having non-squamous histology. Most patients enrolled on the DUBLIN-3 had only one line of prior therapy. Now for the data from the study. The primary objective was met. The addition of plinabulin to docetaxel showed significant improvement in overall survival compared to docetaxel alone, with a significant log-rank P value of 0.0399, less than 0.046 P value threshold. Both median and mean overall survival were significantly increased, with mean overall survival having 2.3 months survival benefit. Attention should be paid to the tail of the Kaplan-Meier curve. Importantly, adding plinabulin to docetaxel had a very durable survival benefit for patients. In addition to increasing overall survival at 12 months post-treatment, the combination doubled overall survival at 24 and 36 months. At 48 months, 10.6% of patients who received plinabulin plus docetaxel survived, versus 0% with docetaxel alone. Looking at secondary endpoints in the trial, adding plinabulin to docetaxel treatment demonstrated a significant improvement in progression-free survival and overall response rate. The combination improved progression-free survival at six, 12, and 18 months. Overall response was doubled with the addition of plinabulin, from just over 6% to more than 12% in the plinabulin-treated patients. Subgroup analysis seen here as the forest plot demonstrates all subgroups equally benefited from the addition of plinabulin. No matter which way we broke these down, we saw promising hazard ratios indicative of clinical benefit in all subgroups. In exploratory endpoints, there was a significant improvement in overall survival for patients in the combination who received more cycle of treatment, as seen here, with at least four and eight cycles of treatment. In both of these graphs, we see the long survival tail in the plinabulin-treated patients. The overall survival hazard ratio improved as patients received more cycles of plinabulin. I'd like to highlight at each cycle, plinabulin added to docetaxel had a longer survival compared to docetaxel alone. The number of treatment cycles was a determining factor in the clinical benefit, further supporting plinabulin's suggested anticancer effect. Now for a breakdown on patients treated with PD-1 and PD-L1 immunotherapies, which are fast moving into the first-line treatment. The DUBLIN-3 trial opened in 2015. This was a global study, and at the time, failure of PD-1 or PD-L1 inhibitors was not required. As you all likely know, that changed during the trial, and as a result, some of the patients received first-line PD-1, PD-L1 immunotherapy during the study. The characteristics of patients exposed to PD-1 or PD-L1 were similar, with a median age of 61 and slight male predominance. PD-1 and PD-L1-exposed patients were more likely to receive two lines of prior therapy, along with equal number of patients from China and rest of the world. In PD-1 and PD-L1-exposed patients, squamous cell histology was more likely to receive plinabulin. Of patients who were exposed to PD-1 or PD-L1 inhibitors, around 23% of total patients, plinabulin and docetaxel arms trended towards a longer overall survival benefit compared to docetaxel alone. The expanded tail of the Kaplan-Meier overall survival curve compared to the intention-to-treat population supports plinabulin augmenting an immune oncology response in patients who received checkpoint inhibitor therapy. Hazard ratio is 0.68, the mean survival benefit is at 4.3 months. At 24 months, overall survival rate is statistically significant with the combination at 36% versus 12% in the docetaxel alone. Overall survival rate at 48 months is 12.5% for the combination versus 0% for docetaxel. Looking at whether study results differed by geography, you can see the subgroup breakdown in the Western-treated patients relative to the full intention-to-treat study population. Shown here, we pooled Western population patients from the phase II Study 101 with the DUBLIN-3, around 20% of the total patients. We only selected patients from the Study 101 for this pooled analysis who received the 30 mg per m² dose of plinabulin and were matched enrollment criteria for DUBLIN-3. On the graph, you can see a trend suggesting a benefit of plinabulin when added to docetaxel in the Western patient, including the long survival tail on the right. The hazard ratio is 0.81, similar to the hazard ratio at 0.822 in the intention-to-treat population. Looking now at the effects of plinabulin on the instance of grade 4 neutropenia, we see that plinabulin significantly reduced grade 4 neutropenia on cycle one, day eight, and significantly reduced neutropenia on day eight of all cycles, confirming the PROTECTIVE-2 study findings about plinabulin's effects on neutropenia and highlighting an added benefit of it for the treatment of non-small cell lung cancer. Continuing to look at safety measures, we see that plinabulin was well-tolerated with lower grade 3 and 4 adverse events than in the docetaxel-alone arm. There was a transient increase in hypertension with plinabulin, which resolved shortly after the plinabulin infusion. At the bottom, you see patients randomized to plinabulin had more treatment cycles. Adverse events were adjusted per patient year. plinabulin, again, demonstrates significantly less grade 3 or greater adverse events using this metric, as well as further hammering home the notion that plinabulin meets safety and tolerability thresholds. The next slide looks at Q-TWiST analysis, an important measure of clinical benefit that takes into account both quality of life as well as disease progression. When plinabulin was added to docetaxel, patients had significantly less time with grade 3 or greater adverse events before progression. Taking both of these into account, plinabulin improved quality-adjusted time without symptoms of disease and toxicity by over 18%, which is clinically meaningful. When treating advanced cancer, we should focus on patients' quality and quantity of their lives. Here in the DUBLIN-3, intent-to-treat population improved overall survival, progression-free survival, and response rate while reducing neutropenia and other grade 3 and 4 adverse events. Remember, DUBLIN-3 met each of these endpoints with broad inclusion criteria. Patients only had to have platinum resistance, EGFR wild type, and measurable disease in the lungs. Plinabulin improved survival, especially in long-term survival, doubling overall survival at 24 and 36 months post-treatment. Also leading to more than one out of 10 patients surviving for four years. The benefit of Q-TWiST is clinically meaningful, as it incorporates progression and treatment toxicities. plinabulin's Q-TWiST is similar to pembrolizumab in advanced non-small cell lung cancer versus first-line treatment platinum-based chemotherapy in KEYNOTE-024, and those treated in second line versus docetaxel KEYNOTE-010. In conclusion, DUBLIN-3 study met overall survival, primary endpoints, and key secondary endpoints. In addition, in PD-1 and PD-L1 exposed patients, plinabulin and docetaxel combination showed more pronounced long-term survival benefits, with overall survival hazard ratio at 0.68 and tripling 24-month overall survival in the combination versus docetaxel alone. Docetaxel and plinabulin is well-tolerated, with lower grade 4 and grade 3 adverse events per patient per year in comparison to docetaxel alone. In addition, plinabulin protected bone marrow by significantly reducing grade 4 neutropenia of docetaxel 28%-5%. All in all, these key conclusions in the plinabulin plus docetaxel had favorable benefits to risk ratio, and this has the potential of preferred second and third-line treatment for non-small cell lung cancer with EGFR wild type. We'd like to thank all the patients and their families for their participation and essential role in the study. We'd like to thank all the investigators and medical staff from around 60 sites in the U.S., China, and Australia, and the study team for their contribution in the study. With that, I'd like to turn the call back over to Dr. Ramon Mohanlal for remarks for up-and-coming clinical development. Ramon? Thank you, Doc Feinstein. Now we have established plinabulin's unique immune mechanism as a SIMBA, and its durable anti-cancer clinical evidence, as shown in the DUBLIN-3 study. We have laid out a broad development plan for plinabulin, a triple combination with immunotherapy in various cancers to address the unmet need we currently have with immunotherapies. These are, as we see, firstly, the reversal of resistance to PD-1, PD-L1 inhibitors. Secondly, to improve on efficacy and safety with IO chemo combinations. Thirdly, the improvement of efficacy and safety with chemo-free IO combinations, in particular addressing immune-related AEs with these IO-free combinations. Number four, to convert cold tumors into hot tumors to make them candidate for immunotherapy. We will also develop triple combinations with plinabulin plus radiotherapy and checkpoint inhibitors. Importantly, we will focus on first-line treatment options with these IO triple combinations. Next slide. This slide summarizes our current studies with plinabulin in triple combinations. We already reported positive phase I data at ASCO this year with a triple combination of plinabulin plus nivolumab plus ipilimumab in small cell lung cancer patients who were either immunotherapy naive or had failed prior immunotherapy. We are looking forward to the initiation of the phase II portion of this trial in refractory small cell lung cancer patients. A study with plinabulin plus radiotherapy plus PD-1, PD-L1 inhibitors with the objective of reversing resistance to these prior PD-1, PD-L1 inhibitors is on the way at MD Anderson in seven solid tumors. This trial was initiated in June of this year. I will hand over to Lan for closing remarks. Lan? Thank you, Ramon. We're very proud of our accomplishments thus far, and we're excited to see the positive impact that plinabulin has on patients. Before opening the call for Q&A, I would like to give a brief overview of what's to come for plinabulin. After today's presentation highlighting plinabulin's anti-cancer effects in non-small cell lung cancer, we have seen evidence that plinabulin can directly treat cancer. This is in addition to the recently announced phase III data in prevention of chemotherapy-induced neutropenia, for which plinabulin is under regulatory review both in the U.S., with a PDUFA date of November 30th, 2021, and in China with NMPA. Additionally, at the recent ASCO conference, data supporting plinabulin's role as part of a triple combination IO treatment regime was presented, rapidly expanding its potential target treatment population. We plan to continue building the case for plinabulin as a pipeline immuno-drug to be developed in multiple cancer indications with potential to help millions of patients globally. I would also like to take the time to thank the patients, our dedicated team, our shareholders, and our partners for their continued support as we work towards improving the current standard of care for cancer patients worldwide. This could not be possible without your tireless efforts. That concludes our prepared remarks today. I will now ask the operator to begin our Q&A session. Operator? Thank you. At this time, we'll be conducting a question-and-answer session. If you'd like to ask a question, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you'd like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. Our first question comes from the line of Jason Gerberry with Bank of America. Please proceed with your question. Hey, guys. Good morning, thanks for the update and congrats on the data update. First question from me is just on the 36-month OS landmark data point. Do you have a sense or any hypotheses, it looks like about 10 patients formed that analysis for the plinabulin chemo arm. Maybe any predictors as to why those patients perhaps did better? I think it's obviously an important subset that could drive the value proposition of plinabulin in the lung cancer setting. I think roughly by our estimate, maybe 70% of patients haven't hit the 36-month time point, so at least for this analysis. Are the data maybe still too immature for that analysis? My second question, can you just share a P value on the median OS? Thirdly, just for Dr. Feinstein, if he's still on the line, any views on if plinabulin's approved for second line plus lung cancer, how you'd envision the treatment algorithm ultimately changing? How you'd consider second line IO retreatment strategies versus a plinabulin docetaxel combination? Thanks. Hi, Jason. This is Lan. Thank you very much for this insightful question. Regarding your question regarding the 36 months, as you see that from our data, you do see this 11.73% patient has a chance of living over 36 months versus 5.27%, which is doubling and with statistical significance. We haven't looked at those 10 versus four patients in depth. As you see that you do see from the ITT population and also from the PD-1, PD-L1 exposed patient, we do see a very pronounced longer-term benefit from the DP arm versus D arm. As you know that this is a randomized study that both arm basically is balanced. The longer survivor from the DP arm is consistent with plinabulin's immune mechanism. As you know, it's GEF-H1 inducer and also leading to the DC maturation and T cell activation, which Dr. Feinstein has explained. We think that if the mechanism action, which is science foundation, is consistent with what we see from the clinical evidence in extended longer survivor, we do believe the data and also is very hopeful that plinabulin using this as a foundation to go into other IO combos in the future. That's the number one question. Number two is, we did calculate the log-rank P value based on the curve, and that's the 0.0399, which we showed, and that's leading statistical significance. For the OS and less than the 0.046 we need to hit. That's the answer. I don't think we did median OS. It's just a log rank P. That's according to the SAP. Of course, we also did the mean OS, which should mean survival time, P value, which is 0.03. That's the second answer. Third one, of course, we let Dr. Feinstein to answer for you, and as he is very experienced in treating lung cancer patients, especially in the current PD-1 landscape. Dr. Feinstein. Hey, I hope you can hear me. I'm sorry. There's a little bit of noise in my background. The question was multifactorial from what I heard was one is, who are these long-term survivors? I think the data's still a little bit immature. It'll mature with time. Trying to find out if there's more of them. Number two, it seems to be a bit with the PD-1, PD-L1 exposed patients too seem to have enhanced long-term survival. Regarding to where do I think this goes in the future? Changing the landscape? Right now, immunotherapy, IO therapy has moved to first line, often combined with platinum agents. Patients will progress eventually. Most will progress eventually on that treatment. There still is a role for docetaxel after progression. Where do I see this? I see this kind of falling in for after your platinum and checkpoint inhibitor failures, which could be second, most often second line, unless it's mostly with IO therapy up front and platinum second. I do see it having a role and, as Lan had said, I do see it having a role later, being combined with IO therapy and being tested in that front there, too. Got it. Thank you. Yeah. Thank you, Jason. Yeah. Dr. Feinstein's still in Paris, just giving the talk now. Sorry for the noise behind. Thank you. Our next question comes from the line of Maury Raycroft with Jefferies. Please proceed with your question. Hi. Good morning, good afternoon, thanks for taking my questions. Congrats on the update. Just checking, at this point, can you provide more insights into subsequent treatments that patients used after they progressed and how that impacted overall survival data? Your question is, have we looked at all the subsequent therapies? How does it affect the OS? We look at the base, of course, all the analysis is based on ITT population. I think the later therapies, mostly, I think most people would use the TKIs, and some use PD-1 or PD-L1, but those are very minimal. I think we're still looking into all of those data. That's going to take some time to look at it. In the end, ITT captures everybody who used all the therapies in the study, and this is a randomized study, and you can see the baseline characteristic is balanced. Okay. You didn't disclose duration of response in the ESMO data update. Just checking if there's a reason why and when we could learn more about the DOR values between the two arms. Yeah. I think at the ESMO meeting, we didn't have this DOR in the analysis. In the future, definitely we will have that data in the publication or in future conferences. As you see from the overall survivor extended benefit and also the PFS showing the benefits, DOR is also in the right direction. Right. Also it's consistent with plinabulin immune benefit. Thanks for bringing this up and thanks for this great question. Got it. Okay. Maybe the last question, just for the PD-1 exposed patients, the KM curves don't separate until 12 months and maybe starting at about six months for the overall population. Can you provide more insight on what's driving the separation at later time points? This is a great question. As you see that the survivor benefit is more pronounced in this PD-1, PD-L1 exposed patients. We think that's very consistent with the plinabulin immune benefit because plinabulin is a potent APC inducer that we think it will add the T-cells into the system. With PD-1 in the system, releasing the brake, the car would go faster and that's analogy and so that's why you see the even more extended survivor in the DP arm. This is a randomized study and in the D arm also have similar amount of patients using, also exposed to the PD-1, PD-L1. The data is pretty consistent with plinabulin immune benefit. I think the early curve is not separating. We think that's coming from the docetaxel more or less, docetaxel early benefit. Right. We are seeing more of plinabulin late benefit here. Got it. Okay. Thank you for taking my question. Thank you so much, Maury. [crosstalk] Great questions. This is Ramon. Would you want me to comment too? I think part of it too is as most immunotherapy arms, you see kind of a late or a prolonged tail survival curve, and the theory on plinabulin's benefit is through immune mechanism with activation of dendritic cells. Most of the beginning is really kind of felt with the docetaxel, and that's kind of why you're not seeing much of a survival difference kind of at the first six months in patients who are exposed to immunotherapy. The thought is that with the prior exposure or with exposure to PD-1, that you're activating more of an immune response. Thank you. Our next question comes from the line of Andy Hsieh with William Blair. Please proceed with your question. Oh, great. Thanks for organizing this event and thanks for taking my questions. I have a question for Dr. Feinstein. Obviously in the absence of biomarker, I'm curious about, let's say, hypothetically, plinabulin gets approved in the setting tomorrow. How would you use this combination? I think in the discussion session, one of the discussants kind of threw this idea out in terms of patients who are elderly and who are at a higher risk of neutropenia might be more of a preferential population. Just kind of curious about your thoughts on that. Then also related to that, Lan, I'm curious about your thoughts in terms of the forest plot in the elderly population. If I remember correctly, if you stratify patients who are older than 61 years old and less than or equal to 61 years old, there's kind of a difference in HR in terms of overall survival. Just kind of curious your thoughts about the elderly subpopulation. Yeah. Dr. Feinstein, [crosstalk] you can go first. Do you want me to go first, Lan or do you? Yeah. I think the first question is [crosstalk] -- Okay. All right. --on the effect of elderly patients with neutropenia. I don't think I would just limit it to elderly patients. When you look at this population, you go back to the old data with platinum-refractory patients, their prognosis was pretty horrible with just supportive care. The average survival was about 4.5 months. Even in a younger patient who's failed platinum therapies, they don't have a very good prognosis with just best supportive care. One of the keys is the problem with docetaxel by itself, even though it originally had showed a survival benefit, is it's a fairly toxic agent. You cause neuropathy, right now in the pandemic, causing neutropenia. These are all problems that make it a challenging treatment that most oncologists aren't always excited about in this palliative setting. Here, what we're showing is that you do have a survival benefit, but you're also reducing the toxicity of docetaxel. The hypertension, which was a side effect, was very transient, usually resolved shortly after the infusion. The GI toxicity was very manageable. When I look at it from that standpoint, even in a younger person, why wouldn't you give them an agent which reduces the toxicity of the chemotherapy and does improve survival? Lan, do you want to take the second part with the Yeah. I think that this answers your question, Andy. Yeah. No, I was curious about maybe your perspective on the differences in hazard ratio, basically showing kind of a lower hazard ratio, so more profound benefit for people older than 61 years old or things like that. I don't know if you have any perspective you want to share from the forest plot analysis. I think probably I can just take this. The first part is looking at different subgroups, and you can see its consistency in the age group and all the other groups. I think for the median age over 61, it looks like the hazard ratio is a little bit better than the median age less than or equal to 61 years old. I would think that's around similar, that you cannot just say they are so much different there. Ramon, you want to add? Yes. To add to what was just said. I see your point, Andy, that with the [inaudible] being slightly better with the older patients. I think the key point that we are conveying here is docetaxel and docetaxel-based regimens have become standard of care in second and third line. The choice of the doctors will be to use the current standard of care or add trametinib to that standard of care. What you will then obtain is not only the survival benefit but also the safety benefit throughout the entire duration that docetaxel is given, and added to that, the quality of life benefit. I think it's important to point out that in second and third line, we still have a large fraction of patients, we estimate it's around 50%, that would not want to have a line in second and third line, not docetaxel-based or nothing, because of overall concern with the added toxicity and the negative impact on quality of life. What we have here is adding trametinib to that, improving overall survival, but during the time that the patients take treatment, they also have a reduced toxicity burden and improved quality of life. We believe that will be an attractive treatment offering to patients. Got it. That's very helpful. I have two safety-related questions, if I may. One is based on the AE profile, and I'm just curious if you could comment on the discontinuation rate across the two arms. I know it's not presented, but just kind of help us understand maybe the direction or any sort of qualitative metrics. Also, one discussion point that was brought up was basically the survival benefit was not due to the chemotherapy dose intensity. I am curious about whether there's any data to support that. Is there basically a balance of chemotherapy dose across the two arms or something like that to support that assertion. Thank you very much. Yeah. Thank you. Probably I can start with the AE, and then Ramon can add a little comment on this. I think you can see that definitely in the AE profile with equal to 10% of patients, the docetaxel arm has a lot more of the white blood cell count decrease and neutrophil count decrease. In our arm, we do see a little bit more of nausea and diarrhea, but those are all very small amounts in the grade 3 and 4, and those are also very short-lasting. Ramon can add more color. In addition, for the hypertension, it's all just grade 3 and also, it's short-lasting. It disappears usually within 24 hours after the infusion. Yes. The hypertension is primarily grade 1 and 2, but we have some grade 3 cases. The key with hypertension is it's so short-lasting. It's around the time of infusion. It lasts for a few hours. It is gone certainly the next day. With short-lasting hypertension, typically, physicians are not that concerned because a healthy human being will have short-lasting hypertension on probably any given day. With hypertension, typically, we are concerned if it's long-lasting. With the overall safety profile, we have to keep in mind that at all times we have more patients in the plinabulin arm, in the plinabulin combination arm than in the docetaxel arm. Typically, if you have more patients, you will have more AEs. Nevertheless, what we see is the opposite. We see an overall reduced grade 4 AE frequency. Even if you look at grade 3, 4 combined, and we look at the overall population over time, we have a reduction. Safety-wise, to come out, typically, if you add an agent A to an agent B, you have added toxicity. With here, with adding plinabulin to docetaxel, what we see is the opposite, reduced toxicity. In terms of the overall docetaxel dose intensity, we looked at that. If we look at the percentage of patients on the full dose docetaxel, they are comparable between the two arms. Therefore, we know that the benefit that we see in the plinabulin combination is due to plinabulin's direct anticancer effect. It is not that we allow more patients to stay on the high chemo dose and therefore we have more benefit. That definitely is not the case. If you look at the percentage of patients on the full dose docetaxel between the two arms, it is the same. Dr. Feinstein, I don't know if you have anything to add. [crosstalk] Probably I can just answer this in addition [crosstalk] to Ramon. Go ahead, An. Sorry. Yeah. If I can just quickly answer this very insightful question from Andy. Basically, you're asking is the anticancer benefit seen from plinabulin is also coming from the CIN benefit of plinabulin, right? As what Ramon said, if you look at a full dose of docetaxel in both arms, the potential is very similar. We do know that it is true that the DP arm had used more cycles. Even though in those cycles, similar extent of patient with a full dose of docetaxel. Also when we look at the same long cycles of treatment, such as six cycles, eight cycles, 10 cycles for both arms, DP arm still showed long-term survival benefit. The more cycles of docetaxel alone do not contribute to longer survival. Furthermore, the plinabulin doubled OR and improved endpoint at predefined time point. Lastly, there was a durable anticancer benefit seen in the combination. At four years, 10.6% of patients were alive with the combination and none were alive with docetaxel alone. This is a randomized study. All these three points is pointing to that plinabulin itself do have direct anticancer benefit. Andy, does it answer your question? Yeah. That's very helpful. Thank you very much. Okay. Thank you. Thank you. Ladies and gentlemen, as a reminder, if you'd like to join the question queue, please press star one on your telephone keypad. Our next question comes from the line of Joel Beatty with Baird. Please proceed with your question. Hi. Congratulations on the presentation today. My first question is, the ESMO presentation shows a favorable trend on hazard ratio in Western patients based on pooled data from the 101 and DUBLIN-3 studies. Are you able to share how the trend looked in patients just from the DUBLIN-3 study? Yeah. It's consistent with this. Hazard ratio 0.81 and 0.82 is similar. We think they are consistent. The W3 is also consistent. Great. Got it. Great. Another question is for non-small cell lung cancer, how could you see using plinabulin in the future if both the neutropenia and the anti-cancer benefit are approved? Would you use plinabulin up front during first-line if a chemotherapy regimen is used, and then also for a later-line therapy for the anti-cancer benefit? Would there be any reason to hold the plinabulin as a neutropenia agent up front to preserve its use as a later-line anti-cancer therapy? This is a key question here. I think probably you heard Ramon saying this very loudly. We think the WH study is really a proof of concept study to showcase plinabulin's immune durable anti-cancer benefit, which is consistent with its mechanism. With this shown that I think the next development program will be moving plinabulin in IO combo, PD-1, PD-L1, plus the chemotherapy which is already in the first line, right? Chemo actually combined with PD-1 actually added double the efficacy than PD-1 alone. That's basically introducing more tumor antigen. plinabulin as a potent APC inducer could introduce more T-cells into the system and then potentially, even more dramatically increase this efficacy. The first line is very important. In addition, plinabulin can also reduce the neutropenia of chemotherapy as additional benefit there. If I can add to that very quickly. With the CIN [crosstalk] Can I add to that? I'm sorry, go ahead. I was going to say, the other thing too you have to look at is the dosing is very different for CIN. The dosing for CIN is 20 mg or 40 mg flat dose versus here we're using 30 mg / m² days one and eight. Even if it's used and approved for first-line, you're dosing with docetaxel is going to be different. Yes, if I can add quickly to that. Of course, we also have, in addition to the lung cancer program, we have the CIN program that, as you are aware, is under FDA review. I just want to point out that with the CIN program, we are targeting all chemos, all cancers, and as we will be aware, breast cancer for CIN is the largest opportunity. Of course, lung cancer is a CIN opportunity with a smaller segment. That creates and supports the validity of also, of course, the second CIN NDA. You just heard the comments about the potential of using plinabulin in first line and second line. We will be going into first line. In terms of CIN with the current KEYTRUDA chemo combo, the amount of neutropenia is quite modest. I think the utility probably here will be in second and first- line. Great, thank you. Yeah, thank you so much. Thank you. Our next question comes from the line of Graham Tanaka with Tanaka Capital Management. Please proceed with your question. Yeah. Hi, congratulations. I wanted to ask a little bit more about the durability of the response, which seems to be incrementally really important. I was wondering if Dr. Mohanlal or Dr. Feinstein might comment or maybe even speculate a bit on what this means for the universality of this treatment into other cancer tumor types. Thanks. Yeah. Thank you so much, Graham. Probably would let Ramon talk about how applicability of this durable anti-cancer benefit in the lung cancer, which is shown here as a proof-of-concept study, how it can apply to other types of solid tumor and also all tumors. Yes. The mechanism of action of plinabulin is immune enhancing through activation of dendritic cells. That mechanism is agnostic for cancer types and therefore should be applicable for multiple cancer types and multiple chemos. The observation that we have with the durable response I think is very important also in the context of the overall product offering. What we show here is that we offer 10% of patients the probability to live longer than four years if the doctor would decide to put the patient on the plinabulin docetaxel combination as opposed to docetaxel alone. To offer patients the prospect of a 10% chance to live beyond four years, I think that's very attractive. Also, because during the time that the patients would live, they would live at reduced toxicity and improved quality of life. From a mechanism of action perspective, we see this as an important proof of concept that we now will apply to as we laid out a broad program in triple IO combination and moving into first line. I also would like to bring under your attention that the anticancer effect that we see here demonstrated, we also have demonstrated that through a second independent study in small cell lung cancer, and that data was presented at ESMO. In particular, what is important there is that we approximately doubled the anticancer effect as we see with Nivo and ipilimumab. Perhaps more exciting is that if the patients would have been on prior IO and chemo and become resistant, that with cenabrin, we can flip that and reverse them back to response. The collective evidence combined with our understanding of the mechanism of action suggests that this is an agnostic immuno approach that is broadly applicable to multiple additional indications that we will go after as we speak. Yes. Thank [crosstalk] you so much. Yeah. I'm just wondering if Dr. Feinstein would comment on the profession's willingness to embrace this. I don't know if you could talk about even using it off label, but it seems to be pretty appealing. Thanks. All right. Can you repeat that question again? I heard part of it. Yeah. I just was wondering, given the evidence, as Ramon mentioned, the collective evidence is pretty interesting as to other cancer types. Do you believe that some in the profession might use this off label should it be approved for non-small cell lung cancer? Thank you. For other types of cancers. Thank you. If we had an era where we could write what we wanted to, probably, but I think in today's era, where we're restricted by the payers, I think probably off-label use is going to be challenging to use. I think it'll be hard to get that approved and paid for. Right. [crosstalk] Okay. Yes. I [crosstalk] would agree with that. Of course, we will want to stay on label, and as a sponsor, certainly propagate that we stay on label. We do promise we will generate more positive data that then will support future labels in the future. Right. Do you anticipate any ability to speed up the approval process on filing for non-small cell lung cancer? I think it's already approved, received priority status, right? No. For this DUBLIN-3 non-small cell lung cancer study, we plan to file first half of next year. So far, the data is very fresh, so we haven't had any discussion with FDA yet. We will plan to in first, fourth quarter. That's still stay tuned. I think the CIN indication we do have priority review, and with specific date is November 30th. Right. Correct. Yeah. Got it. Thank you. Good luck. Yeah. Thanks for the great question. Thank you. Ladies and gentlemen, that concludes our question- and- answer session. I'll turn the floor back to Ms. Huang for any final comments. Thank you, operator. Thank you everyone for joining the call today, this morning, and thank you for your precious time, and also thank you for supporting us. Altogether, we are bringing this transforming medicine to patients in need, and they are our north star, and we work for them. Thank you. Thank you. This concludes today's conference. You may disconnect your lines at this time. Thank you for your participation.