Good morning
and 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 20, 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 preclinical 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 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 20 F and other filings with the SEC, which are available on the Investors section of BeyondSpring's website. Joining us on today's call are Doctor. Lan Wang, BeyondSpring Co Founder, Chairman and Chief Executive Officer Doctor. Ramon Mohanwal, Executive Vice President, Research and Development and Chief Medical Officer and Doctor.
Trevor Feinstein, MD of the Piedmont Cancer Center Institute and a principal investigator for the Dublin III trial. It is now my pleasure to turn the call over to Doctor. Lan Wang. Lan?
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 III study, a global Phase III trial with the Plinabulin and docetaxel combination versus docetaxel in second line and third line non sponsored line cancer patients with EGFR wild type, progressing on a prior platinum based regime. This data were 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 in the drug and has shown promise in 3 separate indications: CIM prevention, non small cell lung cancer and IO combination therapies. We are currently seeking FDA approval with a PDUFA date of November 30 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 twenty twenty two.
We believe that the success of DAPLINK III 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 this IO combo studies in IIT studies first in small cell lung cancer in U. S. Site, which was presented at ASCO this year and in 7 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 a co development and commercialization partnership with Henray in Greater China. We, as a company, are committed to raising the standard care and improving the lives of cancer patients in need using our 1st in class treatment. I will now turn the call over to Doctor. Feinstein, our investigator of Dublin III, for an overview of the Dublin 3 data. As you know, Doctor.
Feinstein currently is in Paris and just gave a talk on the DaVinci study at ASMO. Doctor. Feinstein is a U. S. Board certified medical oncologist.
He joined Pitt Mount Cancer Institute in 2011 and is a certified member of MD Anderson Cancer Network. I will now turn the call to Doctor. Feinstein. Doctor. 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 move 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 1a dose escalation study on days 1eightfifteen in a 28 day cycle with a 30 milligram per meter squared dose of Plinabulin was selected. In 2,008, Plinabulin was studied in second and third line non small cell lung cancer, Study 101 in a Phase 1b study, which expanded into Phase 2. In the Phase 1b dose escalation study 101, Plinabulin was dosed on days 1 and 8 plus docetaxel 75 milligrams per meter squared dosed on days 1 of every 21 day treatment cycle. In the Phase 2 part of the study, two dose levels of Plinabulin were evaluated: 20 milligrams per minute squared 30 milligrams per minute squared, which were given on days 1 and 8 plus docetaxel 75 milligrams per meter squared dosed on day 1 versus docetaxel 75 milligrams per meter squared dosed on day 1 of every 21 day treatment cycle in second and third line non small The 30 milligram per meter squared dose of Plinabulin demonstrated better efficacy than a 20 milligram per meter squared dose. Plinabulin is a 1st in class selective immunomodulating microtubule binding agent, SYMBA.
When Plinabulin binds to tubulin, an immune defense protein, GAF H1 is released from microtubules. GAF 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 3 trial design. Dublin III was a global, randomized, active controlled Phase 3 study evaluating the clinical efficacy and safety of Plinabulin in combination with docetaxel in second and third line therapy for non small cell lung cancer with EGFR wild type.
Inclusion criteria included e COG performance status, 2 oral glass, platinum resistance and measurable disease in the lung. Prior checkpoint inhibitor therapy was allowed. Patients were randomized to docetaxel at 75 milligrams per meter square on days 1 plus or minus penneblin. Penneblin was dosed at 30 milligrams per meter square on days 1 and 8. 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 1 day 8, month 24thirty 6 overall survival, Q Twist and quality of life. The primary endpoint was overall survival from randomized based on intent to treat population. The planned sample size was based on 4 39 death events with approximately 554 patients to be enrolled, which provided 85% power to detect a treatment difference at a 2 sided significant level of 0.05. Final analysis occurred after 4 39 death events reached.
Wahlgrenk 2 sided nominal p value based on Kaplan Meier overall survival curve of less than 0 point 046 was to be statistically significant taken into account 2 interim analysis. Restricted mean survival time method used a 2 sided nominal p value of less than 0.05 to be statistically significant. The patients' baseline characteristics were similar between the two arms, with a median age of 61, slight male prominence, along with more patients having non squamous histology. Most patients enrolled on the Dublin III had only one line of prior therapy. Now for the data from the study.
Firstly, 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 0.046pvaluethreshold. 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 36 months. At 48 months, 10.6% of patients 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 6, 12 18 months. Overall response was doubled with the addition of Plinabulin from just over 6% to more than 12% in the Plinabulin treated patients.
Further 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 and the combination who received more cycle of treatment as seen here with at least 4 8 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 receive more cycles of Plinabulin.
I'd like to highlight that each cycle Plinabulin added to docetaxel had a longer survival compared to docetaxel alone. The number of treatment cycles wasn't a determining factor in the clinical benefit further supporting Plinabulin's suggested anticancer effect. Now for a breakdown on patients treated with PD-one and PD L1 immunotherapies, which are fast moving into the first line treatment. The Dublin III trial opened in 2015. This was a global study and at the time failure of PD-one 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-one, PD L1 immunotherapy during the study. The characteristics of patients exposed to PD-one or PD L1 were similar with a median age of 61 and slight male predominance. PD-one and PD L1 exposed patients were more likely to receive 2 lines of prior therapy along with equal number of patients from China and rest of the world. In PD-one and PD L1 exposed patients squamous cell histology was more likely to receive pinedlon. Our patients who were exposed to PD-one or PD L1 inhibitors around 23% of total patients, Plinabulin and docetaxel arms trended towards a longer overall survival benefit compared to docetaxel arm.
The expanded tail of the Kaplan Meier overall survival curve compared to the intent to treat population supports Plinabulin augmenting an immune oncology response in patients who receive checkpoint inhibitor therapy. Hazard ratio is 0.68 and the mean survival benefit is at 4.3 months. And at 24 months, overall survival rate is statistically significant with a 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 intent to treat study population.
Shown here, we pulled western population patients from the Phase 2 Study 101 with the Dublin III, around 20% of the total patients. We only selected patients from the 101 study for this pooled analysis who received the 30 milligram per meter squared dose of Plinabulin and were matched enrollment criteria for double and 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 intent to treat population. Looking now at the effects of Plinabulin on the incidence of Grade 4 neutropenia, we see that Plinabulin significantly reduced Grade 4 neutropenia on cycle 1, day 8 and significantly reduced neutropenia on day 8 of all cycles, confirming the PROTECTIVE II 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 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 When treating advanced cancer, we should focus on patients' quality and quantity of their lives. Here in the Dublin III, in the attempt 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 III 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 36 months post treatment and also leading to more than 1 out of 10 patients surviving for 4 years. The benefit of Q Twist is clinically meaningful as it incorporates progression and treatment toxicities. Enablon's Q Twist is similar to pembrolizumab in advanced non small cell lung cancer versus first line treatment platinum based chemotherapy in KEYNOTE-twenty four and those treated in second line versus docetaxel KEYNOTE-ten. In conclusion, Double 3 study met overall survival primary endpoints and key secondary endpoints.
In addition, in PD-one 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 pinaablon is well tolerated with lower grade 4 andgrade3 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% to 5%. All in all, these key conclusions in the pinapline 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 wildtype. 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 United States, 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 Doctor. Ramon Mohai Ah for remarks for up and coming clinical development. Ramon?
Thank you, Doctor. Feinstein. Now we have established Plinabulin's unique immune mechanism as a Simba and its durable anticancer clinical evidence as shown in the Dublin III study, we have laid out a broad development plan for Plinabulin as 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-onePD L1 inhibitors secondly, to improve on efficacy and safety with I O 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 4, 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 IL-three triple combination. 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 are either immunotherapy naive or have failed prior immunotherapy. We are looking forward to the initiation of the Phase 2 portion of this trial in refractory small cell lung cancer patients. A study with Plinabulin plus radiotherapy, plus PD-one PD L1 inhibitors with the objective of reversing resistance to these prior PD-onePD L1 inhibitors is underway at MD Anderson in 7 solid tumors. This trial was initiated in June of this year. With that, 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 and A, I would like to give a brief overview of what's to come for Plinabulin. After today's presentation highlighting Plinabulin's anticancer effects in noncortical lung cancer, we have seen evidence that Plinabulin can directly treat cancer. This is in addition to the recently announced Phase 3 data in prevention of chemotherapy induced neutropenia for which Plinabulin is under regulatory review both
in the
U. S. With PDUFA date of November 30, 2021 and in China with NMPA. Additionally, at the recent ASCO conference, data supporting Phenavon'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 in the 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 and A session. Operator?
Thank you. At this time, we'll be conducting a question and answer first question comes from the line of Jason Gerberry with Bank of America. Please proceed with your question.
Hey, guys. Good morning and thanks for the update and congrats on the data update. First question for 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 can drive the value proposition of Plinabulin in the lung cancer setting or I think roughly by our estimate maybe 70% of patients haven't hit the 36 month time point. So at least for this analysis, so are the data maybe still in too immature for that analysis? And then my second question, can you just share a P value on the median OS? And then thirdly, just for Doctor.
Feinstein, if he's still on the line. Any views on if Plinabulin is approved for second line plus lung cancer? How you'd envision the treatment algorithm ultimately changing? How you'd consider second line I O retreatment strategies versus plenabulinbocitaxel combination? Thanks.
Yes. Hi, Jason. This is Lai. Yes. Thank you very much for this insightful question.
So your question regarding the 36 months, as you see that from our data, you do see this 11 point 7 3% patient has a chance of living over 36 months versus 5.27, which is doubling and with statistical significance. So we haven't looked at those 10 versus 4 patients in-depth, but as you see that you do see from the ITC population and also from the PD-onePD L1 exposed patient, we do see a very pronounced longer term benefit from the DPR versus DR. And as you know that this is a randomized study that both arm basically is balanced. So the longer survivor from the DPR is consistent with Plinabulin's immune mechanism. As you know, it's the FH1 inducer and also leading to the deceleration and T activation, which Doctor.
Feinstein has explained. So we think that if the mechanism of 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 we're very hopeful that Plinabulin using this as a foundation to go into other IO combos in the future. So that's the number one question. Number 2 is, we did calculate the log rank p value based on the curve and that's 0.0399, which we showed and that's leading statistical significance of for the OS at less than 0.046 we need to hit. So that's the answer.
But I don't think we did like medium OS. It's just the law of brand PVA. That's according to the SAP. And of course, we also did the main OS, the restricted mean survival time, p value, which is 0.03. Yes, so that's the second answer.
And third one, of course, we've had Doctor. Feinstein to answer for you and as he is very, very experienced in treating lung cancer patients, especially in the current PD-one landscape. Doctor. Feinstein?
I hope you can hear me. I'm sorry, there's a little bit of noise in my background. The question was multi factorial from what I heard was, one is, who are these long term survivors? I think the data is still a little bit immature with time and trying to find out if there's more of them. But number 2, it seems to be a bit with the PD-one, PD L1 exposed patients, 2 seem to have enhanced long term survival.
With regard to where do I think this goes in the future, I'm changing the landscape. Right now, immunotherapy, I O therapy has moved to first line, often combined with platinum agents. Patients will progress eventually, most will progress eventually on that treatment. And there still is a role for docetaxel after progression. So 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 most true with IO therapy upfront and platinum second. So I do see it having a role and as Juan had said, I do see it having a role later being combined with IO therapy and being tested in that front there
too. Yes. Thank you, Jason. Yes, Doctor. Fine is still in Paris, just giving the talk.
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 and thanks for taking my questions. And congrats on the update. So 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?
So, your question is what have we looked at all the subsequent therapies, how does it affect the OS? So we look at the base of course, all the analysis is based on ITT population. I think the later therapies, mostly, I think those paper most people would use the TKIs and some use PD-one or PD L1, but those are very minimum. And I think we're still looking into all of those data. So that's going to take some time to look at it.
But in the end, IGT captures everybody who used all the therapies the study and this is a randomized study and you can see the baseline characteristic is balanced.
Okay. And then 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?
Yes. So I think at
the ESMO meeting, we didn't have this DOR in the analysis, but in the future, definitely, we will have that data in the publication or in future conferences. But as you see from the overall TAVR extended benefit and also the PFS showing the benefit, DOR is also in the right direction, right? And also it's consistent with Plinabulin's immune benefit. Thanks for bringing this up and thanks for these great questions.
Got it. Okay. And then maybe last question, just for the PD-one exposed patients, the Kilometers curves don't separate until 12 months and maybe starting at about 6 months for the overall population. Can you provide more insight on what's driving the separation at later time points?
Yes. This is a great question. So as you see that the survivor benefit is more pronounced in this PD-onePD-one exposed patient. We think that's very consistent with the plenavulin's immune benefit because plenavulin is a protein APC inducer that we think it will add the T cells into the system. And with PD-one in the system releasing the brake, the car would go faster and that's analogy.
And so that's why you see that even more extended survivor in the DTR. And this is randomized study and in the DRAM also have similar modifications using also exposed to the PD-one PD L1. So the data is pretty consistent with Phenerum's immune benefit. I think the early curve is now separating. We think that's coming from the docetaxel more or less docetaxel is early benefit, right?
So, we are seeing more of Plinabulin's late benefit here.
Got it. Okay. Thank you for taking my question.
Thank you so much, Morris. Great questions.
Would you want me to comment too? I mean, I think the 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 kind of through immune mechanization with activation of dendritic cells. So 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 1st 6 months in patients who are exposed to immunotherapy.
But the thought is that with the prior exposure or with exposure to PD-one 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.
Great. Thanks for organizing this with Ben and thanks for taking my questions. So
I have a
question for Doctor. Weinstein. So obviously in the absence of biomarker, I'm curious about your let's say hypothetically, dinabulin gets approved in the setting tomorrow, how would you use this combination? I think in the discussion session, one of the discussions 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 curious about your thoughts on that.
And then also related to that lawn, I'm curious about your thoughts in terms of the forest plot in the elderly population. So, if I remember correctly, if you stratify patients who are older than 51 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?
Yes. Doctor. Simon,
can you
go first?
Do you want me to go first, Juan, or do you?
Yeah, yeah. I think the first question was on the Okay. All right. Elderly patients with neutropenia.
So I don't think I would just limit to elderly patients. I mean, when you look at this population, you go back to the old data with platinum or cracker patients. Their prognosis was pretty horrible with just supportive care. The average survival was about 4.5 months. So even in a younger patient who's kind of failed platinum therapies, they don't have a very good prognosis with just best supportive care.
So one of the keys is, is the problem with docetaxel by itself even though it originally had showed a survival benefit is it's a fairly toxic agent. And 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 bad in this palliative setting. So 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. So when I look at from that standpoint, even in a younger person, why won't you give them an agent which reduces the toxicity of the chemotherapy and does improve survival? Orandi, do you want to take the second part with the
Yes. I think that does this answer your question, Andy?
Yes. 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 51 years old or things like that? I don't know if you have any perspective you want to share from the forest plot analysis.
Yes, I think probably I can just take this. The first part is looking at different subgroups and you can see 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 close to 61 year old. But we think that's like along 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 SFP ratio being slightly better with the older patients. But I think the key point that we are conveying here is those of cell data regimens have become standard of care in second and third line. So the choice of the doctors will be to use the current standard of care or add Plinabulin to that standard of care. And 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 fact cancerous lines, 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 those Excel based or nothing because of overall concerns with the added toxicity and the negative impact on quality of life. So what we have here is adding Plinabulin to that, improving overall survival. But during the time that they 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. And I have 2 kind of 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. So is there basically a balance of chemotherapy dose across the two arms or something like that to kind of support that assertion?
Thank you very much. Yes. Thank you. So probably I can start with AEN and Ramon can add a little comment on this. I think you can see that definitely in the AE profile with equals to 10% of patients, The docetep's arm has a lot more of the red blood cell can decrease and neutrophil can decrease.
But in our arm, we do see a little bit more of nausea and diarrhea, but those are all very small amounts in the baseline 4, and those are also very short lasting, but Limon 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, yes. The hypertension is primarily grade 1 and 2, which we have some great key cases. But the key is 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. So with short lasting hypertension, typically, physicians are not that concerned because as 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 plinabulin arm than in the phenabrin combination arm than in the dose of XL arm. So typically, if you have more patients, you will have more AEs.
But nevertheless, what we see is the opposite. We see an overall reduced grade 4AE frequency. And 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. But here, with adding to XL, what we see is the opposite, reduced toxicity.
In terms of the overall dose of cell dose intensity, we look at that. We have the if you look at the percentage of patients on the full dose, dose of XL, they are comparable between the two arms. So therefore, we know that the benefit that we see in the Plinabulin combination is due to Plinabulin's direct anti cancer 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 of dose XL between the two arms, it is the same. Doctor. Feinstein, I don't know if you have anything to add. Yes?
So probably I can just answer this in addition to one
Go ahead, Juan.
Sorry. Yes, if I can just quickly answer this very insightful question from Andy, right? Basically, you're asking is the anticancer benefit seen from Plinabulin is also coming from the CIN benefit of Plinabulin, right? So as what Ramon said, like it is just if you look at the full dose of Nocitaxinib bosons, the potential is very similar. But we do know that it is true that the DPM has used more cycles, right, even though in those cycles similar percent of patients with a full dose of paclitaxel.
But also when we look at the same long cycles of treatment, such as 6 cycles, 8 cycles, 10 cycles for both arms, so DTM still showed long term survival benefit. So more cycles of docetax alone do not contribute to longer survival. And furthermore, the Plinabulin doubled ORR and improved endpoint as predefined time points. And lastly, there was a durable anti cancer benefit being in the combination, right? At 4 years, 10.6% of patients were live with the combination and now were live use docetaxelol and this is a randomized study.
So all those three points is pointing to that phenylalan itself do have direct anticancer benefits. So Andy, does that answer your question?
Yes, that's very helpful. Thank you very much.
Thank you. Thank you.
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 III studies. Are you able to share how the trend looked in patients just from the Dublin 3 study?
Yes, it's consistent with this. Hazard ratio 0.81 and 0.82 is like similar, right? So, we think they are consistent and the W2 is also consistent.
Okay. Got it. Great. And another question is for non small cell lung cancer, how could you see using Plinabulin in the future if both the neutropenia and the anticancer benefit are approved? Would you use Plinabulin upfront during first line if a chemotherapy regimen is used?
And then also for a later line therapy for the anti cancer benefit? Or would there be any reason to hold the Plinabulin as a neutropenia agent upfront to preserve its use as a later line anticancer therapy?
This is a key question here. I think, Flavi, you heard Ramon saying this very loudly is, I think what we think W3 study is really a proof of concept study to showcase Plinabulin's immune durable anticancer benefit, which is consistent with its mechanism. And with this shown that I think the next development program will be moving Plinabulin in IO combo PD-onePD L1 plus chemotherapy, which is already in the first line, right, because chemo actually combined with PD-one actually added double the efficacy than PD-one alone, that's basically introducing more tumor antigen. Now Plinabulin as a potent APC inducer could introduce more T cells into the system and then potentially even more dramatically increase this efficacy. So, I mean, first line is very, very important.
And then in addition, Plinabulin can also reduce the neutropenia of chemotherapy as additional benefit there.
If I can answer that very quickly. So 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 milligrams or 40 milligrams of flat dose versus here we're using 30 milligrams for meter squared days 18. So even if it's used and approved for first line, your dosing with docetaxel is going to be different.
Yes. If I can add quickly to that. So of course, we also have in addition to the long cancer program, we have the CIN program that, as you will be aware, is on the 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, the best cancer for CIN is the largest opportunity.
And of course, lung cancer is a CIN opportunity the smaller segment that creates and supports the validity of also, of course, the receptive CIN NDA. You just heard a comment about the potential of yuzukinab in first line and second half. 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 2nd and first month.
Great. Thank you.
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.
Yes. Hi, congratulations. And I wanted to ask a little bit more about the durability of the response, which seems to be incrementally really important. And I was wondering if Doctor. Mohanal or Doctor.
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.
Yes. Thank you so much, Graham. Probably would like Ramon to talk about how applicability of this global anti cancer benefit in the lung cancer, which you show here as a proof of concept study, how you can apply to other types of TAR tumor and also TAR tumor?
Yes. The mechanism of axinocinabulin is immune enhancing through activation of dendritic cells. That mechanism is at 8 nanoscopes for cancer type and therefore should be applicable for multiple cancer types and multiple chemos. The observation that we have with the durable stones, I think it's 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 4 years.
If the doctor would decide to put the patient on the plenab and docetaxel combination as opposed to docetaxel alone. To offer patients the prospect of a 10% chance to live beyond 4 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 combinations and moving into first line. I also would like to bring on to your attention that the anti cancer 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 ASMO. In particular, what is important there is that we approximately doubled the anticancer effect as we see with Vivo and APL alone.
But perhaps more exciting is that if the patients would have been on prior IO and chemo and become resistant, that with synabulin, we can flip that and reassures them back to response. So 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.
I was just wondering if Doctor. 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.
Can you repeat that question again? I heard part of it.
Yes. I just was wondering, given the evidence, as Mohan as Ramon mentioned, the collective evidence is pretty interesting as to other cancer types. Do you believe that some of the profession might use the soft label should it be approved for non small cell lung cancer? Thank you. For other types of cancers?
Thank you.
I mean, do I if we had an error where we could kind of 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 kind of challenging to use. I think it will be hard to get that approved and paid for.
Right. Okay.
Yes, I would agree with that. Of course, we will want to stay on label. And as a sponsor, certainly, our top grade that we stay on label. We do promise we will generate more positive data that then will support future labels in the future.
All
right. And do you anticipate any ability to speed up the approval process on filing for non small lung cancer? I think it's already approved, obviously, priority status, right?
No. For this doubling 3 non small cell long term study, we plan to file our first half of next year. So far, the data is very fresh. So we haven't had any discussion with FDA yet, but we will plan to in Q1. And so that's still stay tuned.
I think the CIM indication we do have priority review and what specific date is November 30.
Right. Correct. Yes, got it. Thank you. Good luck.
Yes. Thanks for the great questions.
Thank you. Ladies and gentlemen, that concludes our question and answer session. I'll turn the floor back to Ms. Wang 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. And altogether, we are bringing this transformative medicine to patients in need, and they are all 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.