BeOne Medicines AG (ONC) Earnings Call Transcript & Summary

Hello, everyone, and welcome to BeiGene's ASCO Data Review Zoom Webinar. My name is Craig West, and I'm the Head of Investor Relations here at BeiGene. We have 2 distinguished clinician speakers with us today, Dr. Constantine Tam from the Peter MacCallum Cancer Center in Melbourne, Victoria, Australia; and Dr. Andrew Zelenetz from the Memorial Sloan Kettering Cancer Center in New York, New York. Joining us from BeiGene as presenters are John Oyler, our Chairman, Co-Founder and CEO; CFO -- excuse me, Howard Liang, CFO and Chief Strategy Officer; Eric Hedrick, Chief Adviser; Yong Ben, Chief Medical Officer of Immuno Oncology; and we will also be having Xiaobin Wu; Jane Huang; and Josh Neiman available during Q&A. After the presentations, we will take your questions. [Operator Instructions] As a reminder, today's call will be recorded. I would now like to introduce your host for today's conference, Howard Liang. Howard, let me turn the call over to you.

Thank you very much, Craig. Good evening, and good morning, everyone. Welcome to our ASCO event in a little different setting this year. Today's presentation will start with opening remarks by John Oyler, we'll then delve into 3 studies presented at ASCO today. Zanubrutinib ASPEN study in Waldenstrom's, which Dr. Tam will present; the [ BOVEN ] study on the triple combination, including zanubrutinib in CRL, which Dr. Zelenetz will present; and the Phase III trial for tislelizumab in first-line squamous non-small cell lung trial, which Dr. Ben will present. Dr. Eric Hedrick will then wrap up and open the room for Q&A. Before we get into the presentation, I need to remind everyone that we'll be making forward-looking statements, and our business carries certain risks. Some of these are discussed in our filings with the SEC and the Hong Kong Stock Exchange. In addition, the comments made today of guest speakers do not necessarily represent the opinions of BeiGene and the presentations, discussions may involve indications for which our products are not yet approved for. With that out of the way, I would like to now turn the call over to BeiGene Chairman, Co-Founder and CEO, John Oyler. John?

Thank you, Howard. It's always exciting to be at ASCO, and it's especially exciting for us this year because we're sharing compelling data from 2 of our Phase III trials. After 10 years, BeiGene's science is working, and it's translating into impact for cancer patients. I think this is a real story of our industry. Yet that said, medicines remain unaffordable to the majority of people around the world. Clinical trials consume the vast, vast majority of time and the vast majority of money required to develop a medicine. And we believe that, to develop affordable medicine, the true great challenge of our times is excellence in clinical. This excellence requires global trials, inclusive of China and beyond, applying best practices and technology for operational excellence as opposed to some of the traditional methods and an entirely CRO approach. And it also requires us trying to move towards sources that are more innovative, like real-world data. BeiGene is committed to and on its way to becoming the best company in the world at clinical trials. It's not easy. It doesn't happen overnight. It's not glamorous, but it's critical to transforming our industry into one that's able to innovate and also make affordable medicines. BeiGene is a global headquarterless company. Our clinical development team of over 1,200 is perhaps the strongest, most experienced team in the world at running China-inclusive global clinical trials. Our research team is strong and has developed in-house the medicines you'll hear about today, and many more are on the way. The majority of our efforts over the last several years are focused on novel targets and novel mechanisms. We have a commercial footprint in the 2 largest markets in the world. In China, we have a team of over 1,200, and we've built this team fit-for-purpose to commercialize innovative products. It's a science- and medicine-based team and has a track record of success over the last several years. We have manufacturing strength also through our partnerships with BI and with Catalent and our own internal facilities, including a 50,000-liter biologic manufacturing facility. We have been very productive internally and through partnerships over the last 6 months. In the next 12 to 18 months, we should have more -- even more exciting times. We have up to 11 commercial products, 7 potential NDA filings and 6 Phase III registrational data readouts. We also expect to remain active in partnering to help other potential medicines access the unique capabilities that we've built at BeiGene. We're uniquely positioned to help partners accelerate their programs globally. And with that, let's turn towards the data. I would now like to turn the presentation over to Dr. Con Tam, who will take us through the ASPEN results. Please, Con.

Thank you, John, for the invitation. I'd like to present this very exciting Phase III study, which is the first Phase III study to compare 2 BTK inhibitors head to head, and I'll present this on behalf of [ Peter MacCallum ]. By way of background, BTK inhibition is a standard of care for patients with Waldenstrom's macroglobulinemia, and zanubrutinib is a next-generation inhibitor, different from ibrutinib in that it is more targeted and has advantageous PK and PD properties. Within the BTK inhibitor class, zanubrutinib is also highly favorable in that it has few drug-drug interaction properties and can be co-administered with strong to moderate CYP3A inhibitors as well as proton-pump inhibitors and antithrombotic drugs. Next slide. Thank you. So the ASPEN study is a Phase III study concentration on cohort 1. These are patients who have got MYD88 mutated Waldenstrom's macroglobulinemia. These patients met criteria for treatment. And if they have never had experienced another line of treatment in the past, they must have been considered unsuitable for standard chemo immunotherapy. So cohort 1 is the main study and is the study being presented today, and these are patients who have got MYD88 mutant Waldenstrom's, and they are randomized on a 1:1 basis to treatment with either zanubrutinib or ibrutinib. There is a separate nonrandomized arm, which is cohort 2, and these are patients with MYD88 wild-type Waldenstrom's, and these patients will not be presented today. Next slide, please. Looking at the randomized portion, you can see that there are some imbalances from the randomization. And these imbalances, in general, favor against zanubrutinib. As an example, more patients in zanubrutinib arm are aged over 75 years of age, and more patients in zanubrutinib arm are anemic with a hemoglobin of less than 110. Otherwise, the sex ratio is well balanced as is the CXCR4 mutation status, and you can see that approximately 18% to 19% of patients on this study came on to the study without having experienced treatment in the past and are, therefore, treatment naive. And just to remind the audience, these patients are treated on the basis of them being unsuitable for standard chemo immunotherapy. Next slide, please. This is a primary endpoint. And the primary endpoint is the proportion of patients in very good partial remission, or VGPR, or complete remission, or CR, on the 2 arms as assessed by the central committee, the IRC. Now it is very unusual to get complete remissions of BTK inhibitors in Waldenstrom's. So effectively, this is a direct comparison of VGPR rate between zanubrutinib and ibrutinib. In this assessment of VGPR by the central committee, VGPR was achieved in 19.2% of patients on ibrutinib and 28.4% of patients on zanubrutinib. And although this number is numerically higher, the p-value did not meet significance with a p-value of 0.09:1. So therefore, the study failed to meet its primary endpoint, which is that zanubrutinib will have a higher VGPR plus CR rate as assessed by the IRC. Next slide, please. However, there are a number of secondary indicators to suggest that zanubrutinib may be more effective. Firstly, on the left, you can see that at the same time point as the IRC assessment, in one goal with the investigator assessment at the sites, you will see that the VGPR rate is, in fact, significantly better for zanubrutinib compared to ibrutinib with p-value of 0.04. On the right, when we updated data with an extra 5 months of follow-up, and if you look at the investigator-assessed response rates, you see that the VGPR rate in zanubrutinib arm has now matured to 30.4% given the p-value of 0.0302. In addition, if one examines the IgM reduction under -- area under the curve for the 2 arms, there was a significant advantage to zanubrutinib with a faster and a deeper IgM reduction compared to ibrutinib. However, it is important to emphasize that these endpoints are secondary and exploratory in nature, and that the study did not achieve its primary efficacy endpoint, which is the VGPR rate as assessed by the IRC. Next slide, please. At this current follow-up points, you can see that full progression-free survival and overall survival are highly favorable for both arms, and I think that speaks to how well tolerated these types of drugs are with an advantage, which is not significant at this point in time for zanubrutinib. Next slide, please. The most interesting thing about this study, however, was that this is the first study to give us a readout on toxicity rates between 2 different BTK inhibitors. And to set the background, although ibrutinib is, in general, well tolerated, it is associated with a number of treatment-limiting side effects. And zanubrutinib, being a more targeted drug, theoretically, has a lower risk of adverse events, but this is the first study to really prove this in a randomized manner. In more detail, if I look at the ASPEN data, as listed on the slide here, you can see that zanubrutinib is associated with a reduced number of adverse events leading to death, adverse events leading to treatment discontinuation, dose reduction or dose hold. Next slide, please. If one examined the latest update, which is in January 2020 and looked at the adverse events of special interest for BTK inhibitors, I think this really highlights the difference between zanubrutinib and ibrutinib. Firstly, you can see that the atrial fibrillation and flutter rate is 18.4% for patients on ibrutinib and 3% on patients on zanubrutinib, giving a statistically significant result and a sixfold reduction in AF rate. Ibrutinib is also associated with a higher rate of diarrhea, hemorrhage, hypertension. And really the only disadvantage to zanubrutinib across all the different AEs examined was a higher rate of neutropenia, as shown here, with 22% of patients having grade 3 of rate in neutropenia. However, it is important to stress that this neutropenia did not translate to increased infection rates, as shown here, and did not increase -- translate into any serious clinical [ security ], including infectious -- severe infections on infections tests. Next slide, please. This really examines graphically the incidence of atrial fibrillation on the left and hypertension on the right of the 2 drugs over time and to me the most -- there are 2 compelling messages here. The first is that the rates are lower for those patients on zanubrutinib. And secondly, you can see that there is no real accumulation of AE rates beyond 12 months for zanubrutinib. Whereas for patients on ibrutinib, as -- the longer on the drug, the higher this cardiovascular toxicities, such as atrial fibrillation and hypertension tends to accumulate with time. So therefore, it would appear that if you are going to use this drug in long-term dosing, which you generally do need to do in Waldenstrom's or indeed many other diseases that zanubrutinib is less likely to cause cumulative cardiovascular toxicity compared to ibrutinib. Next slide please. This is a quality of life slide, and I think quality of life is a very important aspect of any Phase III study. On the left, you can see that across all patients, because both these drugs are highly effective, that there is an improvement in quality of life once treatment has started and once the disease comes under control. But what is really interesting to look at, if you look on the right, and these are patients with very good partial remissions so that these are patients where the Waldenstrom's is under very good control and really should not be impairing quality of life. So the main impairment in the patients on the right is potentially from drug side effects. You can see that zanubrutinib is associated with an improved quality of life, which we hypothesized is due to the more benign side effect profile of the drug. Next slide, please. So in conclusion, zanubrutinib is associated with a CR plus VGPR response rate of 28.4%, compared to ibrutinib of 19.2%. This is a statistically nonsignificant result, and therefore, the ASPEN study did not meet its primary endpoint. However, there are secondary indicators of improved efficacy of zanubrutinib, which includes greater response rate as assessed by investigator, both at the original time point and at the updated time point, a deeper and sustained IgM reduction over time, and in general, the direction was favorable for progression-free survival, overall survival and quality of life. Importantly, this is the first study to demonstrate, without doubt, that a more targeted agent such as zanubrutinib can provide advantages in tolerability and safety with a very marked difference in the rate of atrial fibrillation and flutter and lower rates of major bleeding, diarrhea and hypertension. And despite a higher rate of neutropenia in zanubrutinib, there is no difference in the rate of infection or serious complications. And in general, zanubrutinib had 0 AEs leading to death, treatment discontinuation or interruption. And with that, I'd like to thank all my investigators, and I'll hand the presentation back to Eric.

Okay. Thanks very much, Con. Really appreciate you joining us, particularly since we know it's the weekend for you in Melbourne. So thanks very much for joining us. We're going to turn now to a presentation of some other data at this meeting for zanubrutinib, this time in the treatment of CLL. And this is initial data, looking at the combination of zanubrutinib with venetoclax and obinutuzumab, and most folks on this call will know that, that is a -- the BTK, BCL-2 combination regimen is one that's generated quite a bit of interest in the initial therapy of CLL. We're happy to be joined by Dr. Andy Zelenetz from Memorial Sloan Kettering Cancer Center in New York. Especially happy because we understand Andy has just emerged from his clinic. So we're happy that he can join us here this evening and run through some of the data. So Andy?

Eric, thanks very much. And I'm going to be -- it's my pleasure to present the initial results of a multicenter investigator-initiated study of MRD-driven time-limited therapy with zanubrutinib, obinutuzumab and venetoclax in patients with previously untreated CLL. And the name [ BOVEN ] actually came from BGB-3111, not BRUKINSA, but that's okay. It was named -- far before there was actually even a zanubrutinib name. So -- but we are in a golden era of CLL treatment. It is clear that both BTK inhibitors and BCL-2 inhibitors are promising as initial therapy in CLL. Two of the early studies, the CAPTIVATE study, combining ibrutinib and venetoclax in a multicenter trial, and ibrutinib and venetoclax in a single-center trial at MD Anderson, both showed that there were high rates of -- in a particularly unfavorable population, that one could achieve high rates of peripheral blood and bone marrow minimal residual disease. However, this was after a protracted treatment program. And part of the problem here with this combination is ibrutinib is not a very good partner for an anti-CD20 antibody. It -- because of its inhibition of ITK, it inhibits antibody-dependent cell-mediated cytotoxicity, and it does not combine very well with an anti-CD20 antibody. On the other hand, zanubrutinib has minimal impact and actually combines well with anti-CD20 antibodies. Go to the next slide, please. So this is the bovine treatment schema. We -- because of the tumor lysis risk, the idea was to try to reduce patients with obinutuzumab and zanubrutinib initially for 2 months before the ramp up of venetoclax starting cycle 3, day 1. And this was actually a successful undertaking because the vast majority of patients had a significant reduction in their tumor lysis risk between cycle 1 and cycle 3, making ramp up as an outpatient in all but 4 patients. And 2 of them didn't -- that was the physicians' discretion, not because it was protocol dictated. Next slide. There were 39 patients accrued between March of 2019 and October of 2019. The median follow-up at this point is 11 months, ranging from 2 to 14. The reason for the favorable median follow-up is because the accrual to the study was extremely rapid. The median age was 59 years, ranging from 23 to 73 with a male-to-female ratio of 3:1, which is pretty typical, actually for CLL studies. 72% of patients met the [ cliffy ], high-risk or a very high-risk definition for adverse outcomes. And 72% of patients were IGHV unmutated, the unfavorable form of CLL; and 15% had TP53 aberration, either deletion of -- deletion 17p or a mutation of TP53. Next slide. This is a summary of treatment-emergent adverse events. Neutropenia was the most common hematologic toxicity occurring in 51% of patients. But Grade 3 for neutropenia was only seen in 15% of patients. Similarly, there was a relatively high rate of thrombocytopenia, but Grade 3 for thrombocytopenia was only in 5%. For the most part, the -- there were very few other Grade 3 toxicities. We saw some infusion reactions. There was a grade 3 rash. And we had a couple of pneumonias that were grade 3. I want to point out that even though there were no grade 3 or 4 diarrheas, the diarrhea rate was 41%, and it was bothersome to some patients. Most patients had grade 1, but a few patients had grade 2. Next slide, please. If we focus on the adverse events of special interest, again, we see the neutropenia and thrombocytopenia and the infusion-related reactions. Bruising, though seen, there was no -- it was all grade 1 with exception of 1 grade 2. We had pretty minimal bleeding with a single episode of grade 3 bleeding. Hypertension was seen in only 5% of patients and atrial fibrillation was seen in a single patient as well as febrile neutropenia. So despite the fact that 15% of patients had grade 3, 4 neutropenia, febrile neutropenia was not a significant issue here. Just one thing about the grade -- there was a grade 5 bleeding episode. This was an intracranial bleed. It occurred on cycle 1, day 1, and was concurrent with administration of intravenous heparin for pulmonary emboli. And I suspect that this was more of the heparin than having anything to do with study drugs. Next slide, please. Now if we look at the results here, with the induction in 2 months with zanubrutinib and obinutuzumab, I was actually very surprised that anyone achieved undetectable minimal residual disease, but we had 1 patient who did that. But once these -- venetoclax was added, as expected with this regimen, we saw a dramatic increase in the rate of undetectable minimal residual disease. So that this increased at 8 months to 77% in peripheral blood. If we look overall at a median follow-up of 11 months, 83.8% of patients or 31 of the 37 patients, have achieved undetectable minimal residual disease in peripheral blood, and 73% have achieved undetectable minimal residual disease in bone marrow. And these are impressive numbers, but these are actually preliminary because there are a number of patients who are getting ongoing treatment and the rate of undetectable minimal residual disease is actually increasing in the patient population. Next slide. The other way to measure response is with the traditional international working group CLL response criteria and by the iwCLL response criteria, the -- among the patients who have achieved an undetectable minimal residual disease and have been able to come off treatment, the majority of patients have achieved an iwCLL CR, about 1/3 of patients, 1/3 to 40% of patients have an iwCLL CR overall. Now the major reason for failing to achieve a CR, despite the fact that you're MRD undetectable is residual lymph nodes that are greater than 1.5 centimeter in any dimension. And this has been a repeated issue with the iwCLL response criteria. And this study did not require people to achieve an iwCLL CR response to stop treatment because of this issue with borderline-size lymph nodes. Next slide. So in conclusion, this was a well-tolerated combination with low rates of grade 3, 4 neutropenia of 15% and 5% thrombocytopenia. The zanubrutinib and obinutuzumab lead-in resulted in a significant reduction in tumor lysis risk prior to the initiation of venetoclax. And there were no cases of either laboratory or clinical tumor lysis that were seen. But most importantly, [ BOVEN ] achieved rapidly undetectable minimal residual disease. 84% were undetectable in the blood and 73% in the marrow at a median follow-up of 11 months. The primary endpoint of this study was to determine the median time to undetectable MRD. And that was actually with 6 months of triple therapy or 8 months of total therapy. So this truly results in very rapid reduction in disease burden. And we're trying to understand what the differences are between the patients who have very early MRD and those who are somewhat later. The -- we have further -- lots of additional information to emerge from this study. We're looking at other means of detection of mineral residual disease with more sensitive markers. And we also want to see what happens to the group of patients who have discontinued treatment and what their durability of their response is. So very exciting data, but very preliminary and more -- a lot more to come with this. So thank you for the opportunity to present these data, and I'll turn it back to you, Eric.

Okay. Thanks very much, Andy. We appreciate you joining us and presenting that data. We're now going to turn the program over to the tislelizumab or anti-PD-1 development program and some of the data that's appeared here at ASCO. And presenting data from our first-line squamous histology non-small cell lung cancer Phase III trial is Dr. Yong Ben. And I'll turn it over to you, Ben.

Thanks, Eric. I will be discussing our Phase III study of tislelizumab plus platinum doublet chemotherapy versus doublet chemo alone in first-line advanced squamous non-small cell lung cancer. This audience well aware lung cancer is diagnosed in great many people in China, close to 800,000 every year. Treatment in China for advanced squamous disease has been platinum doublet chemotherapy. Similar to treatment in the last -- in pre PD-1 therapy days, although nab paclitaxel is currently not approved for non-small cell lung in China. So tislelizumab is a humanized antibody directed to PD-1, which binds with high affinity and specificity. The antibody is differentiated from other available and broadly used PD-1 therapies by its Fc region, which is engineered to avoid binding the Fc-gamma receptor on macrophages, thereby avoiding -- serving as like an antibody-dependent phagocytosis, which has been independently shown to be a mechanism potential resistant to PD-1 therapy. Previous Phase II study showed that tislelizumab, combined with platinum doublet therapy was generally well tolerated and demonstrated activity. And so we embarked on a Phase III program to confirm the signals of activity and safety. So this is the study design schema. The study enrolled treatment-naive patients with Stage IIIb or IV squamous non-small cell lung cancer with ECOG performance status of 1 or 0. Patients who were randomized at a 1:1:1 ratio across 3 arms, all of which contain the platinum doublet are shown here. 2 arms had tislelizumab added to the doublet, 1 with paclitaxel and the other with nab paclitaxel. In all arms, the doublet was administered for 4 to 6 cycles. Arms A and B were continued on tislelizumab as maintenance and arm C patients could cross over to tislelizumab maintenance upon disease progression. All patients on tislelizumab maintenance couldn't continue until disease progression are intolerable. What's shown here is the demographic and baseline characteristics data. Generally speaking, it was well balanced among 3 arms in terms of age, gender, smoking history, ECOG performance status, PD-L1 status as well as distant metastasis status, except for slightly more small [ curves ] in the nab pack arm and a few more patients with ECOG 1 and stage IV patients in the treatment arms. So here's the safety data. The safety profile of tislelizumab in both combinations in this trial was consistent with the known risks for each study treatment. And no new safety signals were identified. Treatment emergent adverse events were present in essentially all patients in the study as commonly seen with dose chemo regimens. Serious adverse response were somewhat more common in the tisle containing arms, which is expected with the [indiscernible] design, thus were balanced across the arms. In terms of specific AEs, the most commonly seen were hematologic adverse events, which is also expected because of the chemo backbone. So here's the efficacy data. PFS was the primary endpoint. And as shown here, it was 7.6 months for both tisle arms, versus 5.5 months in the chemo-alone arm. This difference was statistically significant at the preplanned interim analysis, which we announced earlier this year. This was the first squamous non-small cell lung readout in Chinese population. PFS was meaningfully improved regardless of PD-L1 expression. This is one of the subgroup analysis included in the ASCO poster. The median OS was not reached at the time of the cut off. In terms of responses, ORR was 73% and 75% in arms A and B, respectively, as compared to 50% in the control arm. Median duration of response was 8.2 months and 8.6 months in arms A and B, respectively, almost doubled as compared to 4.2 months in the control arm. In conclusion, this trial showed that the addition of tislelizumab to standard doublet chemotherapy resulted in significantly improved PFS ORR and duration of response versus chemotherapy alone. The tislelizumab containing regimens were generally well tolerated with the AE profile consistent with that of a doublet chemotherapy and no new safety signals were observed. This study and a similarly designed study in non-squamous histology, which is also in combination with first-line chemo have now both shown positive results at the interim analysis. I think that concludes my presentation. With that, I will hand the presentation back to Eric. Eric?

Okay. Thanks very much, Ben. We appreciate it. I'd like to take just a couple of minutes in closing, and we'd like to leave some time for questions just to put in perspective some of these data and our overall development programs for zanubrutinib and tislelizumab. Next slide. So with regard to zanubrutinib. As most are aware, BeiGene is conducting a broad development program, including 2 Phase III head-to-head comparisons with the first-generation inhibitor ibrutinib. The first in these head-to-head comparisons of BTK inhibitors in the setting of Waldenstrom's was presented here by Dr. Tam, and we believe that the totality of efficacy and safety data support our development hypothesis that zanubrutinib is the best-in-class BTK inhibitor. While the primary endpoint, VGPR by independent assessment did not reach statistical significance, relevant secondary measures such as IgM reduction over time and VGPR by investigator do show distinctions in favor of zanubrutinib have reached statistical significance. Equally or more importantly, zanubrutinib treatment was associated with clear safety advantages over ibrutinib, not only in the overall profile, but specifically with respect to cardiovascular toxicity, where zanubrutinib was associated with a distinctly lower risk for events such as atrial fibrillation and hypertension over the course of treatment. Based on these results, we are in discussions with the FDA and EMA regarding a filing plan to support approval in Waldenstrom's. In CLL, Dr. Zelenetz presented data for the first time evaluating the combination of zanubrutinib, venetoclax and obinutuzumab in the initial treatment of CLL. It is clear that combinations of BTK and BCL-2 inhibitors are being viewed as a viable option for those patients for whom a deep remission fixed duration of therapy is the goal. To this end, the preliminary results of this study look highly promising, nearly 3/4 of patients achieving a molecular remission in bone marrow and over 60% of patients to date able to achieve an MRD-directed treatment completion at a median of 6 months of triplet therapy. These results are the first of a number of points of data to be released in the near future, which should define the role of a zanubrutinib treatment in CLL, including Phase III monotherapy data in the first-line setting as well as a second direct comparison of zanubrutinib and ibrutinib this time in the relapse CLL setting. Next slide. This slide offers a depiction of the zanubrutinib development program, which is directed towards approval of zanubrutinib in multiple treatment settings of CLL, mantle cell lymphoma, Waldenstrom's, marginal zone lymphoma and follicular lymphoma, with these studies intended to support approvals globally, inclusive of U.S., China and Europe. I would also note here that our combination development efforts now include our own potent BCL-2 inhibitor which has entered Phase I testing and will ultimately be evaluated in combination with zanubrutinib in CLL and other B-cell malignant histologies. Next slide. In terms of tislelizumab, Dr. Ben presented the first of 2 Phase III trials, which we have conducted in the first-line non-small cell lung cancer treatment setting, both of which were positive at planned interim analyses. In squamous histology non-small cell lung cancer, the addition of tislelizumab to taxane platinum-based chemotherapy had a robust and statistically significant effect on prolongation of PFS, duration of response and response rate. As you know, the experience with checkpoint inhibitors in this setting has not been universally positive, so we view these results as well as the results of the study in non-squamous histology disease to be presented in the near future as validation not only in these indications, but overall. The scope of the program, and specifically, in lung cancer, is broad, which will allow us to fully understand the role of tislelizumab in both non-small cell and small cell disease. In terms of upcoming milestones, we have filed the squamous non-small cell lung cancer data for approval in China and expect to do so for non-squamous histology this year. Within the next year, we also anticipate registrational trial readouts in hepatocellular cancer, second-line non-small cell lung cancer and second-line esophageal cancer. Next slide. And finally, the breadth of our tislelizumab development program is depicted here. Again, the goal is to support approvals in multiple regions for a variety of solid tumor indications with a specific focus on lung cancers and gastrointestinal cancers. Next slide. An additional facet of the tislelizumab program is a growing list of combination studies, including with our internally developed inhibitors of TIGIT, TIM-3 and OX40. In addition, we have in our combination development portfolio, a number of highly promising partner molecules, including Mirati's multi-kinase inhibitor, sitravatinib, Zymework's HER2 bispecific ZW25. And BioAtla's ph-activating CTLA-4 antibody and our recently announced collaboration with Hutchison for combination work with their VEGF inhibitor portfolio. And with that, we'll end our presentation, and we would be happy to take some questions. So I'll turn it back to Craig.

Great. Thanks, Eric. [Operator Instructions] Our first question comes from the line of Tyler Van Buren.

Tyler Van Buren from Piper Sandler. First question is related to the investigator-assessed VGPR that hit statistics at both the August time point and improved in the January time point. I guess, can you speak towards the significance of that clinical endpoint, even though it was a secondary endpoint and the possibility of it potentially being included in a label, if and when you do file.

Okay. Perhaps I'll speak to that. So assessment of responses in Waldenstrom's can be complicated in that it's multifaceted. And central assessments can be problematic because often the -- sometimes depending on condition like [ coordinating movement ] , the IgM levels can change with transport to a central laboratory and also different interpretations about what constitutes organomegaly on the scan and so forth. So I would say that you have to rely on a single set of agreed referees. And certainly, the agreed protocol was for a central committee assessment. So I think that we have to abide by the rules of the central committee assessment at the time of the August assessment because that was what was in the trial. And we have to go by a single set of referees. So I think that although it's interesting to note that the investigator-assessed responses were different and in fact showed a positive p-value at the August time point, I think at that time point, we have to go with the IRC decision. Now I think the January update is slightly different. So we know that the responses do mature with time. And we know that the longer you treat someone on the BTK inhibitor potentially, the more potent drug will show a bigger difference with time. So -- and at the January time point, the only assessment point we have with investigator assessments, and these were following vigorous protocol-defined procedures, and we can't really ask IRC to go back and do a second read in January because there will be multiple testing. So I will say that at the August time point which we abide by the IRC rule to say that essentially that it was a negative study. However, what I believe what may happen with time is that as we get even further follow-up beyond the January time point with further updates, we will see a widening in the VGPR rates such that it will hopefully meet -- it may meet a positive p-value on multiple time points. And at those time points, I will say that it will be reliable to go with the investigator assessment.

Okay. That's very interesting. Thanks, Dr. Tam. And just as a related follow-up, you guys mentioned that you were in ongoing regulatory discussions with the FDA and the EMA. Can you provide any additional color on those discussions as it relates to the probability of you guys filing in Waldenstrom's?

Yes. Tyler, this is Eric. Maybe I'll take that one. Yes, we're in the midst of discussions. I think the discussions have been based on the totality of data from ASPEN and our experience in Waldenstrom's. As is typical, we would provide public announcement guidance in the event that a filing was accepted. But so it -- I think one of your questions was the regulatory implications of the independent versus investigator assessment. I think until we have a specific filing plan, it would be a little bit too soon to speculate on labeling matters like that.

Okay. That's helpful. And just one final question, if I can sneak it in there briefly. The grade 3 adverse event comparison, adverse event comparison overall in grade 3s, in particular, with the cardiovascular-related events is, of course, very interesting. Can you just speak towards the percentage of patients that have significant cardiovascular risk factors in which, exclusive of the differences in efficacy, you would consider putting patients on zanubrutinib versus ibrutinib?

So I don't have the numbers right in front of me, but essentially, there were a number of patients who have a previous history of atrial fibrillation, I believe, 8 on our ibrutinib arm and 11 on the zanu arm that came into this study. So the study did not exclude to a prior history of AF that came on. And certainly, none of the zanu patients had exacerbation of AF versus a number of the patients on ibrutinib arm certainly did. So there were a number of patients with risk factors who came on the study. They were reasonably balanced. There wasn't an obvious imbalance between the 2 arms in terms of cardiovascular risk factors. We do -- not from this study, but we certainly knew from the ibrutinib data that patients with a history of hypertension, with target abnormalities, including EKG abnormalities, are more likely to get atrial fibrillation than those without. And also, if you note the atrial fibrillation rate on this study is actually quite high, 18%, compared to ibrutinib studies in CLL and mantle cell lymphoma. And in fact, if you look across ibrutinib studies across the board, essentially, the rate of atrial fibrillation in Waldenstrom's tends to be higher. And it's always been my suspicion that a lot of patients with Waldenstrom's have a "amyloidosis of the heart". And I suspect that Waldenstrom's may be particularly susceptible to atrial fibrillation because of our "amyloidosis". So I guess the point of the question is, are there patients that would select to receive a drug, let's say, zanu over ibrutinib ahead of time because of the cardiovascular risks. So I would say that patients of Waldenstrom's are especially high-risk, especially if there's a history of hypertension or atrial fibrillation or cardiac abnormality of any sort. And I will say, as a clinician, if I'm faced with patients and I've got equal access to both drugs, that there may be a driving force in me deciding on using 1 drug over the other.

Our next question comes from the line of Leo Ai. [Operator Instructions]

This is Leo on for Yaron Werber at Cowen. Congrats on the progress. I just have 1 question regarding the bovine combo. Can you please discuss the differentiation of the bovine combo versus the acala combo in the first-line CLL setting?

Yes. It's Eric. Maybe, Dr. Zelnitz, if you're still on and wanted to handle that question. I'll defer that to you. Okay. Yes. So it's Eric again. Maybe I'll try to take this one. And then I'd invite Jane Wong to chime in as well. Again, there are a number of single-arm experiences looking at BTK, BCL-2 inhibitor combinations. So that limits the extent to which you can compare these. I think what you could say about the experience with the bovine regimen, so far, is that the majority of patients achieved the goal of treatment, which is time-defined course of treatment, deep remission and planned treatment discontinuation. And they've been able to achieve that with toxicity. A profile that, in general, looks favorable compared to the other BTK, BCL-2 combinations, specifically with regard to neutropenia and some of the cardiovascular events. So we view the data is sort of comparing favorably to combinations that include either ibrutinib or acalabrutinib.

I see that. Eric, I can make a comment.

All right. Sure, Con. Go ahead.

So the other differential effect that I see is that zanubrutinib achieves much higher and much more intense PDK in addition as a standard dose than acalabrutinib does. So I think that you wanted to say that if you're going to choose the BTK inhibitor that gives you the most target coverage for the longest time, zanu certainly has advantages of acalabrutinib at the clinical dose. And lastly, there are differences in the ability to dose with concomitant drugs, especially proton pump inhibitors, which are very common in our population. The proton pump inhibitors are nonissue for zanubrutinib, whereas for acalabrutinib, they needed to be -- they're not possible to be given the proton pump inhibitors.

Excellent. Our next question comes from the line of Wangzhi Li.

Hello. Can you hear me?

We can. Please go ahead.

This is Wangzhi Li from Ladenburg. The first question is a follow-up by Dr. Tam's comment on the maturation of VGPR over time. Your latest cutoff is in January, I think, is about 24 months of median follow-up and the VGPR rate slightly improved over the previous 90 months follow up in last August. So my question is, do you expect it to continue to improve over time? Because if you look at your Phase I poster, it was a 3-year follow-up, it seems to largely stabilize after 24 months, but it's a smaller number of patients. So I just want to get a further of your thoughts on the maturation over longer follow up after 3 to 4 months?

Yes. Maybe -- thanks a lot for the question. Maybe I'll let Dr. Tam and Jane comment on this.

So yes, the short answer is I do expect the VGPR rate to improve further. I do realize that on the Phase I poster, it seems that most of the benefit is gained in the early phase, but we do know from, let's say, the prolonged brutal experience that the VGPR rate does continue to improve beyond the third and fourth year. So yes, I do expect there to be an ongoing maturation.

Got it. And a follow-up, similarly for the PFS and OS, right now, it's the follow up [indiscernible] maybe sure, just maybe speculating what do you think the difference going to look like over the longer period follow-up in the PF and OS? And also, I don't know, have you ever done any CT scan analysis between the 2 arms, you see what kind of p-value right now it is? Or...

Yes. Maybe, I could.

Go ahead, Eric.

Yes. Maybe I will address that. So keep in mind that this is a relatively small study, 228 patients, 201 that were randomized. It's really not sufficiently powered to detect with statistical significance differences in either PFS or OS. What was seen from the curves that you saw today is a bit of early separation. Now what that will mean in the long run, I think we don't know. We'll certainly continue to follow the study for progression-free and overall survival, but I just wanted to mention the limitation for statistical powering for doing that.

Got it. And if I can, maybe last question is the 1 baseline difference in terms of more patients over 75 years old in the zanu arm and your subgroup, NSC, showed that there's an unfavorable subgroup for ibrutinib. Is there any plausible rationale or biology to support that? Why zanubrutinib do worse in patients over 75-year old? Or is this maybe just some more number of patient kind of incidence?

So no, I mean, we don't have strong evidence that patients who are older do less well specifically in this study. We do know that age is a risk factor, so doing worse for virtually any blood cancer with any treatment. So we're not using the assay. We're just making observation that there is appears to be imbalance against zanubrutinib based on traditional risk factors for adverse outcome, including anemia and age. But as you know, the BTK inhibitors, it was tolerated in general, zanu better than ibrutinib, and even older patients should be expected to have good outcomes because of the ability to dose this drug on time.

Our next question comes from the line of Michael Pan.

Hi. Can you hear me?

We can.

Okay. This is Michael from DBS. So I guess I only have 1 question for Ben. So in terms of the PD-1 clinical trial in squamous, non-small cell lung cancer, I noticed that about 2/3 of the patients are Stage IV. Could you give us some color on how the clinical readout for those Stage IV patients be? Because the reason I ask this question is, if we want to compare with the results from KEYNOTE 407, which is the clinical trial of KEYTRUDA in squamous non-small cell lung cancer, how do we see the difference between our PD-1 and KEYTRUDA?

Yes, that's an excellent question. Yes, absolutely right. So we now 2/3 of Stage IV patients. What I can share at this moment, we have done quite a bit subgroup analysis and the magnitude of improvement was consistent across all the subgroups. We will be sharing the detailed data in upcoming conference publication. So it's consistent across Stage IIIb, which is actually Stage IIIb and c according to the new addition of AJCC and also Stage IV subgroup.

Our next question comes from the line of Matthew Harrison.

Matthew Harrison from Morgan Stanley. I guess I wanted to follow up on the last question, and I guess, 2 parts. One, could you talk a little bit more about some of the other baseline criteria here as we think about comparing a China study versus maybe a more global population than some of the other studies? And then secondly, can you also just comment on how you plan or how you think about bringing [ tezI ] to the U.S. market, given that you had started a bunch of multinational studies with your prior partner and sort of where these data fit in and how to comment on that?

Thanks for the question, Matthew. It's Eric. Maybe I'll let Ben get started on this, and I'll chime in.

Sure. I think when we talk about a cross-study comparison, there's always a caveat of doing that. I would say the baseline characteristics are quite comparable with other PD-1 studies in first-line non-small cell lung. There may be slight and noticeable difference that the patient tend to be a couple of years younger. But I don't think that may make a huge difference. In terms of the U.S. filing plan, so we will continue to discuss the data with the FDA once -- as we get additional data from these trials. And we will have clinical data from a global Phase II data in second, third-line hepatocellular patients and the potential other registration-enabling data from global studies this year. And we will be discussing with the FDA in the next few months on whether we have sufficient data to file. And we'll update our market once we have the clarity.

Our next question comes from the line of Michael Schmidt.

Congrats on the ASCO presentation, and thanks for taking my questions. Maybe just 1 other follow-up on the ASPEN data. We were wondering if you maybe had a chance to stratify the data also by line of therapy and maybe CXCR4. Just curious if that's something you looked at?

So that data is part of the prespecified statistical plan. So in terms of line of therapy, so far, we have not seen a difference in the response rate between first-line treatment and those who have been pre-treated. This seems to be a bit of a signal for BTK inhibitors. If you remember the Innovate data from the pharmaceutic studies that patients who were treated in frontline had similar response rates to those who were treated in -- who are pretreated. So it seems like initial BTK inhibitor therapy, the lines therapy does not seem to matter as much. With chemotherapy, you'll be treating the frontline, you do much better. So we did look at that. So far, there's no difference. In terms of CXCR4 data, now that is a -- you will notice that the rate of CXCR4 mutation as presented here are relatively low, compared to that expected in literature. And that's because the CXCR4 stratification, at the time when the study was set up, was done using the technology that was current at that time. And there was standard sequencing, which is a limited sensitivity for CXCR4 mutation detection. And that was how the study was stratified and set up at a time when it was started. Of course, technology improves, and we now have the ability to assay CXCR4 at a much better sensitivity than previously. And if we go back, and we have sampled -- we've actually reassayed approximately 90% of our samples, and we now have a CXCR4 mutation rate of approximately 28%, which is much more in line with what we expect from the literature in this population. Now the problem we have, of course, is such a stratification was done at a time when we're using the older technology and we can't go back and restratify these patients. But if you look amongst the patients, and in fact, using a more sensitive technology, there is a stratification against zanubrutinib in that there are more patients on zanu arm who was CXCR4 mutates compared to ibrutinib. So there was a disadvantage to zanubrutinib just by the CXCR4 status. Now within individual CXCR4 status. So patients who are mutated CXCR4, the VGPR rates are higher on zanubrutinib compared to ibrutinib. And even for those who has CXCR4 wild-type, the response rates are higher for zanu than ibrutinib. So one can argue that one of the potential contributor to the fact that the study did not meet its primary endpoint was because there was a differential in the number of CXCR4 mutated patients between the 2 arms, but this is really a function of improving technology and detection, and there's nothing that we could have done about it. This is just the way these things work. How many clinical trial is completed, we're stuck with the technology that we had at the time when the clinical trial was started.

Dr. Tam, really helpful. And then maybe switching over to CLL. We noted that you increased the sample size and the -- in the ALPINE study earlier this year. And I was just wondering what drove that? Is there maybe an increased confidence in potentially showing superiority in CLL now as opposed to just non-inferiority as it was planned before?

Eric?

Yes. I'll take that. So we basically -- as I mentioned, there's 2 head-to-head comparisons between zanubrutinib and ibrutinib, ASPEN was the first. As I mentioned, now there was a trial that was fairly limited in sample size. And so some of the observations there you could view as hypothesis generating for the second larger study, which is -- which, of course, is the comparison in relapsed CLL. And so our intent with increasing the sample size was really to increase the power of that study to look at both efficacy and safety distinctions between the 2 drugs and try to define those with a little bit more statistical clarity. The other thing to keep in mind about ALPINE, I think as you mentioned, the analysis is a little bit different. It's a hierarchical analysis that looks at response rate, non-inferiority first and then superiority. And so the design of that study is a little bit difficult.

Okay. And then one last question, just around the bovine study, very exciting data. And I think there's some general excitement in the CLL landscape around sort of time-limited therapies looking at triples and in the frontline setting, and I was just wondering maybe how you think about sort of the space evolving longer-term. And you might come in with the monotherapy trial and whether there's maybe an opportunity to think about a guideline strategy to look -- to include some of those combinations or maybe even run additional registration studies in frontline CLL.

Yes. It's Eric. Maybe I'll start off briefly and then maybe turn it over to Dr. Tam or Zelenetz to comment. But it's our intention with our development program to do definitive studies for zanubrutinib in all of the treatment settings in CLL that might be applicable. And our understanding is that some of those are monotherapy settings. The initial treatment setting may very well, for selected patients, be a combination course limited use. And so it's really our intent with the clinical trials program to cover all those bases. Maybe I'll defer to our clinicians to sort of comment on how they see that landscape evolving. But what we've been trying to do with the development program is really just cover all those potential treatment uses.

So I think that, Eric, you're right, I think the world is moving towards combination therapies capable of eliminating MRD and providing patients with fixed duration of treatment rather than indefinite therapy. And certainly, BeiGene have been very -- have been leader in that field in leading the bovine study. And also in development of its own BCL-2 inhibitor, which is highly potent. And I'm sure that an early development step in non BeiGene's history of combining the products very early will be the development of zanu plus -- at the in-house BCL-2 inhibitor combination for a time-limited therapy. So I think that's a very exciting development really because very few companies have the ability to combine their own in-house BTK, which we have now shown to be more -- much more safe and tolerable than ibrutinib with their own BCL-2 inhibitor. And I think that, yes. It retour. This isn't to say whether the Phase III studies will be conducted right now, but I suspect that once some of these combination studies have shown some more dollar and once the BCL-2 inhibitors have shown some more dollar, that you'd be seeing some pretty interesting things from BeiGene.

Congrats on the progress so far.

Our next question comes from the line of Yang Huang. Yang, I see you as still muted. How about if we move to the next one, and if you want to ask a question, Yang, you can jump back in. So we're going to move to Ling Wang.

Thank you. Can you hear me?

Yes, we can hear you. Sorry, we got confused there.

Okay. And congrats on the data. For the ASPEN study, we definitely see better safety, and we saw numerically better efficacy. Just curious whether there are any prior examples that a drug did not meet the primary endpoint, but finally get approved. I mean, especially considering this is a relatively orphan disease.

Yes. Thanks, Ling, for the question. Without going into too much detail, yes, there is limited precedent for the approval of drugs in the U.S. in studies where the primary endpoint has been missed, both in oncology and outside of oncology. So we think that this, obviously, will not -- our attempt here will not be without precedent. I think the other thing, it's probably worth mentioning here, obviously, BeiGene's intent is to get label indications for as many disease as possible. But also, what we're really trying to do is generate data that effective -- and communicate data that effectively shows the use of zanubrutinib in various diseases, defines the distinctions between zanubrutinib and other BTK inhibitors. And so submission to guidelines like NCCN will be an avenue to do that as well. So we're certainly going to approach regulatory agencies about the ASPEN data, and we have approached them and we are in discussions. But in terms of the data and the information on use of zanubrutinib, there are other venues that we will be exploring as well.

May I ask a follow-up? So zanubrutinib was approved in mantle cell lymphoma in the U.S. with a pivotal Phase II study. So can you maybe comment on what are the differences between these 2 indications that sort of lead to the different requirement for the pivotal study?

Yes. Thanks for the question. In the midst of discussions with the FDA, we probably shouldn't comment too specifically on precedent in Waldenström’s. Again, I would just say that we think that our body of data, including the data and totality from ASPEN, we believe, could support a filing, and so that's the basis of our discussion, and I won't really comment on any other precedent in the disease, but those discussions are ongoing.

We have 2 more in the queue. Our next question comes as a follow-up from Michael Pan.

I guess I pressed it wrong. I don't have any question.

Sure. No problem. And then our final question will come from the line of Shan He.

Congratulations on a pretty fruitful ASCO. So I guess the first question is regarding zanubrutinib. Just to confirm my understanding. So it sounds like our BeiGene team will take the ASPEN data to change -- or update the guideline, and this guideline will potentially have payer indication over -- especially regarding the advantages over ibrutinib.

Yes, Shan, thanks for the question. Yes, our intent certainly is to not only explore discussions about regulatory approval, but also to approve -- to seek guideline listing for Waldenström's and other indications.

Okay. That's good. The second question is, so the bovine data is quite interesting, especially the whole BTK plus anti-CD20 pretreatment that can improve the safety concern. So I guess the question here is how is our plan in terms of moving this combo into registration intent study? Because we have an in-house BCL-2. Are we going to wait for that one? Or we are going to move ahead with combination with venetoclax?

Yes. Thanks for the question. Maybe, Jane, if you're still on, do you want to address that?

Sorry. So we are really exploring all fronts. We are advancing our own internal in-house BCL-2 as quickly as possible and hope to be in combination toward the end of the year. And in terms of the venetoclax combinations, we are continuing to explore those as well. And with multiple strategies, there's additional ISTs that are ongoing that have data, and we have data in our frontline SEQUOIA study with a combination in 17 p-deleted patients.

Okay. One more question from my side is to Dr. -- if Dr. Wu is still on the line. How is the commercial launch so far for anti-PD-1, especially, we got this pretty beautiful data for NSCLC. How will this help the short-term and mid- to long-term competitiveness of tislelizumab in a pretty crowded market in China for anti-PD-1 space?

The initial uptake shows a very positive trend. We are the company. We have not only hematology indication. We have also solid tumor, the bladder indication, which happens to us a lot in the hospital listing and also engaged for 2 teams, solid tumor team and hematology team, the initial uptake is very positive.

Our last question will come from the line of Andy Berens. Andy, can you hear us? Andy, you're not coming through to us. I'm going to give you a count to 5. So I don't think we're hearing from Andy, but we do have one last question from Ziyi Chen coming in.

Just a very quick one. Since we're in discussion with FDA and EMA on the potential filing, NDA filing for zanu and the Waldenström’s indication. So when should we expect we are hearing back for any updates from those regulated bodies about potential strategy for our filing?

Yes. Thanks for the question. So we would typically make a disclosure or public announcement at the time of the acceptance of the file, and that would be the case here. So that you would hear, again, in the event that we had submitted a file and then it is accepted by the regulatory authority.

Great. And as a follow-up, because we already launched the drug in the U.S. on the MCL indication, so can we get more color on what is the marketing medical message that we deliver to doctors in MCL, particularly after we got more data on the ASPEN study? So in the future, in terms of marketing strategy in the U.S., what kind of medical methods we're going to deliver, combining all those data?

Yes. Thanks. If Josh is still on, maybe I'd invite him to address this.

Sure. Thanks. Yes. So let me first begin by saying, of course, we're not going to be promoting the ASPEN results in advance of an indication there. So in the near term, it's not going to affect our messaging. That said, I do think that the results support the long-term hypothesis that we do have a best-in-class BTK inhibitor. Since we've launched BRUKINSA for mantle cell here in the U.S., we really have focused on the overall efficacy with the high response rate, the general safety profile, and what we found with our clinicians is that they've appreciated the sort of ability to use across a broad range of mantle cell patients not really having to compromise on any other strategies, given their ability to administer it, either BID or QDs. Or as Con mentioned earlier, there's a number of patients for whom proton pump inhibitors are important to maintain their quality of life. And in contrast to other BTK inhibitors where those can't be co-administered with BRUKINSA, they'd have to make those tradeoffs. So generally speaking, we focus on the efficacy, the overall ability and the ability to really customize their approach to the individual patient needs.

Okay. Well that's the end of the Q&A. We're concluding the question-and-answer portion of the call, and I'll now turn the call back to Howard for closing remarks. Howard?

Thanks very much, everyone, for joining us today. We'd like to especially thank our 2 distinguished guest speakers, Dr. Tam and Dr. Zelenitz with their time and insight. We hope that you can tell from our -- from today's presentation, I would say that we are about our 2 internal development lead assets. We'll be providing an update on our early-stage pipeline in coming weeks so please stay tuned. Thanks again. Good night, and good day.

Goodbye.