Good morning, my name is Krista and I'll be your conference operator today. At this time I would like to welcome everyone to the Jazz Pharmaceuticals Zanidatamab R&D Day. All lines have been placed on mute to prevent any background noise. After the speaker's remarks there will be a question and answer session. If you'd like to ask a question during that time simply press star followed by the number 1 on your telephone keypad, and if you'd like to withdraw that question again press star 1. Thank you. I would now like to turn the conference over to Bruce Cozadd, Chief Executive Officer. Bruce, you may begin your conference.
Welcome everyone. I'm Bruce Cozadd, Chairman and CEO of Jazz Pharmaceuticals. I am very excited about the potential of zanidatamab to transform the current standard of care in multiple HER2-expressing cancers. Today we're looking forward to sharing information on our development plans for zanidatamab, focusing first on our near-term indications: biliary tract cancers, or BTC, and gastroesophageal adenocarcinoma, or GEA. We'll also dive into our breast cancer development plan. This is a very broad space so we're initially targeting areas where we believe zanidatamab can immediately contribute to advancing patient care and has a high probability of success based on existing clinical data. We're very pleased to welcome several external experts who have experience with zanidatamab, including participating in our clinical trials and presenting data.
They will provide their perspectives on the current standard of care for GEA and certain HER2-expressing breast cancers, along with zanidatamab data in those areas and where zanidatamab potentially fits into the treatment landscape. Turning to slide two, as a reminder we will be making forward-looking statements. Please consult our SEC filings for more details. On slide three you'll find an agenda for today's program. I'd like to briefly introduce today's speakers: Rob Iannone, Executive Vice President and Global Head of Research and Development at Jazz; Dr. Geoffrey Ku from Memorial Sloan Kettering Cancer Center in New York, who specializes in the treatment of GEA. We're also pleased to have three breast cancer specialists joining us today: Dr. Sara Hurvitz from the Fred Hutchinson Cancer Center in Seattle; Dr. Santiago Escrivá-de-Romaní from the Vall d'Hebron Institute of Oncology in Barcelona; and Dr.
Paula Pohlmann from the MD Anderson Cancer Center in Houston. Also joining us is Abizar Gaslightwala, who leads the U.S. Commercial Oncology Business Unit at Jazz. Moving to slide five. Zanidatamab is a truly novel and differentiated HER2 therapy with the potential to address critical unmet patient needs. It has unique mechanisms of action, and importantly preclinical and clinical data have shown that Zanidatamab has the potential to be a best-in-class therapy for multiple HER2-expressing tumors. We're executing a regulatory strategy that we believe will enable us to bring Zanidatamab to the market in the near term in our initial indication of BTC, with the opportunity to rapidly advance other indications. In total we believe our development program can deliver for patients in need and generate a significant commercial opportunity of over $2 billion.
Now I'll hand the call over to Rob to overview Zanidatamab's MOA and our development in BTC.
Thank you Bruce. Good morning and thank you everyone for joining. I'll start on slide eight. Zanidatamab, as we will further outline, is a HER2-targeted agent that has demonstrated activity in multiple HER2-expressing cancers. It has a unique mechanism of action, a bispecific monoclonal antibody with biparatopic binding. Zanidatamab simultaneously binds to extracellular domains 2 and 4, which correspond to the domains of Herceptin and Perjeta. However, Zanidatamab's unique mechanism of action has shown greater efficacy relative to the combination of Herceptin and Perjeta in both preclinical and clinical experiments. Zanidatamab binds in a biparatopic fashion such that each antibody typically binds to two receptors. This results in multiple mechanisms of action, all resulting in tumor cell death. As seen on the left side of the figure, Zanidatamab interferes with HER2 signaling and also disrupts heterodimerization of HER2 and HER3, further inhibiting tumor cell signaling and growth.
Zanidatamab causes receptor clustering and receptor internalization, as shown in the middle part of the slide, and induces immune destruction through ADCC, ADCP, and CDC, as shown on the right and bottom. We think that Zanidatamab induces CDC at a level that is highly differentiated in the category. Slide 9 compares several HER2-targeted agents using super-resolution microscopy. Notably, you'll see significant and unique clustering of HER2 receptors on the surface of cells exposed to Zanidatamab, which drives enhanced internalization and downregulation of the HER2 proteins, resulting in tumor cell death. Moving to slide 10. HER2 clustering and cap formation, shown on the prior slide, is also believed to induce better effector activity. Importantly, Zanidatamab is differentiated with respect to activation of the complement pathway, eliciting complement-dependent cytotoxicity, which is believed to contribute to the clinical efficacy.
On slide 11, in these preclinical models of gastric cancer, we see that zanidatamab reduces tumor volume compared to both placebo and trastuzumab, and the combination of trastuzumab and pertuzumab. As highlighted on slide 12, since closing the transaction in December 2022, the zanidatamab opportunity has been increasingly de-risked through additional clinical data. Clinical data for zanidatamab generated to date has demonstrated activity as monotherapy in combination with other agents in patients previously treated with other HER2 agents, and results in durable responses with encouraging PFS and OS data. I'll walk you through some of the data in more detail, starting with slide 13. Zanidatamab has resulted in high rates of deep objective responses across multiple HER2-expressing tumor types as monotherapy. The data in second-line plus biliary tract cancer, shown at the bottom of slide 13, are the basis for the FDA rolling submission.
Here on slide 14, zanidatamab has also demonstrated clinical efficacy when combined with chemotherapy, PD-1 inhibitors, and antihormonal therapy in early and late lines of therapy and across tumor types. Slide 15 highlights strong activity in patients who have progressed after HER2 therapy, including commonly used combinations such as trastuzumab and pertuzumab, and after ADC such as T-DM1 or T-DXd. These data have helped establish the rationale for developing zanidatamab in relapsed refractory breast cancer. Furthermore, here on slide 16, responses with zanidatamab are durable. In both monotherapy and as part of combination regimens, as shown in these four panels, zanidatamab has shown durable responses in multiple tumor types and lines of therapy. There is a significant and growing body of research demonstrating durable responses with a manageable tolerability profile in multiple tumor types. We have advanced the development program rapidly since acquiring rights.
Zanidatamab is the highest priority within Jazz R&D. Drilling down on the BTC opportunity on slide 18, BTC is our fast-to-market strategy given the high unmet need with no other HER2-targeted therapies approved. The HERIZON-BTC-01 study has demonstrated compelling efficacy compared to the current second-line standard, shown here. We have initiated a rolling BLA for second-line BTC in the U.S., which we expect to complete in the first half of 2024 with potential for accelerated approval. Moving to slide 19, we estimate there are approximately 12,000 cases of HER2-expressing BTC across first-line and second-line in the U.S., Europe, and Japan combined each year, which typically presents in an advanced stage and has a very poor prognosis. In the U.S., there are approximately 3,000 first and second-line cases each year. Zanidatamab represents a meaningful advance for patients who currently do not have an approved HER2-targeted treatment.
Here on slide 20, the BLA submission in the U.S. is underway and will enable us to file supplemental BLAs for subsequent indications. We expect an updated data cut from the HERIZON-BTC-01 trial with longer follow-up, including median OS, in 2024. Depending on the FDA review timeline, we are prepared to launch in 2025 or earlier with ex-U.S. commercial launches to follow. Moving to slide 21, we are also developing zanidatamab in first-line BTC and have initiated a Phase III trial based on agreement with the FDA. PFS in IHC 3+ patients is the primary endpoint. Secondary endpoints include PFS, OS, ORR, duration of response, and safety in all comers. Now it is my pleasure to introduce our first external speaker, Dr. Geoffrey Ku from Memorial Sloan Kettering Cancer Center in New York. Dr.
Ku is an expert in the treatment of gastroesophageal adenocarcinoma and is head of the esophageal gastric section on the GI oncology service in the Department of Medicine at Memorial Sloan Kettering Cancer Center. He has published extensively on a variety of gastric cancers and is a member of the esophagogastric task force of the National Cancer Institute. I'll note Dr. Ku has been an investigator on several Zanidatamab trials and is an author on multiple Zanidatamab presentations and publications.
Well, thanks, Rob. So starting on slide 24 is an outline of the treatment paradigm for patients with GE junction and gastric cancer, and we focus both on resectable as well as advanced unresectable disease. So focusing initially on the right part of the slide, the KEYNOTE-811 study established a new reference regimen with pembrolizumab, trastuzumab, and chemotherapy. And this regimen was initially approved in May 2021 for all patients, but the approval was actually narrowed in September of 2023 to include only tumors that are PD-L1 positive. And that's really because in subset analysis, tumors that were PD-L1 negative did not derive any benefit from the addition of pembrolizumab to trastuzumab and chemotherapy. In fact, there was some suggestion that those patients were harmed, although those are small patient numbers.
So clearly there remains an unmet need certainly in the PD-L1 negative patient population, but even for patients with PD-L1 positive tumors, there's certainly significant room for improvement in terms of outcomes for our patients. Now, focusing on the column on the left, for patients who have resectable GE junction and gastric cancer, the standard of care in addition to surgery is either perioperative chemotherapy or preoperative chemoradiation. The treatment is the same irrespective of whether tumors are HER2 positive or HER2 negative, and that's really because no anti-HER2 therapy has been found to be beneficial in this setting. Therefore there is also a significant unmet need for these patients, and one that zanidatamab has the potential to address.
I would point out that we are actually developing concepts within the AACR, which is the American Association for Cancer Research, as well as NRG, which is one of the large cooperative groups in the U.S., to address specifically this space and this unmet need. The HERIZON-GEA-01 study, which we will come back to, is an ongoing trial that's enrolling HER2 positive first-line gastroesophageal adenocarcinoma patients with unresectable, locally advanced, and metastatic cancer, and patients are currently being enrolled to this ongoing study. On the next slide, on slide 25, we see that the first potential area for zanidatamab is in the front-line setting for HER2 positive disease in patients who are PD-L1 negative.
Turning to slide 26, we can see the currently available standards of care in the first-line setting, along with the results from the Phase II study of Zanidatamab plus chemotherapy that was conducted here in the U.S., and these results were last presented in 2023 by my colleague, Dr. Yelena Janjigian. So the TOGA regimen or the TOGA study established in 2010 that trastuzumab plus chemotherapy is a standard of care in the first-line setting for HER2-positive GE junction gastric cancer, and those results are shown in dark gray. The lighter color range represents the control arm of trastuzumab plus chemotherapy from the KEYNOTE-811 study. And so basically you'll see that outcomes in KEYNOTE-811 with their control arm were better than with the experimental arm in the TOGA study, both of which were the same, trastuzumab plus chemotherapy.
One possible explanation for that is that the definition of HER2 positivity has actually changed in the last decade so that we are now enrolling patients who we think do derive more benefit from anti-HER2 therapy, and that may account for the improved outcomes from one study to the next. Then in dark gray, we also see the results from the experimental arm of KEYNOTE-811, pembrolizumab plus trastuzumab, and chemotherapy. Finally, in terms of cross-trial comparison, we see the results from the zanidatamab plus chemotherapy study. Again, with all the caveats of cross-trial comparison, we see that these results compare very favorably. In particular, if you look at median duration of response as well as median progression-free survival, as well as response rates, all of those are numerically higher for the zanidatamab plus chemotherapy arm.
Turning now to slide 27, we see that in the zanidatamab plus chemotherapy study, there are responses seen with all three chemotherapy regimens that were used. So this was a study that explored three chemotherapy regimens: CAPOX or capecitabine oxaliplatin, FOLFOX6, which is typically the regimen that's most commonly used in the U.S., as well as kind of a historical reference regimen of 5-FU cisplatin. And we also see with the spider plot that there is significant durability in terms of the responses, which as a clinician who treated some of these patients, was really quite impressive and a significant differentiating factor from other treatments. Turning now to slide 28, we also see that these early results demonstrate extremely promising survival outcomes. The progression-free survival, again, as discussed, is 12.5 months, and median overall survival actually was not reached at the time of last analysis.
For the 12-month overall survival rate, it was 88%, and the 18-month overall survival rate was very close at 84%. I would note that progression-free survival is certainly a clinically meaningful endpoint, but it is also a key measurement that the FDA assesses when reviewing therapies in the first-line setting, and again, longer than with the currently approved combinations in both PD-L1 positive and PD-L1 negative population. This Phase II study remains ongoing, and we certainly have patients at Memorial Sloan Kettering who are still on treatment. Turning now to slide 29, we also focus on the PD-L1 positive population in which there is the potential to evaluate the combination of zanidatamab and chemotherapy, now with tislelizumab, which is an anti-PD-1 antibody. This triple combination is one of the experimental arms in the ongoing pivotal trial, the HERIZON-GEA-01 study.
On slide 30, we again see a cross-trial comparison. These are early results from this triplet regimen of tislelizumab, zanidatamab, and chemotherapy. This was a study that was performed in East Asia compared to patients who received zanidatamab plus chemotherapy here in the U.S., as well as the other historical regimens that we've talked about already, the ToGA study and the KEYNOTE-811 study. Again, here we see very promising outcomes for the triplet regimen. The response rates seem comparably high for both zanidatamab and chemotherapy with or without tislelizumab, but it does seem that we're seeing a signal where the addition of tislelizumab to zanidatamab and chemotherapy may increase the median duration of response and therefore also push up the median progression-free survival.
Turning now to slide 31, we see exactly this again in the swimmers plot, that the treatment duration and response and progression-free survival are all very encouraging in the patients who received the triple combination of Tislelizumab with zanidatamab and chemotherapy. Durable responses were seen in patients that were both PD-L1 positive and negative, although I would note that in this study, a slightly different way of assessing PD-L1 was used relative to what was used, for example, in the KEYNOTE-811 study. Turning now to slide 32, I've hinted at this already, but now I'll discuss the actual design of the HERIZON-GEA-01 study. So this is a first-line multi-center global study that's evaluating zanidatamab in HER2 positive GE junction and gastric cancer that's essentially locally advanced, unresectable, and metastatic.
So the way the study works is that patients and physicians choose one of two chemotherapy regimens, either CAPOX or 5-FU cisplatin. Patients are then randomized to three arms. Control arm is trastuzumab with chemotherapy, and there actually are two experimental arms. One is zanidatamab with chemotherapy alone, while the other experimental arm is the triplet regimen that we've talked about, tislelizumab with zanidatamab with chemotherapy. The study has a dual primary endpoint of progression-free survival as well as overall survival. The plan is to enroll a total of 918 patients, and the study was actually recently expanded to improve power for detecting an improvement in overall survival while maintaining the original planned time and statistical power for the PFS readout. So I'll now turn the call back over to Rob.
Thank you, Dr. Ku. As shown on slide 34, we have an opportunity to advance care significantly for patients with GEA in the neoadjuvant, adjuvant, and metastatic settings. In neoadjuvant and adjuvant settings, zanidatamab could be used as an addition to chemotherapy and radiation therapy or in combination with anti-PD-L1 inhibitors. As a differentiated HER2 bispecific antibody and based on data Dr. Ku reviewed earlier in the presentation, we expect to replace trastuzumab plus chemotherapy as the standard of care in the PD-L1 negative metastatic first-line setting. In the PD-L1 positive setting, we expect to be the HER2 agent of choice for use in combination with a PD-1 inhibitor. Moving to slide 35, GEA is a significantly larger patient population compared to BTC, with an estimated 63,000 new cases annually across the U.S., Europe, and Japan.
Our first opportunity to reach patients will be in the U.S., where there are approximately 8,000 first-line HER2-positive GEA cases annually. HERIZON-GEA-01 is an ongoing global Phase III trial recruiting in North America, Europe, and Asia, including Japan. Looking at slide 36, noting that we will limit our promotional activity to labeled indications, we do anticipate that experience with BTC may help with the introduction in GEA, given the unmet need for patients. A prior approval in BTC would allow adoption of GEA treatment into the guidelines prior to the GEA label update. The trial is event-driven, and we are targeting top-line PFS data from HERIZON-GEA-01 later this year to support a supplemental BLA filing in the U.S.
Building on success seen in BTC and GEA, we see significant opportunity for zanidatamab in early and late-stage breast cancer, supported by data for both late-line chemotherapy combinations as well as monotherapy in patients with early-stage disease. As you can see here on slide 38, this includes novel combinations such as in HR positive, HER2 positive patients, where we think combining with CDK4/6 inhibitors and fulvestrant allows us to utilize a chemotherapy-free regimen building on the interaction with the cyclin D1 CDK4 pathway. The biggest opportunity is to target and build a robust dataset in patients who have progressed on T-DXd, where we think zanidatamab has an opportunity to provide patients with an effective and well-tolerated therapy in a setting where there are little data to support the use of other HER2 therapies.
We're excited to announce today that we expect to initiate a Phase III trial in patients who have progressed on T-DXd in the second half of this year. Dr. Hurvitz will review the trial design in more detail shortly. It is now my pleasure to introduce our external breast cancer experts, Dr. Hurvitz, Escrivá-de-Romaní, and Pohlmann. We will start with Dr. Hurvitz covering late-stage HER2 positive breast cancer. Dr. Hurvitz serves as the senior vice president of the clinical research division at Fred Hutch and the head of the division of hematology and oncology at the University of Washington Department of Medicine. She has extensive experience leading oncology clinical trials in all phases of development. Dr. Escrivá-de-Romaní has participated in multiple zanidatamab breast cancer studies and is an author on a number of zanidatamab presentations and publications.
He is a medical oncologist in the breast cancer unit at Vall d'Hebron Institute of Oncology in Barcelona, Spain. His main focus and interest is in HER2-positive breast cancer and in the development of new treatments and therapeutic strategies. Dr. Pohlmann is a medical oncologist specializing in clinical trial design, Phase I drug development, and in breast cancer research and treatment. She currently serves as an I-SPY investigator and agent chaperone, as well as a member of the I-SPY Safety Biomarker and New Agents Committee.
Thank you, Rob. Shown here on slide 41 is the current treatment landscape for HER2-positive advanced breast cancer. The standard of care first-line therapy remains trastuzumab, pertuzumab, and taxane, or the THP regimen, based on the practice-changing findings from the CLEOPATRA study in which adding pertuzumab to trastuzumab and taxane was associated with an improved progression-free and overall survival. In addition, the second-line standard of care right now, after trastuzumab and taxane, is trastuzumab deruxtecan, or T-DXd, the anti-HER2 targeted ADC, which was shown to improve both progression-free survival and overall survival when compared to the standard of care at the time, T-DM1. Tucatinib, trastuzumab, and capecitabine is also indicated in patients who've received trastuzumab and taxane previously based on the HER2CLIMB study. In this study, patients who had previously treated HER2-positive metastatic breast cancer, having received at least two prior lines of therapy, were enrolled.
This study was unique because up to half of the patients enrolled had brain metastases. Therefore, when the tucatinib went up for FDA approval, it did receive an approval in patients, even in the second-line setting, if they have brain metastases. And for this reason, many see tucatinib-based therapy as a standard regimen for patients with brain metastases. The third-line setting and beyond remains a bit of the wild, wild west. Right now, there are a variety of treatment options available, not a ton of data about how these various therapeutic options in the third and fourth-line setting work after T-DXd. And so this is an area where we really are interested in seeing more clinical trials to better establish the efficacy of new tolerable regimens that have efficacy in this setting.
On slide 42, as mentioned earlier, the activity of other anti-HER2 therapies has not been well defined after disease progression on T-DXd. If T-DXd becomes the standard of therapy in the second-line setting, these second-line treatment options are going to be very undefined. At this point, I would predict that T-DXd will become the standard first-line therapy, given the very high progression-free survival and overall survival rates, which, based on cross-trial comparison with CLEOPATRA, seem to compare favorably. There's going to need to be effective post-T-DXd therapy in the second-line setting once those data from the DESTINY-Breast09 study become available. Slide 43, zanidatamab has demonstrated efficacy in HER2-positive metastatic breast cancer across multiple lines of treatment, regardless of the hormone receptor status or the combination therapy. In this table, you can see an example of three different clinical trials run evaluating zanidatamab.
In the first-line setting, zanidatamab was combined with docetaxel in 37 patients, and an objective response rate was seen exceeding 90%. These are very notable findings in that first-line setting. In the third-line setting and beyond, so in more heavily pretreated disease, zanidatamab was evaluated in combination with chemotherapy in the ZW25101 study and was evaluated in combination with a CDK4/6 inhibitor, palbociclib, and an endocrine therapy, fulvestrant, in HER2 positive breast cancer with coexpression of hormone receptors in the ZW25202 study. Although these studies were both fairly small, the objective response rate was over 30% in both of these studies, with a progression-free survival of 7 months in patients with chemotherapy and 12 months in patients where zanidatamab was combined with the CDK4/6 inhibitor and hormonal-based therapy. I think these latter two examples are very notable because the patients had been very heavily pretreated previously.
And so these progression-free survivals and objective response rates are actually very promising. Slide 44 shows zanidatamab plus chemotherapy data from the 25101 study and compares it to the data that we saw from the SOPHIA Phase III clinical trial evaluating margetuximab plus chemo versus trastuzumab plus chemo. Although cross-trial comparisons are not necessarily fair because patient characteristics differ from one study to another, it is a valuable exercise to see where zanidatamab stands when looking at a more heavily pretreated patient population. Zanidatamab was associated with an objective response rate of 36% and a PFS exceeding 7 months, whereas in the SOPHIA study, trastuzumab with chemo had an objective response rate of only 14% and a PFS of 4.4 months, and margetuximab had an objective response rate of 25% and a median PFS of 5.7 months.
Again, we can't make a fair comparison of zanidatamab to these data, but it does give us reassurance of the activity of this HER2 bispecific. Slide 45, on this slide, we are looking at the waterfall plot from the Phase II clinical trial evaluating zanidatamab with fulvestrant and palbociclib. So each of the columns is representing one patient's best response to therapy. If you look to the right of the plot, you can see all these patients have a column that is below zero indicating their tumors have shrunk based on this therapy. The light blue shadow indicates those patients who had previously been treated with T-DXd. And so what I think is notable is that we are seeing patients whose disease has become resistant to T-DXd, and yet they are having a response to this novel chemotherapy-free regimen of zanidatamab, fulvestrant, and palbociclib.
Slide 46, as I've indicated earlier, treatment after disease progression on T-DXd is an uncharted territory, and it is an area of unmet need. We have an opportunity now to look for a better treatment option that is both effective and maintains quality of life. We know zanidatamab has a novel mechanism of action, is demonstrating solid early evidence of efficacy, and a safety profile that is advantageous compared to chemotherapy-based products, including antibody-drug conjugates after T-DXd. Physicians are looking for an answer to the sequencing dilemma and therapies that are indicated after progression on T-DXd. And so the goal of generating robust zanidatamab data is to fill gaps in sequencing after progression on T-DXd because there is a dearth of data relating to how we should treat our patients after T-DXd.
Zanidatamab has the potential to be the first HER2-targeted therapy to demonstrate efficacy and safety after disease progression on T-DXd. So the plan is to launch a Phase III study in patients whose disease has progressed on T-DXd. Slide 47, shown here is the design of a randomized Phase III clinical trial evaluating zanidatamab plus chemotherapy in patients who have received T-DXd previously and have HER2-positive advanced breast cancer. Patients will be allowed if they have not had more than 4 prior lines of HER2-directed therapy in the metastatic setting. Patients will be randomly assigned 1:1 to receive zanidatamab plus physician's choice of chemotherapy or trastuzumab plus physician's choice of chemotherapy. Patients with a history of treated brain metastases whose disease is clinically stable in the brain are eligible, and patients are required to have at least 1 measurable disease.
The primary endpoint of this clinical trial entitled EmpowHER will be progression-free survival, with secondary endpoints including overall survival, objective response rate, and safety. Slide 48, shown here, is a graphic indicating the potential HER2-positive advanced breast cancer treatment paradigm, where we are now seeing the opportunity for Zanidatamab for the first time to have a place post-T-DXd based on solid clinical trial evidence. Tucatinib, trastuzumab, and capecitabine will still be an option, potentially, for patients who have brain metastases based on the practice-changing results of the HER2 CLIMB study. And after the second-line therapy is shown here, then again, we have uncharted territory in figuring out how to sequence a variety of agents, including T-DM1, tucatinib-based therapy, chemotherapy plus trastuzumab, Margenza, and other HER2 targeted TKIs. And now I will hand the call over to Dr. Escrivá-de-Romaní.
Thank you, Dr. Hurvitz.
Starting on slide 51, around 50% of HER2-positive metastatic breast cancer patients also present hormone receptor expression. In this slide, you can see the current treatment paradigm for this population of HER2-positive, hormone receptor-positive, late-stage breast cancer as recommended by international guidelines. As Dr. Hurvitz was commenting earlier, treatment is often similar for HER2-positive metastatic breast cancer patients regarding hormone receptor status along the subsequent lines, except for the current first-line treatment. Here, endocrine treatment, often with aromatase inhibitors, is given as a maintenance therapy combined with double HER2 blockade with trastuzumab and pertuzumab after taxane chemotherapy induction. We can see in the algorithm that at the present time, there is no standard use of endocrine receptor-directed therapies after maintenance in first line. In the second line, there is a preferred use of the antibody-drug conjugate trastuzumab deruxtecan (T-DXd).
From the third line on, there are different recommended regimens of anti-HER2 therapies such as antibodies or tyrosine kinase inhibitors in combination with chemotherapy. So I might point out that current treatment paradigms do not take full advantage of hormone receptor status and the potential synergy from blocking the HER2 and endocrine pathways as a therapeutic option for this patient population that might provide efficacy with a better toxicity profile compared with other chemotherapy-based options. Moving to slide 52, here, we have the results of the available trials exploring endocrine therapy and CDK4/6 inhibitors in combination with anti-HER2 antibodies. All of these are Phase II trials. The PATRICIA trial tested the combination of palbociclib plus trastuzumab with or without letrozole. Represented here, we have the best results obtained, which were with a triplet combination. The monarcHER trial compared abemaciclib plus trastuzumab with or without fulvestrant to chemotherapy plus trastuzumab.
Even compared with chemotherapy and trastuzumab, the best results represented here were also obtained with a triplet arm, including anti-HER2 therapy, endocrine therapy, and a CDK4/6 inhibitor. Here, we can also see the data recently presented at San Antonio Breast Cancer Symposium in 2023, studying the triplet of zanidatamab, palbociclib, and fulvestrant in this population of hormone receptor positive, HER2 positive, metastatic breast cancer patients. In this cross-trial comparison of these two trials with a triplet with zanidatamab, we can see how all these combinations show efficacy in terms of clinically significant overall response rate and PFS. In particular, the chemo-free triplet combination, including zanidatamab, palbociclib, and fulvestrant, was active with an interesting overall response rate and promising PFS in the overall population of the study, but especially for patients centrally confirmed as HER2 positive.
Here in slide 53, in this slide, we can see how the waterfall chart of the triplet combination with zanidatamab demonstrates significant activity in heavily pretreated patients with previous treatment with trastuzumab, pertuzumab, and T-DM1 that were required for protocol and also many other anti-HER2 therapies, including other antibodies, tyrosine kinase inhibitors, and ADCs. We have also seen earlier in Dr. Hurvitz's presentation that there were also responses in patients that had already been treated with T-DXd. These responses were comparable to those of the overall population, with achieved a response rate of 35% for patients with measurable disease that went up to 48% in patients with centrally confirmed as HER2 positive, including also complete responses.
Next in slide 54, here, the Swimmer plot also shows how patients achieved durable responses with a median PFS of one year for the whole population and again with better results of up to 15 months for patients centrally confirmed as HER2 positive. We can also see that there are patients still ongoing and obtaining benefit from treatment. I would also like to remark that 67% of patients were free of progression after six months, which was the primary endpoint of the trial. Finally, in slide 55, this slide illustrates the possible multiple opportunities that zanidatamab has in patients with HER2 positive, hormone receptor positive, late-stage breast cancer. There is a significant remaining patient need of active chemotherapy-free options that might provide a better quality of life profile without compromising efficacy compared with the available chemotherapy regimens.
In the first-line maintenance setting, the PATINA trial is a Phase III randomized trial studying the role of adding CDK4/6 inhibitors to the endocrine treatment. The trial ended recruitment some time ago, and the results are still pending. If that PATINA data are negative, there is an opportunity for the combination of zanidatamab with endocrine treatment and CDK4/6 inhibitors in the first-line maintenance setting by optimizing the available anti-HER2 therapy. As Dr. Hurvitz pointed out earlier regarding the possibility of T-DXd with or without pertuzumab moving to the first-line treatment, there would be an opportunity for new post-T-DXd second-line combinations since there is no evidence of how the available options will perform in this setting. In this case, and even if the PATINA trial results are positive, I still see an opportunity for an active chemo-free option combining zanidatamab with endocrine therapy and a CDK4/6 inhibitor.
This triplet combination optimizing the blockade of the HER2 and estrogen receptor pathways would be a very relevant chance for patients to be spared of the potential toxicity of the available chemotherapy options without compromising the required efficacy. Thank you. I will now hand the call over to Dr. Pohlmann.
Thank you, Dr. Escrivá-de-Romaní. Good morning. I am Dr. Paula Pohlmann, breast medical oncologist at the MD Anderson Cancer Center, where I serve as the chief for breast cancer research at the Department of Breast Medical Oncology. Starting on slide 58, we are very excited about the progress on treatment for patients with HER2-positive breast cancer in the past several years. We have significantly increased the number of patients who survived the disease.
Here you see the current standard of care treatment for patients who present with early-stage disease involving, on the left, upfront surgery followed by adjuvant chemotherapy and anti-HER2 therapy with trastuzumab with or without pertuzumab, or a preferred approach of neoadjuvant systemic therapy, typically with chemotherapy, trastuzumab, and pertuzumab followed by surgical resection. More recently, even patients with stage I disease have been treated in the neoadjuvant approach because both neoadjuvant surgical pathology can be used to tailor adjuvant treatment recommendations, informing about the potential additional benefit of antibody-drug conjugates such as trastuzumab and T-DM1. Although very effective, the use of cytotoxic agents such as chemotherapy and certain antibody-drug conjugate payloads is associated with the potential development of important long-term toxicities.
These toxicities include but are not limited to heart failure, new secondary malignancies, disabling peripheral neuropathy, maybe not very important at the time of the diagnosis, but these patients are expected to survive a long period of time, and the peripheral neuropathy becomes problematic towards the end of life, cognitive dysfunction, premature menopause, sexual dysfunction, infertility, and liver dysfunction. Slide 59. Again, the neoadjuvant setting is key to learning and to personalizing treatment. It permits a timely efficacy readout. It allows tailoring of treatment, more for those when needed, less for those who do not. It facilitates improvement and investigation of success and failure. Here you see one example of success measurement to residual cancer burden in patients with HER2-positive disease, the I-SPY clinical trial that was done in the neoadjuvant setting. The residual cancer burden gives you prognostic value that goes beyond pCR.
On the left graph, you see the early event-free survival data for the cohort of patients that have ER/PR positive, HER2 positive disease, and on the right, you see the cohort of patients with ER/PR negative, HER2 positive disease. You can see that those patients achieving RCB0, which is pCR, or RCB1, which is a very small amount of disease left after neoadjuvant therapy, have a very good prognosis. So again, RCB0 and RCB1 associated with outcome when compared to RCB2 and 3 when there is more residual disease after the neoadjuvant therapy or surgery. In the next slide, number 60, based on the information about the prognosis based on the result of neoadjuvant therapy, we would like to share a couple of zanidatamab studies focusing on the neoadjuvant development.
This first study is a single-arm, open-label study of zanidatamab in patients with stage I and II HER2-positive breast cancer who have measurable, though small, tumors, approximately 1-3 centimeters, and lymph-node-negative disease at diagnosis. This study started with zanidatamab monotherapy followed by surgical resection and adjuvant post-surgical treatment as per treating physician's choice. In order to obtain additional information about the potential efficacy of zanidatamab combined with chemotherapy, the protocol is also being amended to include a cohort of patients treated with chemotherapy combinations. I will get to this later. Next slide, number 61. I wanted to share with you the initial results of the first 20 patients treated in this trial. This was presented at the San Antonio Breast Cancer Symposium in 2023. Here you see a 30% rate of PCR and a 50% rate of combined PCR and RCB1.
Since we felt these results are encouraging, though with small numbers, the protocol has been amended to include additional 20 patients to this cohort. Again, zanidatamab was well tolerated with acceptable safety profile. There were no grade III or grade IV treatment-related adverse events, and this trial is still ongoing. Moving forward to slide 62, based on the results in the metastatic setting as well as the results on this MD Anderson early-stage neoadjuvant trial, zanidatamab was selected for inclusion in the I-SPY trials. Here is a representation of the I-SPY II neoadjuvant clinical trial that enrolls patients with high anatomic and molecular risk early-stage breast cancer. In the I-SPY II trial, the patient has three chances of achieving a pathologic complete remission with sequential therapies. Zanidatamab monotherapy is currently being evaluated as a no-chemotherapy blockade regimen. We plan to enroll 100 patients in this arm.
It will provide information. In lymph node positive and lymph node negative disease, you see in the I-SPY 2 neoadjuvant trial, the patient navigates through three potential blocks of therapy with the aim of achieving a pCR. If the patient achieves the pCR after Block A, which is typically a no-chemotherapy regimen, the patient can go straight to surgery. And we know, based on our data from more than 1,000 patients, it doesn't matter how you get to pCR. If you get to a pCR or RCB1, the outcome is very good, as I mentioned before. And so Zanidatamab is being evaluated as a Block A regimen. For those patients where a pCR is not predicted at the end of the Block A 12 weeks, then they move forward to receive the rather standard of care backbone of T followed by AC neoadjuvant therapy.
For HER2-positive patients, blockade B of the taxane includes double anti-HER2 therapy with trastuzumab and pertuzumab. And then if still after blockade B the patient has not achieved the pCR, then we go with blockade C, which is the rescue with AC. Moving to slide 63, we also want to test a combination of two targeted therapies without chemotherapy in the I-SPY 2 trial. However, we do not have safety data on the combination. And so we established a pre-I-SPY arm of zanidatamab with CDK4/6 so that we can hopefully move this quickly forward to I-SPY 2 neoadjuvant trial. The pre-I-SPY trial is a Phase Ib multi-site platform study that utilizes the same I-SPY network.
Evaluate new regimens for safety and early preliminary efficacy information so that we can move them forward to either the I-SPY 2 neoadjuvant trial or other trials in a timely manner. In this arm of zanidatamab and tucatinib, we have a Part 1 of those findings and a Part 2 of those expansion in which the patients are treated with the primary endpoint of recommended Phase II dose safety, tolerability, and preliminary efficacy. We also have translational endpoints that hopefully will help us with the development. In this slide number 64, I show you again the diagram of current standard of care treatment for patients with early-stage HER2-positive breast cancer in which we are favoring what is on the right side of neoadjuvant therapy, as we discussed before.
And we see a great opportunity for no-chemotherapy regimens in the neoadjuvant setting at the starting point, only rescuing people with chemotherapy as needed and personalizing that treatment recommendation based on response to therapy and molecular information from the tumor. And so the overall goal of this study is to develop a highly effective and less toxic regimen in the curative setting. We really would like to focus on the development of Zanidatamab in the pre-op neoadjuvant setting, either as a single agent or in combination, personalizing the intervention. We feel there is a great potential for no-chemotherapy containing regimens based on currently available efficacy and safety data, as well as on patient preference. Thank you. Now, heading over to Rob.
Thank you all for your participation and discussion today.
Moving to slide 67, there are four core areas where zanidatamab has the potential to meaningfully advance treatment in breast cancer: neoadjuvant node positive or node negative, with the goal of maintaining or improving efficacy with a better tolerated regimen. Late-stage T-DXd experienced patients, where there are scant data to support other regimens following progression after T-DXd. By building on a robust dataset with zanidatamab, we think there will be an appealing option even if T-DXd were to move to frontline based on the ongoing clinical trial. A late-stage combination with a CDK4/6 inhibitor and fulvestrant in HER2 positive, HR positive patients takes advantage of the role of expression and offers patients a possible chemotherapy-free solution. Moving to slide 68, breast cancer represents a significant global patient population expected to have a long duration of therapy.
Despite recent advances in therapies, there remains significant unmet medical need in HER2-positive breast cancer, with an estimated 150,000 new cases annually in the U.S., Europe, and Japan. Additional global trials will be needed for regulatory approval, and we are excited to announce the initiation of a registrational trial later this year for patients who have progressed on T-DXd. And now I will hand the call over to Abizar Gaslightwala, our head of U.S. commercial.
Thanks, Rob. I'll start on slide 71 in biliary tract cancer, or BTC. We are excited as we prepare for a potential approval and launch of zanidatamab for BTC in 2025 or earlier. Our launch planning and team preparedness are already underway in the U.S. We expect an updated data cut with longer follow-up, including meeting overall survival, which will add to the compelling body of data supporting this launch.
As we prepare for launch, our current oncology customer footprint is well aligned with where the BTC patients are currently diagnosed and treated. We plan on leveraging this footprint to help accelerate the launch and uptake of zanidatamab for BTC patients. Our current customers within these institutions and accounts that we call on today convey a high unmet need for advancing the care of HER2 positive biliary tract cancer patients given the poor prognosis and outcomes for these patients today and the lack of any currently approved targeted HER2 therapies for this population. The compelling data for zanidatamab and HER2 positive BTC highlighted during today's presentation resonates well with oncologists and healthcare providers and translates into a strong willingness to rapidly adopt and use zanidatamab for BTC patients.
In addition, these customers also note the other key benefits of zanidatamab's profile, including its safety, tolerability, and administration, making it a great fit for their current outpatient treatment protocols for BTC patients. The initial launch of BTC will enable our customers and accounts to get rapid experience in using zanidatamab and incorporate it into their specific treatment algorithms and pathways for BTC. We are currently working on the pricing for this novel and innovative therapeutic, and we strongly believe in the value and benefits that zanidatamab can deliver to patients and healthcare systems in terms of significantly improved and sustained clinical responses. We are confident this value story will resonate in discussions with payers and reimbursement authorities. Moving to slide 72, given the current unmet needs in HER2-positive metastatic GEA, we believe that superior HER2-targeted therapy like zanidatamab can significantly improve outcomes and benefit for these patients.
HER2 is the key biomarker and oncogene that drives differentially worse outcomes in GEA, and current trastuzumab-based regimens have not met the ongoing needs for metastatic GEA patients in terms of durable and sustained efficacy and outcomes. As we think about the first-line metastatic GEA market, based on the Phase II data presented by Dr. Ku, we believe that zanidatamab can establish a new standard of HER2 inhibition and outcomes in this setting, either as a doublet regimen with chemotherapy in patients with lower levels of PD-L1 expression or as a triplet in combination with an anti-PD-L1 inhibitor and chemotherapy in patients with higher levels of PD-L1. In the PD-L1 negative segment, which is approximately 45% of HER2 positive metastatic GEA patients, we believe this is a white space opportunity for zanidatamab in these patients.
In the PD-L1 positive segment, we believe the triplet combination of zanidatamab plus tislelizumab plus chemotherapy has the chance to set a new bar for efficacy and outcomes relative to current standard of care. The central premise here is more effective HER2 inhibition is the key to better outcomes in HER2 positive patients irrespective of PD-L1 levels, and this is where we believe zanidatamab will compare very favorably relative to trastuzumab. With the potential success within GEA, we would expect rapid inclusion of zanidatamab into NCCN treatment guidelines, with potential uptake occurring post this event. While we only promote indications in our label, pending zanidatamab's approval in GEA, zanidatamab may start to see use by clinicians that have already had positive experience with the on-market use of zanidatamab for BTC.
As we wait for final approval of a formal GEA indication, as appropriate, our sales teams will provide disease state education to relevant clinicians, which overlaps significantly with those that treat BTC. Our medical field teams will be communicating the Zanidatamab peer-reviewed data through scientific exchange interactions with these customers as well. Post approval of the GEA indication, we will leverage the strong data, NCCN guidelines, and the positive customer experience with Zanidatamab in BTC to further accelerate rapid uptake in this new indication of GEA. Next to slide 73, as presented earlier, Zanidatamab has a unique opportunity to own and redefine the treatment paradigm in HER2 positive metastatic breast cancer after progression on T-DXd.
No other HER2 targeted agents are currently approved with data demonstrating efficacy after progression on T-DXd, and this will be an increasingly large population as T-DXd continues to expand in the metastatic HER2 positive breast cancer space. On slide 74, in addition to these three tumor types, we believe zanidatamab has the opportunity to establish itself as effective HER2-directed therapeutic in solid tumors that express HER2, including lung, colon, bladder, ovarian, and several others. We will continue to invest in data generation opportunities through both Jazz Clinical Trials and investigator studies as appropriate, based on unmet need and opportunity to expand zanidatamab's potential. So turning to slide 75, in summary, our peak commercial opportunity for zanidatamab exceeds $2 billion. The initial launch in BTC in 2025 or earlier will help establish zanidatamab as a best-in-class HER2 targeted therapy that demonstrates significant benefit for patients.
This will be followed by a launch in the much larger HER2 positive frontline GEA patient segment, where we expect broad and rapid uptake. This rapid uptake will lay the foundation for future launches in various indications, including breast cancer as well as other potential HER2 positive pan-tumor opportunities. Zanidatamab is a unique, differentiated, and highly effective bispecific targeted HER2 therapy that has the opportunity to redefine what is possible in HER2 positive tumors and represents a broad array of opportunities across the entire HER2 positive solid tumor category. This is a global opportunity for Jazz across multiple markets, across all major geographies. Importantly, we are well positioned with our current oncology footprint, capabilities, and strong teams in place to realize this opportunity rapidly and efficiently. Thank you, and I would like to now turn the call over to the operator for Q&A. Thank you.
As a reminder, if you would like to ask a question, please press star followed by the number 1 on your telephone keypad. If you would like to withdraw that question, again, press star 1. Thank you. Your first question comes from the line of Jessica Fye from J.P. Morgan. Please go ahead.
Hey, this is Nick on for Jess. Thanks for taking our questions. First, maybe a question for Dr. Ku and how you envision the use of zanidatamab and GEA in the context of the KEYNOTE-811 regimen for PD-L1 positive patients. For those PD-L1 positive patients, we heard some feedback from docs that wish the KEYNOTE-811 regimen were in the control arm as that's now standard of care for the majority of patients.
Recognizing that may not have been a possibility when the trial kicked off, we hear some reluctance to sub-Zanidatamab for Herceptin as part of the Pembro triplet, even if Zanidatamab chemo arm beats the Herceptin chemo arm, because we won't have the pure triplet versus the triplet comparison in the same trial and kind of would be forced to compare Zanidatamab plus Tislelizumab plus chemo to Herceptin plus Keytruda plus chemo on a cross-trial basis. So I guess the question is, what do you need to see from the HERIZON-GEA-01 trial to use Zanidatamab in your PD-L1 positive patients, and how do you expect your colleagues to think about that?
Yeah, I think that's a great question. So I think as you kind of surmised based on the question itself, so at the time that the study was designed, there were different standards of care globally.
So based on KEYNOTE-811, pembrolizumab was approved for all patients at the time, whereas it was approved nowhere else in the world. So as this was a global study, the control arm really remained trastuzumab plus chemotherapy alone. And I can tell you that certainly, I think U.S. investigators like myself were disappointed because I think so we ultimately have not opened the study because it would be difficult for us to enroll those patients. Now that the FDA approval has been dialed back a little bit and it applies only to PD-L1 positive, potentially it's an option the study would be an option for PD-L1 negative tumors, but I digress. And I think your point is a very well-taken one, and I think that it really depends, I think, at the end of the day, how dogmatic one is in terms of cross-trial comparison.
With the GEA-01 study, there are two experimental arms, and ultimately, we'll have to see how both of them compare to the control arm. And then I think at that point, we'll also make cross-trial comparisons. And as you know, the tislelizumab-containing arm of the GEA-01 study, it's not meant to be directly compared to the zanidatamab plus chemo arm, but again, that is a comparison that all of us will make. So I think it's really going to depend on the totality of the data within the study itself, within both experimental arms, and then cross-trial comparison with KEYNOTE-811. And I think ultimately, everyone will, I think, probably come to their own conclusions. But I think to me, I mean, I think the strong hope and feeling, certainly based on the Phase II data, is that zanidatamab is superior to trastuzumab.
So I think the zanidatamab chemotherapy arm and trastuzumab chemotherapy arm will be a straightforward comparison. But you're right. I mean, I think the pembrolizumab versus tislelizumab arm, pembrolizumab versus zanidatamab plus chemo arm, I think we really will have to see what the magnitude of the benefit in the GEA-01 study is. And again, like I said, everyone treats cross-trial comparisons a little bit differently. We all do it. How much we publicly kind of acknowledge that is a different issue.
Great. And maybe just one more, and sorry if we missed this, but I think prior to the upsizing of the GEA trial for the OS analysis, you were 80% powered to detect 0.27 OS hazard ratio for the triplet arm versus the Herceptin chemo arm.
Can you talk about what your OS powering is now for the Zanidatamab plus chemo arm versus the Herceptin plus chemo HR of 0.72 for the arm C versus arm A at the time of the final OS analysis?
Yeah. So I mean, we actually had an ad board a couple of months ago about this. I don't remember the granularity anymore. Again, the premise of increasing the sample size was really to kind of increase the power for OS, but at the same time, kind of maintain the readout for PFS. I want to say that I mean, maybe someone from the Jazz team or certainly, I mean, the statistician team can comment, but I thought the hazard ratio went up to maybe 0.85, but I could be sorry, not the hazard ratio, the power, but I could certainly be wrong.
Yeah, I'm happy to jump in.
This is Rob Iannone. I don't believe we shared any of the details around specific powering or the critical hazard ratios under the new sample size. What I can say is that we were able to do that without changing our timing or impacting the power for PFS, which will be the primary endpoint for approval, and also then raising the sample size that is essentially now comparable to the KEYNOTE-811 trial. So we maintained PFS and improved our power for OS. We also introduced an interim analysis for OS, so if the results are robust, we could actually see an early OS result that are roughly on time with what the original plan was. I'd also like to just go back a bit to the question you had around the Tislelizumab arm.
So certainly, we believe that zanidatamab is the best-in-class anti-HER2 agent and will be competitive relative to Herceptin chemo. But we also think that tislelizumab, now approved in the US, is a PD-L1 inhibitor that has shown data as strong as any other PD-L1 inhibitor. So we don't think the PD-L1 inhibitors are differentiated from one another, whereas zanidatamab certainly is differentiated from other HER2 agents. So we think strong data in that second experimental arm, even without a direct comparison to Keytruda, will drive practice in this space.
Great. Thanks so much.
Your next question comes from the line of Joon Lee from Truist Securities. Please go ahead.
Hey, thanks for the thorough presentation and for taking our questions. Are the cancer treatment algorithms in the US different materially compared to ex-US, where BeiGene is developing zanidatamab in their respective cancers?
Just curious how much of a read-through we can expect as there may be some non-overlapping indications. And related to that, it seems like BeiGene is also developing zanidatamab/zovodolimab/ADC combination. Do you have any plans to develop a similar ADC strategy based on zanidatamab as a backbone? Because ADC comes up a lot in our conversations with investors. Thank you.
I think your first question. This is Rob Iannone again. I think your first question is whether the treatment landscape across tumor types differs in the BeiGene region. I mean, certainly for the cancers that we're pursuing in partnership, in particular GEA, there is fairly standard practice across global areas, with some small differences potentially in terms of the combination chemo that might be used. That was mentioned in the presentation that there is an option around CAPOX versus 5-FU cisplatin. But generally, the practice is very similar.
We haven't yet disclosed. I think the second part of your question was around, are we thinking about combining with ADCs? We haven't yet disclosed specific plans around that. But we certainly are looking at opportunities across all tumor types because we think zanidatamab is active wherever HER2 is amplified and overexpressed. But for the moment, we see the opportunity to be on the market in the near term, as early as this year, for BTC, have data in frontline GEA, again, targeting the end of this year, and by that time to have a pivotal breast cancer program go well underway. And beyond that, we certainly are looking at other combinations and indications.
Thank you.
Your next question comes from the line of Pavan Patel from Bank of America. Please go ahead.
Hey, guys. This is Pavan Patel on for Jason Gerberry. Thanks for taking our questions.
My first is, given how competitive breast cancer is, maybe can you frame the HER2 positive metastatic breast cancer opportunity in the U.S., and specifically the post-T-DXd therapy in second-line advanced breast cancer? Would it be fair to characterize that as the most attractive subset patient population from the commercial opportunity? And then I have a follow-up question as well.
I might frame that and then ask some of our guests and experts to join in, as well as Abizar from our commercial organization. I mean, I think you heard Dr. Hurvitz say that with the emergence of T-DXd in second line and potentially ultimately in first line, it's created a significant data gap in terms of what treatments would optimally follow patients who are either intolerant to or progressed on T-DXd.
We think our data are strong across all the breast cancer studies that we've done so far, and we certainly think we're accumulating data showing activity after HER2 agents. Dr. Hurvitz highlighted specifically activity after T-DXd. So we do think that conducting the study that we're planning to conduct, we may be the first to demonstrate definitively activity in that post-T-DXd space. And maybe I would ask Dr. Hurvitz to jump in there with anything she might add before turning it over to Abizar for a commercial perspective.
No, I think you said it very well. I think there is this paucity of data post-T-DXd that we're trying to scramble to understand how to best utilize our existing therapies after T-DXd. There's a lot of reluctance to use drugs like T-DM1, another antibody-drug conjugate, which is so heavily reliant on high expression levels of HER2.
There is some concern that a mechanism of resistance to T-DXd may be downregulation of HER2, and so using an agent that requires such high levels of expression is felt to be problematic. Use of trastuzumab after T-DXd has just not been well-defined. And so there's just a lot of questions about how to best go about it. And as we indicated earlier, I think the fact that zanidatamab has compelling data already, albeit from smaller studies, it is incredibly promising. And if you look at the patients in the positive, HER2 positive setting, and look at those patients with centrally confirmed HER2 positive breast cancer, the outcomes were really quite impressive. I was quite blown away. I've talked with colleagues in the breast world. I think a lot of us are very excited to see this move forward. With a chemo-free regimen, it's done beautifully.
If you look at pairing it with chemo, the results are just outstanding. They're along the lines of what we saw with CLEOPATRA with THP, maybe even better, so in the first-line setting when zanidatamab was combined with docetaxel. So I just think that this is a real opportunity that'll be lost if we wait too long. But with the momentum we've gained from the early data with zanidatamab in this setting, I think it's time to test this theory in a larger study.
Thank you. And then let me I'll just add a couple of words. This is Abizar from our commercial side, Jazz. So just to kind of build on Dr. Hurvitz's points and Rob as well, I'll go back to the word Dr. Hurvitz used. There's currently a dearth of data post-T-DXd in the metastatic breast cancer space.
As T-DXd continues to have uptake and will probably move up to the front line, as outlined earlier, there is this dearth, and that's where we think zanidatamab has this unique opportunity based on the current data we've seen, how we're structuring the Phase III trial that will start soon, to specifically have T-DXd non-responders or people who don't tolerate it as well. We have to remember, T-DXd, as great of a therapy it is, patients do progress. We see progression rates. It's not curative in the metastatic setting, or they have to discontinue it due to tolerability AE issues as well, namely the interstitial lung disease. So we think this is a great opportunity to take these people who progress or can't tolerate, show them what a better HER2 inhibition strategy is, whether that's in the hormone receptor positive or negative space.
The other benefit, again, just think about zanidatamab, because it's not an antibody-drug conjugate, we have the ability to use different chemo regimens, and clinicians have the ability to titrate those chemos to kind of manage the toxicities in these metastatic patients. So there's a lot of flexibility to this molecule as well in terms of incorporating it in different kind of treatment regimens. So for those reasons, as Dr. Hurvitz said, let's go get the data, and let's demonstrate how it can meet the unmet need.
Thank you. And then for my follow-up question, I wanted to get your thoughts on whether you guys need to potentially expand the field force as you look to a second-line biliary tract cancer launch in 2025 and how much incremental SG&A that could entail.
Maybe if you can also frame these oncology launch prep efforts in the context of possible impact on operating margin improvement laid out in the Vision 2025 guidance. Thank you.
Abizar for me? Sure. So I'll go ahead and maybe start on maybe you can start on launch timing and effort required, and then I'll jump back in at the end.
Great. Thanks, Bruce. So just to answer your question up front around how we think about the commercial planning, launch planning, it could be 2025 or earlier, depending if we get a prior review after we finish the filing later this year. To give you a sense of our kind of planning, what we feel right now, we have a really well-established oncology footprint in the solid tumor space. We're going to highly leverage that footprint.
That footprint's currently in the clinics and accounts and institutions where biliary tract is treated, along with other solid tumors. So it's a highly synergistic launch for biliary tract to add into our existing capability. So we won't comment in terms of how we think SG I mean, I won't comment in terms of SG&A may modulate, but what I would say is it's highly leverageable. We're in the places today. We will continue to promote our current products as well as new ones, and we feel there's a lot of synergy and other great fit for us in terms of our overall oncology portfolio. Bruce, oh, sorry. In terms of preparation, we are actively doing both medical communication, and we will do field sales disease state education when the time is right.
We are actively in the market with some scientific exchange already and building out the kind of right capabilities. The teams are in place. We're building those up as well. Most of them are staffed. So we're really excited about how we're thinking about this launch and being prepared when the day comes. Bruce, I'll turn it back to you to comment further.
Yeah. Thanks, Abizar. And I'll just say on margins generally, we're in the fortunate position right now to be investing in growth drivers on the commercial side of our business across sleep, epilepsy, and oncology. We're making significant investments in R&D, particularly in Zanidatamab. As we look forward, I think Abizar gave you a sense for the incremental nature of this launch relative to our current oncology efforts, which I think are positioning us well.
Margin will also depend in the future on any corporate development transactions we do, which could change the denominator, right, the revenue side of that equation. So probably a little too early to comment specifically just on the impact of a zanidatamab launch in BTC on overall margins.
Your next question comes from the line of Joel Beatty from Baird. Please go ahead.
Hi. Thanks for the presentation. For the Phase III EmpowHER study designed to establish zanidatamab for potential second-line use, what makes trastuzumab plus chemo the relevant control arm, as it was shown on the slides, is typically being used as a fourth-plus-line choice?
Hi. This is Rob Iannone, and I could clarify that. So we're positioning the trial as a post-Enhertu trial, recognizing that the treatment landscape is likely to evolve even during the conduct of the trial.
So while Enhertu is most commonly used now in second line, sometimes used in third line, it is likely to move to front line, where patients will either get it front line or potentially second line. So initially, the patients who are enrolling will have received other therapies as well. We think ultimately, as this trial reads out, of course, the main question, the main scientific and clinical question, will be, what do you give a patient who is either intolerant to or progresses on Enhertu? And we expect zanidatamab to have the only data in that space, maybe analogous to what Dr. Hurvitz described for tucatinib, where the indication is aligned earlier than was studied based on its activity and brain mets.
Positioning it this way, we think, allows for the most practical and appropriate control arm while also generating data that will be relevant as the treatment landscape evolves. But I'd be happy for Dr. Hurvitz to also comment further, should she like.
Hi. Thank you. You said it really well. And I think the way the inclusion criteria are written, it gives us the freedom to enroll patients up to four prior lines of therapy. But I think many patients will be enrolled who've had two or one line of therapy if they receive T-DXd or two lines of therapy. And it's really just allowing us to look at the post-T-DXd space.
Great. Thank you. Your next question comes from the line of Gregory Renza from RBC Capital Markets. Please go ahead.
Good morning. This is Tanisha on for Greg. Thanks for hosting this session on zanidatamab, and thanks for taking my questions.
Just on the upcoming PFS top-line readout for the Phase III HERIZON-GEA-01 trial, how are you setting expectations for bar of success, perhaps with precedent trials? And then on breast cancer and the previously discussed potential of Zanidatamab in multiple breast cancer settings, beyond just commercial opportunity, where do you see the lowest hanging fruit in terms of clinical execution? Thanks so much.
So in terms of I'll start. This is Rob Iannone. In terms of what we expect and what would be clinically meaningful for the PFS readout, I would just start by saying we're very, very well-powered for PFS, probably even beyond what most would consider to be a clinically relevant difference. So I have no concern about the powering, even though we've kept that analysis at the original 714 patients while increasing the sample size to improve power with OS.
Ultimately, what would be satisfactory to the regulators and even to practitioners will take into account the overall benefit-risk, not just the efficacy but the tolerability, etc., and the ease of administration. But if you're looking for recent precedents, you could see for KEYNOTE-811, for example, the PFS difference was certainly less than three months. And if you reference then the data we've generated in that front line, either plus chemo or plus tislelizumab and chemo, you can see we're trending well beyond that. Before going on to the second part of your question, maybe I would pause and ask Dr. Ku if he has anything he would add. Yeah.
So I think that beyond an absolute difference of 2, 2.5, 3 months, I mean, anything like that, I think the other things that we would absolutely consider clinically relevant would be also duration of response. So I think one of the things that I think a lot of us who've given the drug in the previous HERIZON-BTC-01, which is the Phase II study, noted was I mean, the durability of the response was really remarkable. We actually have patients who remain on treatment 3, 4 years into the study, which is really kind of unprecedented, certainly compared to trastuzumab chemotherapy, but even compared to pembrolizumab chemo. And we did the original Phase II study of that regimen at Memorial. So I think that, of course, there's kind of the top-line results and what's required for regulatory approval.
But I think, as Rob pointed out, I mean, I think beyond that, I think toxicity, certainly durability, those are all I think I mean, those are also kind of key clinical indicators that we'll be looking out for. And I think your second question was around breast cancer and clinical execution in our pivotal trial. So I would just say that you heard from Dr. Hurvitz, who could comment further, the lead investigator in that trial. We've spoken to many, many KOLs around the world who are all identifying the same change in the treatment landscape and the gap, the evidence gap, and as well as the excitement around the data that we've generated so far in breast cancer with Zanidatamab. And so we're finding that there's a lot of interest in this trial and not necessarily a lot of competition.
We're already well underway in the planning for this trial, and we hope to be moving with haste into the space in a global trial that would support rapid enrollment. Let me just check to be sure that was answering the question you asked.
That's great. Thanks so much.
Your next question comes from the line of Akash Tewari from Jefferies. Please go ahead.
Hello. This is Stevie Yanon from Akash. On Horizon GEA, which is expected later this year, can you talk about PFS and what signal you feel you need to show in order to hit on overall survival? And additionally, will you have additional prespecified OS interim readouts after the expected year-end interim along with the PFS read? And if so, is there a predefined sort of event rate that the OS interim read requires? And any color on alpha spend for this would be helpful.
Thank you. Great. Thanks. I partially answered some of your question earlier, and so to Dr. Ku, in terms of what kind of magnitude of benefit would be meaningful. So I'll just move on to some of the other logistics that you mentioned. So yes, it's an event-driven trial for the first analysis, which will be the one and only PFS analysis. That's what we said we're targeting by the end of the year. But we will look at OS as an interim at that time. And the reason to do that is that while PFS would support approval globally, health authorities want to be sure that there's not a negative trend, which would be odd, but nonetheless, they want to see how OS is trending at that time. The next two analyses will be based on OS events. And you're right.
There is another interim OS analysis that's timed around the time that we would have done the final analysis and the initial protocol design. And then we allow events to accumulate further for the final OS analysis. So overall, three analysis points, one for PFS and three for OS. We haven't gotten into details of how we're splitting alpha or that kind of thing.
Okay. Very helpful. Thank you.
Your next question comes from the line of Troy Langford from TD Cowen. Please go ahead.
Hi. Thanks for taking our questions and for all the additional detail today. For BTC, how much off-label use of Enhertu do you all currently expect in the space? And can you all just walk us through the incorporation of Zanidatamab into the various treatment guidelines across indications post-approval?
I could certainly start with that, and I'm happy to allow others to comment as well.
I would just start by saying the data that we have in BTC with zanidatamab are really compelling relative to what's been published with other agents, whether that be you mentioned Enhertu but also Herceptin and Perjeta. Compelling both in terms of the number of patients we treated. Remember, it was two separate trials, one smaller in about 20 or so patients, and then another follow-up trial that was the basis for that was a pivotal trial and basis for the submission in more than 80 patients. Very high response rates, over 40%, and the duration of response, which I think is really important. Last median that we checked was 12.9 months. But importantly, as a bispecific antibody, not chemotherapy, not an ADC that's loaded with a toxin, the tolerability was extremely good.
And so we think when you compare that to the other data in the field, it's quite favorable. So at this point, we don't know whether or when Enhertu will get an approval in that space, but we think the zanidatamab data really kind of stand on its own, and it makes us very optimistic about the first-line trial that we're starting.
Great. Great.
And I'll just jump in to build on Rob's point on current use and where we see guidelines. What we currently see in some of the market research and talking to KOLs, there is no approved HER2-directed therapy in second-line HER2-positive BTC, and that's still true today. The majority of use today is still a challenge with chemotherapy, again, which has poor outcomes, less than 5% five-year survival still in this population. So clearly, there is a need for a new agent.
First, for HER2-directed therapy like zanidatamab, we still think there's significant unmet need today. In terms of guidelines and how we think those get updated, NCCN is pretty responsive in general to peer-reviewed publications when products are approved and taking that data and adopting their guidelines appropriately. In particular, for high unmet needs areas like this, we've seen that with other places we've been in, with lung cancer and other places where we see NCCN make guideline updates pretty rapidly. So we will submit those as appropriate when the time's ready, and we expect hopefully rapid adoption.
Great. Thanks, Rob and Kohler.
Your next question comes from the line of Jeffrey Hung from Morgan Stanley. Please go ahead.
Hello. This is Katherine on for Jeff Hung. Thank you so much for taking our question.
For the KOLs, we were curious if you could provide any color on how to think about HER2 copy numbers as we've seen studies to suggest between 25-50 HER2 copies in breast cancer. Is there a minimum amplification threshold for seeing a drug response, or is the thought that response improves with increased copy numbers?
I think that question could probably go to just about anyone across the disease areas, but maybe I would give Dr. Scribadee Rahmani a chance to comment first.
Yes. Hello. Well, regarding the copy number question, we usually use the ASCO guidelines, the ASCO-CAP guidelines, to define HER2-positive patients. Usually, we know that patients that are HER2/3+, usually they respond better to anti-HER2 therapies. That doesn't mean that patients that are HER2-amplified would not respond.
So I would guess that with the data we have till now, that patients that are HER2 3+ would perform better in general with anti-HER2 therapies. And patients that are amplified would perform also well but maybe not so well. We also have defined a population of patients that maybe are not HER2-positive, but they have some expression of HER2 and that they are called now HER2-low. And these patients may also respond to anti-HER2 therapies. So I don't think we should base the treatment on the number of HER2 copies. And I'll hand the question to some other KOL.
Yeah. This is Sara Hurvitz. There's not been a threshold that's been defined for activity, at least in breast cancer, of HER2-targeted agents. This is an area of active research looking not only at copy numbers but also receptor expression level and quantifying receptor expression level needed for activity.
This is particularly pertinent for drugs like T-DM1 and then more recently for T-DXd, where activity is seen even with very low levels of expression of HER2, which are considered normal levels. For Zanidatamab, I'm not aware of any data that has defined the threshold needed in terms of amplification or expression level. So maybe one of the Jazz people wants to comment on that. But I think the mechanism of action of Zanidatamab with the clustering of HER2 is pretty exciting. And I'm not I would be interested in seeing it just not only in HER2 overexpressing and amplified but maybe even in a lower expressing level later if it passes the clinical trials that have been designed in the HER2-positive space for breast cancer.
Yeah. I mean, thanks, Dr. Hurvitz.
I would only add that it's something that we're looking at, and we certainly are looking at experimental combinations where you might then target patients with differing levels of expression like our ongoing ALX trial with anti-CD47. So thanks for those responses. Maybe we can move on to the next question.
Your next question comes from the line of David Amsellem from Piper Sandler. Please go ahead.
Hey. Thanks. A commercial question. Can you talk about pricing and how you're thinking about it to the extent you can or what comparators might guide us in how to think about pricing assumptions? And does the availability of trastuzumab biosimilars enter into your calculus regarding pricing of zanidatamab at all? Thank you.
Yeah. Thanks for the question, David. So just to answer, I think we consider all of the above. I mean, we look at not only potential. And biosimilar trastuzumab.
I mean, there are generic chemos out there as well that are used today in current standard of care. There are other branded agents that may be used: off-label trastuzumab and Perjeta, pertuzumab, which is still a branded agent. So we look at all those analogs whenever we look at a new price point. What we also do, though, is we look at the value drivers and what we continue to see and how we think about pricing the product and thinking about the outcomes we're delivering. In particular, for this agent, we look at not only the data we've seen on activity for objective response rate and PFS but, as we will continue to update, the overall survival.
And what we increasingly see on this product in biliary tract is the quality of that survival in terms of the tolerability and the safety and the manageability of a single agent, zanidatamab, in this population. Not only are we seeing really impressive overall survival data, but the quality of those patients and the quality of life in that is pretty compelling. There's an interesting data at a poster at ASCO-GI that talks about opioid tapering in a cancer population on zanidatamab. So again, another tangential benefit. So these are the kind of things that we will put into the value drivers of this product to say what are the outcomes we're delivering, what other costs are we avoiding in terms of supportive care, hospitalizations, other things that this product can deliver, we think will deliver based on the evolving dataset.
I think whether we look at comparators and analogs, that we always do that. I think what we want to do is really talk about the value drivers. What we think on Zanidatamab, what we're seeing in BTC are some pretty unique value drivers that may have no precedent in the HER2 space because of the way this agent works and the quality data we're seeing. We'll take all that into consideration as we think about pricing this.
Thank you.
Your next question comes from the line of Gary Nachman from Raymond James. Please go ahead.
Okay. Great. Thanks for the presentation. It was very informative. So for HER2-positive advanced breast cancer, can you quantify roughly what percentage of breast cancer patients progress to third-line plus?
I know it's still early, but a rough guess of what the percentage of patients that are expected to progress after T-DXd if that ultimately becomes the standard of care. And then, Rob, how long will it take to enroll that pivotal Phase III study? You said rapid, but just how quickly do you think we might have top-line data on that? Thank you.
Sure. Let me start. I certainly won't invite our experts to chime in as well. I mean, we've been looking at the epidemiology around this, and I don't think it's necessarily crystal clear what percentage progress line to line. But what I would say is we're enrolling a patient population with metastatic disease who are not likely to be cured and need subsequent therapies. But also, therapies are effective enough where the great majority tend to progress into the subsequent line of therapy.
I would say that's true in terms of going from first-line to second-line or even second-line to third or even third-line to fourth. So patients tend to get multiple lines of therapy, and they always require HER2 therapy. And some of the data we have in later lines, patients have gotten multiple different HER2 agents and still progress. I don't have an exact number to give you, but I do think that we capture a great majority of patients beyond that first-line setting. And I think that will remain true even in patients who've gotten Enhertu, whether that be in second-line or in first-line. In terms of how quickly this trial will read out, like I said, we've been moving aggressively to get this trial up and running, and there's significant interest in what will be a global trial.
And so we certainly will lean into sites around the world in order to ensure brisk enrollment. And we know from our interactions with various health authorities that PFS could be the approval endpoint even if we continue the trial for OS. So while we don't have a timeline, we're quite excited about the level of interest in this trial, the unmet need, and our ability to enroll briskly. I might pause there and see if any of our experts would want to add to that.
Yes. I'll just go ahead. Yep. So this is Paula Pohlmann. I was just going to mention that we expect all the patients to eventually progress, right? So 100% of the patients with metastatic disease will progress based on the current data. But I can give you some data from the DESTINY-Breast03.
That is the study that led to the approval of T-DXd as second-line therapy when compared to T-DM1. So if you look at the progression-free survival curves of T-DXd, approximately 25% of the patients were off treatment after one year, and 50% of the patients were off treatment after two years. So maybe this gives you some clarity for the question.
Yes. That's helpful. Thank you. Yep.
Your next question comes from the line of Charles Duncan from Cantor Fitzgerald. Please go ahead.
Hi, team. This is Asiya on for Charles. Thank you so much for taking our question. I want to ask, how do you feel using the Zanidatamab plus chemotherapy combination in the heavily treated patient population in terms of safety? Are there any concerns that may be out of line from what was observed with the trastuzumab and margetuximab chemo combination?
Additionally, for the Phase III EmpowHER study, what are key next steps you are considering to ensure initiation is on track?
Thank you. This is Rob Iannone. I can start and also ask others or other experts to chime in. We do have prior data combining zanidatamab with various different chemotherapies across different tumor types. What we're finding is it's generally well tolerated. We know what needs to be managed. Certainly, diarrhea is one of the adverse events that needs to be proactively managed, and we do that in our clinical trials. Overall, we think that it combines well with chemotherapy. In the planned Phase III, there'll be an investigator. There'll be a set of chemotherapies that investigators can choose from so that it's tailored to patients' particular situation. Yeah, I think your second question was around startup activities.
We haven't given a specific timeline around that, but I would say that we presented today based on a lot of work that's been done up to this point, including consultation with health authorities as well as key experts who'll be running the trial. So we're pleased with the progress, and we're poised to move very quickly into the next study startup stages. We'll keep you posted as we make progress. But I would invite maybe any of the experts that we have on the line to comment about your personal experience with zanidatamab and its tolerability profile.
Yeah. This is Jeff. I can chime in. I mean, I think, Rob, you identified that I think diarrhea, certainly when combined with 5-FU-based regimens or fluoropyrimidine-based regimens, is the major toxicity. But I think with appropriate management, it's become much more tolerable.
The drug is monotherapy, has a much lower incidence of diarrhea. And again, I mean, we've had patients be on the monotherapy with minimal toxicities for several years, actually.
Thank you. That makes a lot of sense.
Thank you. We have no further questions in our queue at this time. I will now turn the call over to Rob Iannone for closing remarks.
Thank you. Let me start by just expressing my sincere thanks to our presenters, Dr. Ku, Hurvitz, Santiago Escrivá-de-Romaní, and Pohlmann. Really appreciate your presentation and your insights this morning. And I'd like to just conclude by saying how excited we are for Zanidatamab. It's our top priority in R&D. And we look forward to a pretty productive year where we could have approval in the U.S. for BTC as early as the end of this year.
We are targeting top-line data for GEA by the end of the year. Now, as you've heard today, we've initiated a pivotal program in breast cancer as we also consider other opportunities in zanidatamab, given our belief that it's a highly differentiated and best-in-class HER2 therapy that really has potential across tumor types anywhere that HER2 is amplified or overexpressed as monotherapy or in combination. So I'd like to thank you all for your attention and close the meeting now.