Chugai Pharmaceutical Co., Ltd. (4519) Earnings Call Transcript & Summary

I am Takaki Koga, Polivy Lifecycle Leader at Chugai Pharmaceutical Company. Today, I will give you an overview of what Polivy is and then ask Dr. Izutsu to make his presentation. The name of the product is Polivy Intravenous Infusion, 30 milligram or 140 milligrams, and the generic name is polatuzumab vedotin, genetical recombination. It's indications are relapsed or refractory diffuse large B-cell lymphoma, but the name of the disease is a bit long. And so I'd like to use the English abbreviation, DLBCL. The name Polivy has been coined with Po coming from its generic name, polatuzumab vedotin, liv standing for life and y derived from the symbol for an antibody as it is an antibody drug conjugate. Thus, its English name is Polivy and Japanese name, Polivy. On development history, in overseas, development was started by Roche in 2011. In Japan, a Phase I study was started in 2014. And in the same year in overseas, a global Phase Ib/II study was started for second-line treatment of patients with relapsed or refractory follicular lymphoma, which includes those with DLBCL. This study was called GO29365 and is the most important pivotal study in the application for approval this time. It has turned out, as Dr. Izutsu will explain later that this study has demonstrated a very high efficacy and safety of the drug, which led to filing for approval with the data from the Phase II study in U.S. and EU. Based on this information in Japan, though we had initially been planning to conduct a Phase III study, we developed our plan to perform a bridging study immediately in 2018. That was called P-DRIVE study, which is a second pivotal study for the application. Then the approval was granted in the U.S. in 2019 and in Europe in January 2020. In June last year, we filed for approval in Japan. Since the drug was designated as an orphan drug, we were given approval in March this year after just 9 months. As a result, there was a drug lag of only 1 year and 9 months from the U.S. and 1 year and 2 months from you, both shorter than 2 years, which we believe was the fruit of our efforts. Here's the schematic of the structure of Polivy, which is slightly more complex than ordinary antibodies. The antibody part of the drug recognizes CD79b expressed on the surface of B cells. The antibody has linkers, which is stable in circulating blood and decompose inside a cell. At the end of those linkers is MMAE, a toxin that induces cell death. This structure is called an antibody drug conjugate. Now how does it work exactly? You can see the mode of action on this page. Polivy, after binding to CD79B on the surface of B-cell, moves inside the cell. Once it is inside the cell, the linkers will be cleaved by lysosomal proteases, releasing a toxin called MMAE. MMAE works by binding to microtubules which are necessary for cell division and proliferation and inhibit their function. When this happens, it will inhibit the cell division of tumor cells, triggering cell death called apoptosis. Compared to common chemotherapies, this drug when used in combination with bendamustine and rituximab, or BR, has much higher sell specificity and therefore, will go into the cell, it needs to target and work from inside the cell, which is quite a reasonable design. As for the positioning of this drug in the overall treatment of DLBCL, if after the first-line treatment, patients have turned out to be either refractory or experience relapse, provided that they are relatively young and have enough physical strength, they are supposed to undergo stem cell transplantation. If not, they will be administered salvage chemotherapy. Patients with transplantation failure will sometimes be provided with salvage chemotherapy as well. In this treatment algorithm, the portions highlighted in yellow refer to the cases that regimen of Polivy in combination with BR or Pola-BR is indicated for, i.e., refractory or relapse DLBCL. However, I'd like to add here that in those particular studies mentioned, patients enrolled were dose ineligible for stem cell transplantation. And therefore, there is no evidence for efficacy and safety of Pola-BR as a salvage chemotherapy for transplantation eligible patients, so we did obtain an approval for that indication as well. One thing of note is that in any of either domestic overseas guidelines, there's no definite standard therapy available for second-line refractory or relapsed DLBCL other than stem cell transplantation. We have reviewed every single guideline in and outside of Japan, and found no description of a standard therapy, backed up by a comparative study. Therefore, G029365 study is the first comparative study that demonstrated a clear efficacy of a regimen for this group of patients. As you can see in the chart on this page, in terms of overall survival, or OS, this Pola-BR regimen has shown the superior result in efficacy to the comparator arm. As for the characteristics of Polivy, it is sold as lyophilized product and is supposed to be dissolved in the injection liquid when used. Now on dosages and administration, Polivy is administered together with bendamustine and rituximab in one cycle, and this will be repeated up to 6 cycles with a 3-week interval, taking 18 weeks to finish the whole process. Rituximab should be given on day 1, only in the first cycle from the perspective of safety. Here, you can see conditions for approval. A risk management plan, or RMP, should be formulated and implemented appropriately. Given the very limited sample sizes in clinical trials in Japan, as the number of subjects enrolled in P-DRIVE study with 35, a post-marketing all patient drug use surveillance is required until data on a certain number of patients has been collected in order to gather data on the safety and efficacy of the product, which should be used to ensure the appropriate use of the product. Now more on the risk management plan. In the safety specification, important identified risks include bone marrow depression, peripheral neuropathy, infection and infusion reaction. Important potential risks are, PML, tumor lysis syndrome, reproductive toxicity and hepatic function disorder. Based on those identified risks we have put together pharmacovigilance plan and risk minimization plan. In pharmacovigilance plan, on top of items usually addressed, the additional actions required are collecting information by early post-marketing phase vigilance, all case surveillance and extension of a clinical study. In risk minimization plan, we will prepare a package insert and drug guide for patients. We will also provide information by early post-marketing phase vigilance and put together a guide for proper use. What is indicated in the dotted line box is our own voluntary activities, such as providing a patient handbook and providing information through explanation in advance or via website. That concludes my part of the presentation. Thank you.

Good afternoon. I am Koji Izutsu from Department of Hematology of National Cancer Center Hospital. At Department of Hematology, I'm responsible for malignant lymphoma as a hematologist. I have been involved in the clinical study as part of the clinical development of Polivy or polatuzumab vedotin. I will make a presentation titled Treatment Options for Relapsed or Refractory DLBCL. This is the disclosure, my COI. My presentation today will cover the following items: first, I will discuss what is the positioning of DLBCL or diffuse large B-cell lymphoma in malignant like lymphoma and how many patients there are? Next, I will talk about what is the refractory or relaxed DLBCL. Then I will explain about conventional standard second line treatments for younger patients without organ disorders, who are eligible for autologous stem cell transplantation. Then I will share with you possible situations in case those standard second line treatments do not work. In particular, I will discuss second line or later treatment options for those mainly elderly patients ineligible for autologous transplantation, where I will also mention the clinical performance of the combination therapy of polatuzumab vedotin and BR or Pola-BR. First of all, what kind of disease is malignant lymphoma? And what is the positioning of the DLBCL in it? Malignant lymphoma is a malignant tumor derived from lymphocytes or cancer, which develops from lymphocytes. The number of people who are diagnosed as malignant lymphoma per year in Japan is about 30,000 to 35,000, of which DLBCL is the most frequent type of disease. This is a trend seen commonly across nations in the world. The data shown here is based on the cancer registry and shows that, in fact, DLBCL cases account for as much as 45% of the patients diagnosed as malignant lymphoma. Malignant lymphoma is classified into 3 grades, low, intermediate and high, according to the speed of the symptom progression. Of those, DLBCL falls under the category of intermediate grade or aggressively lymphoma, where the lesion would become larger on a monthly basis, if left untreated. Now the clinical features of DLBCL include a representative type of disease among aggressive B-cell lymphomas, accounting for 45% of malignant lymphoma, as I repeatedly said. The median age of the onset is 60s and 70s and has a tendency to be slightly more common among males. The locations of the lesion include not just a superficial lymph nodes, but lymph nodes in the spinal or abdomen as well as various organs other than lymph nodes such as stomach and large intestines. As prognostic models, International Prognostic index, or IPI, and some other similar models are known. There are different treatment options used for DLBCL. To mention one by one, drug therapy, radiotherapy, hematopoietic cell transplantation and CAR-T cell therapy, which has emerged more recently. Of those, what constitutes the basis of the treatment is drug therapies. Drug therapies are the mainstay of the treatment of DLBCL. And usually, chemotherapies using combinations of multiple drugs are chosen in both the first-line and post-relapse treatments. As I explained later, as a first-line treatment for DLBCL, what is called R-CHOP regimen is used where survival and remission rates have been improved compared to the period before R or anti-CD20 antibody drug, rituximab became available. Radiotherapy is used in combination with drugs chemotherapies or with the aim of mitigating the symptoms. Hematopoietic cell transplantation is performed for patients who have failed to respond sufficiently to drug therapies with expectation for cure. CAR-T cell therapy is positioned similarly. I will elaborate on those therapies later in my presentation. As a representative first-line therapy for DLBCL, a combination chemotherapy called R-CHOP regimen is used. A regimen to use 4 drugs, cyclophosphamide, doxorubicin, vincristine and prednisolone has been used for -- as top regimen since around 40 years ago. Since about 20 years ago, after the development of rituximab, R-CHOP regimen was rituximab added to CHOP, has been standard of care for DLBCL. More specifically, in this regimen, those 5 drugs are administered every 3 weeks, with prednisone being the only oral drug and the rest infusion drugs. It can be provided in an outpatient setting once every 3 weeks through infusion. In some cases, patients need hospitalization for the initial therapy, but basically, it can be administered in an outpatient setting. It is repeated up to 6 or 8 cycles and can be completed in about 5 or 6 months. By providing these treatment, it is said that DLBCL can be cured in about 60% or a little more than 60% of the total number of patients. This is R-CHOP regimen data from Canada. As you can see, time to progression curve flattened at around 60%, so we can expect this disease to be cured by chemotherapy. But unfortunately, some patients may not respond to R-CHOP regimen. Others may achieve CR with R-CHOP, but their disease could relapse later. What we aim for with R-CHOP therapy is CR, complete response. According to the current criteria, we aim for no more positive lesion based on imaging, pet/ct in particular. In many of the patients who achieve CR, we can expect their disease to be cured without any relapse. But soon after the end of the treatment or 2 to 5 years later, there can be an early or late relapse. During R-CHOP treatment or after the end of R-CHOP therapy, some of the patients will have progressive disease. Or due to insufficient treatment response, there can be almost no tumor shrinkage from before treatment on imaging. SD and PD during treatment or right after treatment as well as relapse after achieving CR post-treatment accord relapsed or refractory cases. These patients were indicated for second-line treatment. Regarding how to select and consider second-line treatment for relapsed or refractory DLBCL, whether or not patients eligible for autologous transplantation based on their age organ disorders and comorbidities will change the direction of the treatment. Patients eligible for autologous transplantation will receive potent combination chemotherapy. If they respond with tumor shrinkage, they will move on to high-dose chemotherapy with autologous hematopoietic SCT according to a general treatment flow. As for the combination chemotherapy, to be used here due to R-CHOP refractory disease and to recycling such as doxorubicin, a key drug in R-CHOP regimen will not be used and noncross-resistant drugs will be selected. Generally speaking, those eligible for autologous transplantation are aged up to 65 to 70 years old. Different medical institutions and different hematologists or different countries may have a different view on the upper limit of age, but autologous transplantation is rather difficult in elderly patients. Then what about the selection of second-line treatment for patients ineligible for autologous transplantation, options listed on the slide are being used for the time being. If patients are ineligible for autologous transplantation, it cannot be implemented. If they can receive potent treatment, combination chemotherapy can be used. But due to strong toxicity in patients ineligible for autologous transplantation, those will be slightly reduced compared to younger patients, such considerations may be necessary. And unfortunately, when autologous transplantation is not going to be used, we cannot aim for a cure after relapse. We treat patients while maintaining their QOL as much as possible. We may select treatments such as single-agent chemotherapy and radiotherapy, which can be provided in the outpatient settings or we may provide best supportive care without directly treating cancer, generally speaking. For patients eligible for autologous transplantation, it is better to provide treatment, including autologous transplantation as second-line treatment after relapse based on the results of this Phase III study published a long time ago in 1995 as a rationale. This is a clinical study in patients with relapse to refractory lymphoma, intermediate or high-grade lymphoma, which relapsed after CR. The study was implemented before rituximab became available. DHAP salvage chemotherapy was given as second-line treatment. If patients responded, they were randomized to an arm of high dose chemotherapy, peak regimen together with autologous hematopoietic SCT, although carmustine included in peak regimen is not approved for the treatment of lymphoma in Japan or they were randomized to another arm to continue DHAP regimen to which they responded with 8 courses in total. PFS and ORS were compared. As you can see, not only event-free survival, but also overall survival results were better with autologous transplantation. If patients eligible for autologous transplantation respond to salvage chemo with partial response or above, it would be better to proceed to autologous transplantation as this data is supporting. There are a variety of second-line treatments in patients eligible for autologous transplantation. Let me explain typical regimens used in Japan so far. Like R-CHOP therapy, anti-CD20 antibody rituximab is used in combination, also in second-line treatment in many cases. R-ESHAP, R-DHAP, CHASER, R-ICE, R-DeVIC, R-GDP and R-GCD, there are various regimens, those indicated with the Japanese trademark combination chemotherapies developed in Japan. Whichever it is, many of the regimens are platinum-based, including agents such as cisplatin and carboplatin. Regimens can be classified into those containing high dose cytarabine and those without or regimens not containing high dose cytarabine with or without gemcitabine. But all regimens are using multiple agents in combination, so infusion is necessary continuously for several days instead of infusion, just for a day per cycle like R-CHOP regimen. And also some of the drugs require continuous infusion for 24 hours, even while patients are sleeping. Due to strong mylosuppression, a typical adverse reaction of anticancer agents, treatment is administered while patients are hospitalized for most of the regimens. We had no other option but to use these regimens before. These regimens were also used in elderly patients by reducing the dose. Which regimen is better out of the various second line treatments? Several comparative studies were conducted but we don't have results from those comparative studies to say which treatment is superior. This is a representative study. R-ICE regimen, which does not contain high dose cytarabine, and R-DHAP regimen containing high dose cytarabine when compared in relapsed or refractory DLBCL patients. The target population was relapsed or refractory DLBCL. If patients achieve PR or higher after these savage chemo, they would proceed to autologous transplantation according to the study settings. The response rate to the salvage chemo was about 60%. About 50% of the patients were able to move on to autologous transplantation. However, unfortunately, if you look at event-free survival, counting from the start of salvage chemotherapies, results were not so different between R-ICE and R-DHAP. Ultimately, long-term survival or cure can be expected in some patients. The ratio of those who remain relapse-free beyond 2 to 3 years is just about 30%. And unfortunately, in relapsed to refractory DLBCL, disease could be cured in just some of the patients by second line salvage chemo followed by autologous transplantation. Even in patients eligible for autologous transplantation based on their age or organ disorder or function, myelosuppression could still be strong. 30% to 50% of the patients require platelet transfusion. After chemotherapy, patients may develop adverse events such as infection like febrile neutropenia. If there are 100 treatment-naive DLBCL patients, fortunately, close to about 60% can be cured by R-CHOP. If there are 100 relapsed or refractory DLBCL patients, half of them are ineligible for autologous transplantation due to their age and other reasons. Even if they are considered eligible for autologous transplantation, and if they do not respond to second line treatment, they cannot proceed to autologous transplantation. Even if patients are able to receive autologous transplantation, those who can maintain long-term survival without relapse will be just less than half. If there are 100 relapsed or refractory DLBCL patients, cure can be expected with salvage chemotherapy followed by autologous transplantation in just 1/10 of the total. In other words, autologous transplantation would not work to cure the disease in the remaining 90%, colored in blue. These cases can be called challenging situations. Once again, young patients eligible for autologous transplantation, who do not respond to second-line treatment due to disease refractory to second-line salvage chemo cannot proceed to autologous transportation. Patients may receive autologous transplantation that relapse afterwards. Also, some patients cannot move on to autologous transplantation and are considered ineligible due to older age and other reasons. For these patients, there was no good treatment option before. First, in younger patients, if they do not respond to second-line service chemo, one of the combination chemotherapies used at second-line treatment options could be selected and given as third-line treatment. If they respond to that, they can move on to hematopoietic SCT. That's one of the treatment approaches being used so far. In the Phase III CORAL study, I mentioned before, to compare second line salvage chemotherapies in DLBCL, if patients do not respond to second line treatment, such as our DHAP regimen, for example, places of chemotherapies can be changed to use rice regimen, which does not contain high dose cytarabine. If patients do not respond to R-ICE, R-DHAP regimen containing hydro cytarabine can be used. By changing the types of salvage chemotherapies and giving them a third-line treatment, some of the patients would respond. In patients who do not respond to second-line treatment, the ratio of their response to third-line regimen is about 30%, as its shown here. PR is not enough, but if there is a good response to third-line regimen to achieve CR, third-line treatment, followed by subsequent hematopoietic CET specifically autologous transplantation in many cases, long-term survival can be expected in some of the patients. There can be a relapse after autologous transplantation. This is the survival curve of patients who relapsed after autologous transplantation in the same Phase III study. Response rate to third-line chemo is more than 40% in patients who relapsed after autologous transplantation, but median OS is just a month. So treatments are required where we can expect the cure or long-term disease control in these patients. In relapsed or refractory DLBCL, prognosis is particularly poor among patients with SD or PD while on R-CHOP, those who did not respond to second-line therapy, resulting in SD or PD and those who had an early relapse after autologous transplantation. After their DLBCL is considered refractory, there is data on the response to the next line therapy and subsequent event-free survival. Response to the next line therapy in this retrospective study was overall response rate of 26% and CR rate of 7%. Response to treatment as well as prognosis was extremely poor. Those who can survive for a long time is just 10% to 20% only. For these patients, there is another hematopoietic SCT different from autologous transplantation. That's allogeneic HSCT, where hematopoietic stem cells of HLA identical siblings, bone marrow bank donors or cord blood bank dollars are transplanted instead of using patients on cells. This is a type of immune therapy. Thanks to allogeneic immune response, malignant lymphoma cells will be attacked. That is the way of thinking behind this treatment. This is effective to a certain extent for those who relapse after autologous transplantation and those who do not respond to chemotherapy. There is global hematopoietic SCT registry data, mainly from the United States. Based on that, data is summarized here on allogeneic transplantation for those who relapsed after autologous transplantation. In case of ALO SCT, after failing autologous SCT, about 30% to 40% of the patients relapsed in 1 year. But there are a few who relapsed beyond 1 or 2 years. PFS curve became flat from around the second year. Allogeneic transplantation is also effective in patients who relapse after autologous transplantation. It can be said, this is a treatment where long-term survival and cure can be expected. But on the other hand, there are issues non relapse mortality or treatment-related mortality is estimated to be at least 20%, and data this was summarized for patients who could proceed to allogeneic transplantation. In reality, about 3/4 or majority of the patients were chemo sensitive before allo transplantation. There are not many cases where chemotherapy would be effective for patients who failed autologous transplantation. So this data is just from quite selected patients. So there was no good treatment option for these patients before. Recently, CAR-T cell therapies have been developed and have emerged as a treatment targeting these patients. Also in Japan, CAR-T cell therapy called this again lecluse was approved in 2019. This is already being used in the clinical settings. In 2021, Acticell and Lycocell have been approved. These are going to be used at medical institutions from now on. In the clinical studies of these CAR-T therapies in relapsed or refractory DLBCL, median age was late 50s to early 60s, but patients up to early 70s were also the target. It is known that long-term cure, or PFS, can be expected in patients with relapsed or refractory DLBCL. These patients are okay, but then what are the options available for elderly patients who are ineligible for auto transplantation? Traditionally, for elderly R/R DLBCL patients, multidrug salvage chemotherapy that I explained earlier was used to reduce doses in many cases. Why do you need to reduce doses? Early patients have poor metabolisms and thus, the side effects of chemotherapy, mainly bone marrow suppression is enhanced or patients already have renal insufficiency from the beginning, and the conditions often become worse with the treatment. And thus, doses have often been reduced. But there is no published paper describing a prospective study in elderly RL DLBCL patients, evaluating reduced dose multidrug chemotherapy use for younger patients, such as ICE or DHAP therapy. In addition, it is very rare that patients are cured without auto transplantation. Also, such therapies usually require hospitalization since daily infusion is necessary and severe myelosuppression can occur. Since you cannot expect cure for elderly patients, long-term hospitalization is not desirable considering the QOL. On the other hand, several anticancer monotherapy agents are used, but you cannot expect sufficient effects from them. So there was not a good treatment option for elderly patients with RL DLBCL in the past. This is a French study comparing R-CHOP and CHOP in initial DLBCL patients. They looked at the relapses after R-CHOP and CHOP. The survival curve shows relapsed patient after R-CHOP regimen. As you can see, more than half of the patients died in 1 year. The prognosis is very poor. Polatuzumab vedotin or Pola was developed mainly for such patients. Pola is an ADC antibody drug conjugate, where anti-CD79B antibody is conjugated with MMAE, monomethyl auristatin E as a payload. It inhibits volumization of microtubules. CD79B is a cell membrane antigen that is expressed on normal B-cell, and most of B-cell tumors. Polatuzumab vedotin is used as IV infusion, and through the blood of patients, it binds with CD79B on the surface of the B-cell tumor. Then it is internalized into the cell, together with CD79B and the bond between the antibody and its payload, MMAE is broken by lysosomal probasis. And thus, MMAE is activated. Since MMAE inhibits the polinization of microtubules and thus suppresses some growth, this leads to hepatosis of the tumor cells. MME has already been used for an ADC against CD30 brentuximab vedotin. MMAE is already used as a payroll and its typical adverse event includes peripheral neuropathy since it inhibits Parmelia ion of microtubules. This is an overseas randomized Phase II study for polatuzumab vedotin, comparing Pola-BR and BR. This was a pivotal study. BR is bendamustine with rituximab regimen. R/R DLBCL patients who are ineligible for auto transplantation were enrolled in this study. Patients were randomized one-to-one, the control arm received BR, that is 90-milligram bendomustine for 2 consecutive days and usual dose of rituximab on day 1. This cycle was repeated 6 times every 3 weeks. Bendamustine was not indicated for DLBCL in the past, but 90 milligram is used with rituximab for indolent B-cell lymphoma and mantle cell lymphoma, usually for every 4 weeks. So it has already been used. For Pola-BR, Pola was added to BR on day 2 on cycle 1 and day 1 on cycle 2 to 6. So it was administered every 3 weeks. Pola was infused IV over 90 minutes for the first dose and the 30 minutes afterwards. The primary endpoint of this study was pet CR, that is see our ratio assisted by pet at the end of treatment. This is the baseline characteristics of the enrolled patients. 40 patients were enrolled in either arm. The median age was 67 and 71, and the majority was elderly. DLBCL is categorized into ABC type and the GCB type by gene expression profile, and they were included about half and half. Transplantation ineligible patients were included. And the reasons for inability were age, insufficient response to salvage therapy and failed prior transplantation. The median number of lines of prior therapy was 2 for both arms. This is the primary end point, PCR ratio at the end of treatment. It was 40% for Pola-BR and 17.5% for BR. It was shown that the Pola-BR was significantly better than BR. This is the secondary endpoint, progression-free survival. It was shown that the Pola-BR was significantly better. The median PFS was close to 1 year for Pola-BR. Overall survival was also better for Pola-BR, as shown here. This is safety data showing all grade AEs and Grade 3 for AEs in Pola-BR arm and BR arm. You can see that the hematological toxicity is increased when Pola is added on to BR. Neutropenia increased from 38.5% to 53.8%. And as a result, some patients needed transfusions of red blood cells or platelets, but the ratio of patients needing transfusions did not increase with the addition of Pola. Similarly, the incidence of infectious diseases did not increase with Pola. In this study, the use of G-CSF was not mandatory, but about 70% of the patients received G-CSF. A typical nonhematological toxicity was peripheral neuropathy. Looking at all grades, the rate was about 7% with BR and about 43% with Pola-BR, clearly higher when Pola was added. But rates of neuropathy of Grade 3 and higher were 0% for both arms. Since this drug targets CD79B, the relationship between the CD79B expression and the efficacy is of interest. Immunostaining was used to show the CD79B protein expression and the relationship with efficacy was analyzed. No correlation was observed. Although the drug is targeting CD79B, its expression was not included in the inclusion/exclusion criteria, and it is not necessary to check the expression of CD79B when this drug is used in clinical settings. How many cycles of this treatment could be used? The maximum was fixed, and the median for Pola-BR arm was 5. In the BR arm, the median was 3, and many patients who are not able to complete 6 cycles, mainly because of disease progression. About 46% of patients completed 6 cycles in Pola-BR arm. Some dose reduction or delay in dosing were observed due to peripheral neuropathy, hematological toxicity or various other reasons. But AEs were generally manageable. So far, I have been discussing overseas randomized Phase II study, not including Japan. Phase II study called P-DRIVE was carried out in Japan to evaluate safety and efficacy in Japanese patients. This study also enrolled R/R DLBCL patients who were ineligible for autologous transplantation, just like a randomized Phase II study I discussed earlier. This study was a single-arm study using the same dosage and administration as the randomized Phase II study. The primary endpoint was also pet CR rate at the end of treatment. Statistical hypothesis included expected CR rate of 40% and a threshold CR rate of 17.5%. This is the baseline characteristics. The median age was 71. Transplantation ineligible patients were included. As for the prior therapy, about 42% had 3 lines or more. Patients with a long history of therapy were included as with the overseas study. As for the efficacy, the primary endpoint was met with CR rate of 34.3%. The follow-up period is not very long yet, but median duration of response, DOR, and the median progression-free survival, PFS, were reported, as shown on the slide. With regard to safety, hematological toxicity was also observed in a similar manner and so was peripheral neuropathy. Prophylactic administration of G-CSF was mandatory for this study. Median of 5 cycles of Pola-BR therapy was given in Japan as with the overseas study. Based on the results of overseas studies and the Phase II study in Japan, polatuzumab vedotin, Polivy was approved for the indication of R/R DLBCL and is available for clinical use. The following is my expectations for Polivy. First, various antibody drugs have been developed for a long time for R/R DLBCL, but Polivy is the first one to be launched in 18 years since reduction. Compared with pure cytotoxic drugs, antibody drugs are advantageous, especially in terms of hematological toxicities. Also, it is another advantage that this drug can be used immediately when it is needed. As I mentioned, Brentuximab vedotin has been approved and used for lymphoma, but Polivy is the first ADC approved for DLBCL. It is unfortunately difficult to aim at cure for DLBCL patients who are eligible for autologous transplantation, and treatment strategy to allow patients to live longer while maintaining QOL is very useful. But unfortunately, many of currently available regimens require hospitalization or have severe AEs. Private is beneficial in that patients can be managed as outpatients. In summary, a therapeutic strategy for R/R DLBCL. The second-line therapy is initiated, depending on whether or not the patient is eligible for autologous transplantation. If the patient is eligible, salvage chemotherapy or strong multidrug chemotherapy is given to proceed to autologous transplantation. This treatment option still holds true. Recently, CAR-T cell therapy is an option for such younger patients. But unfortunately, the number of CAR-T therapies that can be carried out is limited, which is still an issue. For patients who are ineligible for autologous transplantation, there were no good treatment option in the past, and patients often had to be hospitalized. Pola-BR allows treatment as an outpatient in terms of its dosage and administration. Since certain AEs may occur such as hematological toxicity, you need to be careful, but I have high hopes for Polivy because it offers ambulatory treatment option according to the results of clinical trials. That is all. Thank you for your attention.

Hashiguchi Kazuaki from Daiwa Securities. My first question is on Page 26. I would like to ask a clarification on how to look at this chart first. Am I correct to say that the target patient population for the indications approved this time are in this chart, the sum of 50, 25 and 15 or 90, while the currently ongoing POLARIX study with Polivy used as a first-line drug is targeted at the 300 patients at the top of this chart? Secondly, in your gut feeling, do you think that once this drug is approved as a first-line drug for DLBCL, it will become the kind of drug that you would use for most of the 300 patients without hesitation? Or do you feel that you don't know yet about your choice as a first-line drug until you see the result of the study?

I will answer the first question and ask Dr. Izutsu to take the second one. First, the currently ongoing Phase III study, POLARIX was a drug used as a first-line treatment is targeted at previously untreated patients. And therefore, in this chart on Page 26, the 300 patients at the top are eligible. With regard to the target population of Polivy used in a second line regimen, if the patients are not eligible for transplantation, they are part of the target population. For patients eligible for transplantation, transplantation is the standard of care, and therefore, they will undergo transplantation first. But there are patients who unfortunately have experienced relapse after the transplantation or have turned out to be nonsensitive to Politrans plantation salvage chemotherapies. Those together would lead to the sum of 50, 25 and 15 or 90 in this chart, roughly speaking.

Izutsu speaking. I would like to respond to the question on the first-line treatment and also to the first question from my point of view. As you said, out of the 100, if you subtract 10, the remaining 90 highlighted in blue in this chart are potentially the target of the Pola-BR regimen. However, of these, if there are those who directly go to CAR-T therapy, then they could be subtracted from the 90. That said, currently, the patients eligible for CAR-T therapy are fairly limited. Therefore, you may want to take that into consideration. With regard to the first-line treatment of the previously untreated DLBCL cases, only those determined to be IPI, International Prognosis Index, 2 to 5 are eligible. However, you could also look at this from the other side of the coin and say that only those with IPI 71 are excluded. Therefore, my understanding is that a large part of these 300 patients in this chart are eligible for POLARIX study. Therefore, if the primary endpoint of this study is met, and ultimately, the approval is granted. I believe most of the previously untreated patients will go through the combination therapy of polatuzumab and R-CHOP as their first-line treatment.

My second question is about CAR-T therapy. You previously said that there is a limitation as to how many cases CAR-T therapy you can administer. Could you clarify what you meant by that? And in order to resolve that limitation, what do you think would be required? And if that limitation is resolved, in light of efficacy and safety, do you feel there is a potential in CAR-T therapy to be used more broadly, including those at earlier stages of the disease?

That is a very difficult question. My choice of the word may not necessarily have been right. In CAR-T cell therapy, you need to harvest lymphocytes from the patient, which will be used as a material for CAR-T cells, spend 2 weeks or more, depending on the type of CAR-T, our manufacturing CAR-T cells at a manufacturing facility and have them return to the patient. Therefore, the question is, first of all, whether or not the material or lymphocytes can be harvested and whether or not the patient can control his or her underlying disease for the several weeks it takes for the lymphocytes harvested to be engineered into CAR-T cells and return to the patient. So far, it was quite difficult for patients with a refractory disease to overcome those issues. Therefore, there were often patients for which we did consider application of CAR-T therapy but stop short of actually performing it. So that is one major obstacle. Another hindrance is that clinics authorized to administer CAR-T therapy are still limited as it requires leukocyte apheresis and cell infusion. Since DLBCL is the kind of disease with a large number of patients, it is currently treated at many sites, providing second line or third line treatments. Of those sites, only a very small number can administer CAR-T cell therapy. So CAR-T therapy, by its nature, cannot be the kind of therapy that can be commonly provided at any medical institutions. Therefore, the fact that only a limited group of -- in refractory or relapsed patients are eligible for CAR-T therapy is unlikely to change because of the aggressiveness of the disease, and the nature of the therapy.

Muraoka from Morgan Stanley speaking. I have a question to Dr. Izutsu. Recently, in the United States, an anti-CD19 ADC was approved for DLBCL in the third-line settings, if I remember correctly. What is the positioning of Polivy versus this product? When this drug becomes available in Japan in the future, how should we think about its positioning? If we talk about second-line or third-line settings, that's it perhaps, but could you please comment on this point?

I think these 2 agents can be quite close in terms of the patient population where they can be used. Having said so, the anti-CD19 ADC is used as monotherapy, not in combination therapy. So there is a possibility that patients with more comorbidities or older age could also be the target, perhaps. Still, it's quite difficult to compare clinical study results. So it's difficult to comment. Pola-BR is positioned as combination of chemotherapy and under CD19 ADC is a regimen targeting a similar patient population, in my view.

I haven't studied enough but as a future new treatment of DLBCL, is there anything you are paying attention to? Or anything that is still in early stage, but you have expectations for the future?

Thank you for the question. Now the screen is showing immunotherapies targeting CD19. CAR-T therapies as an immunotherapy perform genetic engineering of cells. So it takes time, which is an issue. Another immunotherapy is bispecific antibody. Bispecific antibodies designed to bind to tumor cells and T cells responsible for the immune system are under development. For malignant lymphoma, multiple bispecific antibodies targeting CD20 are under development. Bispecific antibodies have an advantage as they can be readily available as an off-the-shelf treatment unlike CAR-T therapies. So I'm watching the progress of their development.

I have not been able to follow this myself but the CD19, CD3 bispecific antibody was put on clinical hold in the United States the other day due to side effect. Am I wrong?

I am not aware of that. I was talking about CD20, CD3 bispecific antibodies. What you mentioned is not happening to the 3 representative drugs where development is making progress.

Yamaguchi from Citigroup speaking. Just one question, but sorry for my late person's question. Overseas and domestic studies were presented with different background. In the Japanese study, time to survival reaching plateau seemed much shorter and different at a glance. But the range of CR, et cetera, was similar. These differences come from certain backgrounds or just by chance.

Izutsu speaking, I don't know whether this interpretation is correct or not, but P-DRIVE in Japan had a very short observation period. Its primary endpoint was met, and data cutoff was done very early. So I think we need to look at PFS curve carefully.

There can be some difference depending on the setting of the observation period, correct?

Yes.

Zhou from Goldman Sachs speaking. I also would like to ask you about how to interpret overseas and domestic study data? I got the impression that age is an important factor in terms of the target patient population indicated for the treatment. Between overseas and Japanese studies, the median age was also quite different. As for PFS curve, there is a difference, about 10 months overseas and about 5 months in Japan. How much is the involvement of age as a factor here?

Well, as for the age, the median age in Japanese study was 71 and 67 for Pola-BR arm in overseas study. There was a 4-year difference, but the median age for control arm or BR arm in overseas study was 71. And so I don't think median age was very different. The primary reason for transplantation in eligibility was age for 65% of Japanese patients, and the rate for failed prior transplantation was low in Japanese patients. That was the difference between overseas study and Japanese study in terms of the reason for transplantation in eligibility. It is difficult to explain the difference. But in overseas, they tend to avoid citing age as a reason for transplantation in eligibility. While in Japan, it is often judged that patients over 65 or over 70 are transplantation ineligible. There may be some differences in the thinking about autologous transplantation.

This is Sakai, Crédit Suisse. I also have questions about Japan versus overseas in the table on Page 49. I now understand the factors of age and the fail of prior transplantation. The prognosis of this disease is not good. The patients of this disease have strong desire or eagerness to receive treatment like second line and third line. Are there high needs by the patient? This is my first question.

Thank you for your question. When patients have relapsed refractory hematopoietic tumor, well they tend to continue positive treatment and move on to second line and third line or rather receive best supportive care? Actually, in the case of hematopoietic tumors, compared with solid tumors, patients tend to choose some kind of chemotherapy until their conditions become very poor or treatments do not work at all rather than receive best supportive care or palliative care. It is because chemotherapies temporarily help to mitigate the symptoms of patients. Patients choose the treatment and also doctors expect that the chemotherapies will improve the patient's conditions temporarily and often continue the treatment.

I understand. Another question is about bendamustine. Bendamustine is getting more attention in the Japanese stock market. In this table, a question mark appears for prior bendamustine treatment. Is there any reason for that? Is bendamustine used as a base? And is the dose to be reduced or increased later?

Thank you for your question. When this study with Pola-BR was conducted in Japan, bendamustine was not indicated for DLBCL. I think that was the reason of the question mark. Bendamustine is now indicated for DLBCL and BR regimen without Pola is a treatment option. Bendamustine dose is 120 milligram when it is administered without Pola. Phase II study and the single-arm Phase III study were conducted in Japan. The results of the Phase III study have already been presented in a scientific congress and approval was granted based on the study. When bendamustine is administered at 120 milligram every 3 weeks, hematological toxicity is very often observed. In the clinical trial during the development, the median number of cycles was 4, which was 1 cycle less than that of Pola-BR study.

So from the point of Pola, is it possible to increase the dose of bendamustine to 120 instead of 90 milligram when it is combined with Pola?

It is difficult due to hematological toxicities. It may be difficult to choose polatuzumab vedotin for patients who suffer from severe peripheral neuropathy with a prior therapy because the drug may aggravate it. In the case, BR therapy at 120 milligram will be a good option.

In any case, outpatient treatment is possible with or without Pola. Is it right?

Yes. I think outpatient treatment is possible, while you are careful about hematological toxicity. Thank you very much. [Statements in English on this transcript were spoken by an interpreter present on the live call.]