Jazz Pharmaceuticals plc (JAZZ) Earnings Call Transcript & Summary

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. [Operator Instructions] 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 Zani, 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 Zani 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 Zani, 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 Zani data in those areas? And where Zani potentially fits into the treatment landscape. Turning to Slide 2. As a reminder, we will be making forward-looking statements. Please consult our SEC filings for more details. On Slide 3, 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. Geoff Ku, from Memorial Sloan Kettering in New York, who specializes in the treatment of GEA. We're also pleased to have 3 breast cancer specialists joining us today. Dr. Sara Hurvitz from the Fred Hutch Cancer Center in Seattle; Dr. Santiago Escrivá de Romaní from the Vall d’Hebron Institute of Oncology and Hospital Vall d’Hebron in Barcelona; and Dr. Paula Pohlmann from the MD Anderson Cancer Center in Houston. Also joining us is Abizer Gaslightwala who leads the U.S. commercial oncology business unit at Jazz. Moving to Slide 5. Zani 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 Zani 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 Zani 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 Zani data maps MOA and our development in BTC.

Thank you, Bruce. Good morning, and thank you, everyone, for joining. I'll start on Slide 8. 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 biparatopic binding. Zani simultaneously binds to extracellular domain 2 and 4, which corresponds to the domains of Herceptin and Perjeta. However, Zani'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 2 receptors. This results in multiple mechanisms of action, all resulting in tumor cell death. As seen on the left side of the figure, Zani interferes with HER2 signaling and also disrupts heterodimerization of HER2 and HER3, further inhibiting tumor cell signaling and growth. Zani 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 in bottom. We think Zani ADCC and CDC at a level that is highly differentiated within 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 the cells exposed to Zanidatamab, which drives enhanced internalization and down regulation 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 Zani 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 derisked 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 ruling submission. Here on Slide 14, Zanidatamab has also demonstrated clinical efficacy when combined with chemotherapy, PD-1 inhibitors and anti-hormonal 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 ADCs, 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 Zanidatumab are durable in both monotherapy and as part of combination regimens as shown in these 4 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 for the manageable tolerability profile in multiple tumor types. We have advanced the development program rapidly since acquiring rights, Zani 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 time line, 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 IHC3+ 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. Geoff 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 Esophagogastric 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 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 in 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 of the subset analysis, tumors that were PD-L1 negative and did not derive any benefit from the addition of pembrolizumab, trastuzumab and chemotherapy. In fact, there was some suggestion that those patients were harmed or those of 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 are certainly significant room for improvement in terms of outcomes for our patients. Now focusing on the column on the left, the patients who have resectable GE junction and gastric cancer, extended care in addition to surgery is either perioperative chemotherapy or preoperative chemo radiation. And the treatment is the same irrespective of where the 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. So 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 the space and this unmet need. And then 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. So on the next slide, on Slide 25, we see that the first potential area for Zanidatamab is in the frontline setting for HER2-positive disease in patients were PD-L1 negative. Turning to Slide 26. We can see the currently available standard 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, Elena Elimova. So the TOGA regimen or the TOGA study established in 2010 that trastuzumab plus chemotherapy as a standard of care in the first line 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. And 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 come 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. And finally, in terms of cross-trial comparison, we see the results from the Zanidatamab plus chemotherapy studies. And again, with all the caveats across trial comparisons, 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 chemo therapy study, the response is seen with all 3 chemotherapy regimens that were used. So this was a study that explores 3 chemotherapy regimens. CAPOX, capecitabine and 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 cisplatin. And we also see with fire part that there is significant durability in terms of the responses, which, as a clinician, we treated some of these patients, it was really quite impressive and quite -- 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 loss analysis for the 12-month overall survival rate 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 and it's also a key measurement that the FDA assesses when reviewing therapies in the first-line setting. And again, longer than with the currently approved combination in both PD-L1 positive and PD-L1 negative population. And 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. And 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 the 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 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 with 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 [indiscernible] 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 have hinted at this already but now I'll discuss the actual design of the HERIZON-GEA-01 study. So this is a first-line multicenter global study that's evaluating Zanidatamab in HER2-positive GE junction and gastric cancer that's potentially locally advanced unresectable and metastatic. So the way the study works is that patients and physicians choose 1 or 2 chemotherapy regimens in either CAPOX or 5-FU cisplatin. Patients are then randomized to 3 arms, control arm is trastuzumab with chemotherapy and there actually are 2 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 end point 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 over detecting an improvement in overall survival while maintaining the original planned time and specific 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 and metastatic settings. In neoadjuvant and adjuvant settings, Zani can 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 the PD-1 inhibitor. Moving to Slide 35. GEA is a significantly larger patient population compared to DTC 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 from 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 an 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 CyclinD1-CDK4 pathway. The biggest opportunity is to target and build a robust data set 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. And we're excited to announce today that we expect to initiate a Phase III trial of 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. So 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 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 Zani presentations and publications. He is a medical oncologists in the Breast Cancer Unit at Vall d'Hebron Institute and Hospital 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 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, deruxatecan 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, TDM1. 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 2 prior lines in therapy were enrolled. And 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 have not been well defined after disease progression on T-DXd. And if T-DXd becomes the standard of therapy in the second-line setting, the 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 and there's going to need to be effective post-T-DXd therapy in the second-line setting once those data from the DESTINY BREAST 09 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 3 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 ZW25-101 study and was evaluated in combination with the CDK4/6 inhibitor, palbociclib, and an endocrine therapy, fulvestrant in HER2-positive breast cancer with co-expression of hormone receptors in the ZW25-202 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 2 examples are very notable because the patients have been very heavily pretreated previously. And so these progression-free survival and objective response rates are actually very promising. Slide 44 shows Zanidatamab plus chemotherapy data from the 25-101 study and compare 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 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 Zani 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 slide, you can see all these patients have a column that is below 0, 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. And 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. And 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 one measurable disease. The primary endpoint of this clinical trial entitled EMPOWER 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 HER2CLIMB study. And after the second-line therapy shown here, then again, we have uncharted territory and figuring out how to sequence a variety of agents, including T-DM1, tucatinib based therapy, chemotherapy plus trastuzumab, margetuximab 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 a 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 HER-2 blockade with trastuzumab and pertuzumab after a 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, and 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 therapeutical option for this patient population that may 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 is 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 is compared to have abemacliclib 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 the 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, starting 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 digital trials with a triplet with Zani, we can see how all this combinations show efficacy in terms of clinically significant overall response rate and PFS. In particular, the chemo-free triplet combination including Zani, 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 HER-2 positive. Here on Slide 53. In this slide, we can see how the waterfall chart of the triplet combination with Zani demonstrated 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 have already been treated with T-DXd. These responses were comparable to those of the overall population. We've achieved a response rate of 35% for patients with measurable disease that went up to 48% in patients with centrally confirmed HER2 positive, including also complete responses. Next in Slide 54. Here, the summer plot also shows how patients achieve durable responses with a median PFS of 1 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 6 months, which was the primary endpoint of the trial. And finally, on 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, starting the role of adding CDK4/6 inhibitors to the endocrine treatment. The trial and that 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 [indiscernible] 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, an estrogen receptor pathways would be a very relevant chance for patients to be a part 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'm 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 [indiscernible] disease. Here, you see the current standard of care treatment for patients who presented early stage disease involving on the left, up from surgery followed by adjuvant chemotherapy and the HER2 therapy with trastuzumab with or without pertuzumab or a preferred approach of neo-adjuvant-systemic therapy, typically with chemotherapy with trastuzumab and pertuzumab followed by surgical resection. More recently, even patients with stage 1 disease have been treated in the neoadjuvant approach because both neoadjuvant surgical pathology can be used to favor adjuvant treatment recommendations, informing about the potential additional benefit of antibody drug conjugate such as trastuzumab emtansine. 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. This success has 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 peripheral neuropathy becomes problematic too early in this life. Cognitive dysfunction, premature menopause, sexual dysfunction, infertility and liver dysfunction. Slide 59. So 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 and 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 the 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. And you can see that those patients achieving RCB-0, which is PCR or RCB1, which is very small amount of disease left after new adjuvant 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 that in neoadjuvant therapy or surgery. On the next Slide #60, based on the information about the prognosis based on the result of new adjuvant 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 Zani in patients with stage I and II HER2-positive breast cancer, who have measurable small tumors, approximately 1 to 3 centimeters, and if lymph node negative disease at the diagnosis. This study started with Zanidatamab monotherapy followed by surgical resection and adjuvant postsurgical treatment as per treatment of 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 this later. Next to Slide #61. I wanted to share with you the initial results of the first 20 patients heated in this trial. This was presented at the San Antonio Breast Cancer Symposium 2023. Here you see a 30% rate of pCR and a 50% rate of combined PCR and RCB1. This result -- those results are encouraging though it's small numbers. The protocol has been amended to include additional 20 patients in this cohort. Again, Zanidatamab was well tolerated with acceptable safety profile. There were no grade 3 or grade 4 treatment-related adverse events and these trials are 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-2 neoajuvant clinical trial that enrolls patients with higher atomic and molecular risk early stage breast cancer. The I-SPY-2 trial, the patient has 3 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 the -- if you provide information in lymph node positive and lymph node negative disease. You see in the I-SPY-2 neoadjuvant trial, the patient navigates through 3 potential blocks of therapy with the aim of achieving a PCR. If the patient achieved the PCR after Block A, which is typically a no chemotherapy regimen, the patient can go through to surgery. And we know based on our data from more than 1,000 patients, it doesn't matter how you get a PCR, if you get to PCR or RCB 1, 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 blockade of weeks, then they move forward to receive the rather standard of care backbone of team, followed by AC neoadjuvant therapy. So for HER2-positive patients, Block B of the taxane [indiscernible] HER2 therapy with trastuzumab and pertuzumab. And then if still after Block B, the patient has not achieved a PCR, then we will go with Block C, which is the rescue with AC. Moving to Slide 63. We also want to test a combination of 2 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 tucatinib so that we can hopefully move this quickly forward to I-SPY 2 neoadjuvant trial. So the pre I-SPY trial is Phase Ib multisite platform study that utilizes the same I-SPY network and 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, Zanidatamab and tucatinib, we have a part 1 of those filing and part 2 of those expansion in which the patients are treated with primary endpoint of recommended phase to do safety, tolerability and preliminary efficacy. We also have translational endpoints that hopefully will help us with the development. And the Slide #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. We see a great opportunity for no chemotherapy regimens in the neoadjuvant setting at the starting point, only resting 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 [indiscernible] neoadjuvant setting, either as a single agent or a combination personalizing the intervention. I feel there is a great potential for no chemotherapy-containing regimens based on currently available efficacy and safety data as well as the patient preference. Thank you. Now handing over to Rob.

Thank you all for your participation and discussion today. Moving to Slide 67. There are 4 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 scan data to support other regimens following progression after T-DXd. By building on a robust data set 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 and also a late-stage combination with a CDK4/6 inhibitor and fulvestrant in HER2-positive, HR-positive patients takes advantage of the role of ER 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 Abizer Gaslightwala Head of U.S. Commercial.

Thanks, Rob. I'll start on Slide 71 and biliary tract cancer or BTC. We are excited as we prepare for a potential approval and launch as many data about for BTC in 2025 or earlier. We're 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 in HER2-positive BTC highlighted during today's presentation, resonates well with oncologists and health care 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 get rapid experience and use 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 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 of chemotherapy in patients with lower levels of PD-L1 expression? Or is the 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 series 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 to 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 overlap significantly with those that treat BTC. And our medical field teams will be communicating the Zanidatamab peer-reviewed data there is 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 for 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 the HER2-positive metastatic breast cancer after progression of 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 3 tumor types, we believe Zanidatamab has the opportunity to establish itself as effective HER2-directed therapeutic in solid tumors 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 presented 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 demonstrate significant benefit for patients. This will be followed by a launch of a 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 target HER2 therapy that has the opportunity to redefine what is possible in HER2 positive tumors that 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.

[Operator Instructions] Your first question comes from the line of Jessica Fye from JPMorgan.

This is Nick on for Jess. First, maybe a question for Dr. Ku and how you envision the use of Zani 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-Zani and for Herceptin as part of the pembro triplet, even if Zani chemo arm beat the Herceptin chemo arm because we won't have the pure triplet versus triplet comparison in the same trial kind of would be forced to compare Zani plus, tisle plus, chemo to Herceptin plus chemo on a cross trial basis. So I guess the question is, what do you need to see from HERIZON GEA trial to use Zani in your PD-L1 positive patients? And how do you expect your colleagues to think about that?

Yes, I think that's a great question. So I think as you kind of surmise based in the question itself. So at the time that the study was designed, there actually was -- there were different standards of care globally. So based on KEYNOTE-811 pembrolizumab was approved for all patients at that time, whereas it was approved and nowhere else in the world. So as this was a global study, the control arm really remain 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. And 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. 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 2 experimental arms. And ultimately, we'll have to see how both of them compared to the control arm. And then I think at that point, we'll also make cross trial comparisons. And as you know, the atezolizumab-containing arm of the GEA-01 study, it's not meant to be directly compared to the Zani 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 will probably come to their own conclusions. But I think to me, I mean, I think a 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 trastuzumab arm, pembrolizumab versus Zani 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 a 0.27 OS hazard ratio for the triplet arm versus the Herceptin chemo arm? Can you talk about what OS powering is now for the Zani 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.

Yes. So I mean we actually had [indiscernible] 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 are certainly -- I mean [indiscernible] team can comment, but I thought the hazard ratio went up to maybe 0.85, but I could be not sorry, not the hazard ratio, the power but I could certainly be wrong.

Yes, I'm happy to jump in. This is Rob Iannone. I don't believe we shared any other 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 should 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 the interim analysis for OS. So if the results are robust, we could actually see an early OS results 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 best-in-class anti-HER2 agent and will be competitive relative to Herceptin chemo. But we also think tislelizumab now approved in the U.S. is a PD-1 inhibitor that has shown data as strong as any other PD-1 inhibitor. So we don't think the PD-1 inhibitors are differentiated from one another where Zani 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.

Your next question comes from the line of Joon Lee from Truist Securities.

Are the cancer treatment algorithm in the U.S. differ materially compared to ex U.S. where BeiGene is developing Zani in their respective cancer? Just curious how much of a refill we can expect as there may be some non-overlapping indications. And related to that, it seems like BeiGene is also developing Zani Zovo ADC combination. Do you have any time to develop a similar ADC strategy based on Zani as a backbone because ADC comes up a lot in our conversations with investors.

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 and that was mentioned in the presentation that there is an option around CAPOX versus 5FU 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 over expressed. But for the moment, we see the opportunity to be on the market in the near term, earliest 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 well underway. And beyond that, we certainly are looking at other combinations and indications.

Your next question comes from the line of Pavan Patel from Bank of America.

This is Pavan Patel on for Jason Gerberry. 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 these are from our commercial organization. I mean I think you heard Dr. Hurvitz saying 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 HER-2 agents and 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-TDXD space. And maybe I would ask Dr. Hurvitz to jump in there with anything she might add before turning it over to Abizer 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 TDM-1, 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 down, regulation 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 ER-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. And 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 even -- maybe even better. So in the first-line setting when Zani was combined with docetaxel. So I just think that this is a real opportunity that will be lost if we wait too long. But with the momentum we've gained from the early data with Zani in this setting, I think it's time -- it's time to test this theory in a larger study.

And then -- let me -- I'll just add a couple of words 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 dearth. There is currently a dearth of data post T-DXd in the metastatic breast cancer space. And 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 Zani 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-DX nonresponders 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, where they have to discontinue 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 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 Zani, because it's not an antibody-drug conjugate, we had 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 a different kind of treatment regimens. So for those reasons as Dr. Hurvitz said, let's go get the data and what's demonstrated how we can meet the unmet need.

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 track cancer launch in 2025? And how much incremental SG&A that could entail? And 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.

I'll go ahead and start on -- maybe you can start on launch timing and effort required and then I'll jump back in at the end.

Great. So just to answer your question upfront around how we think about the commercial planning, launch planning, it could be 2025 or earlier, depending if we get a priority 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 is 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 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. Sorry, in terms of preparation, just 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 with the day comes. Bruce I'll turn it back to you to comment further.

Yes. Thanks Abizer 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 Abizer 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 on 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.

For the Phase III EMPOWER study designed to establish Zanidatamab for a potential second-line use, what makes trastuzumab plus chemo the relevant control arm as it was shown on the slide, is typically being used as a fourth plus line choice.

Hi, this is Rob Iannone. I could clarify that. So we're positioning the trial as a post HER2 trial, recognizing that the treatment landscape is likely to evolve even during the conduct of the trial. So while in HER2 is as commonly used now in second line sometimes used the third line and is likely to move to frontline where patients will either get it frontline 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 critical question will be, what do you give the patient who is either intolerant to or progresses and hurt you. And we expect Zanidatamab to have the only data in that space may be analogous to what Dr. Hurvitz described for tucatinib, where the indication is aligned earlier than was studied based on its activity in 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 like.

I think you said it really well. I think the way the inclusion criteria are written, it gives us the freedom to enroll patients up to 4 prior lines of therapy that I think many patients will be enrolled, who've had to one line of therapy if they receive T-DXd or 2 lines of therapy and it's really just allowing us to look at the post-TDX-d space.

Your next question comes from the line of Gregory Renza from RBC Capital Markets.

[indiscernible] on for Greg. Thanks for hosting this session on Zani. Just on the upcoming PFS top line readout for the Phase III HERIZON GEA trial. How are you setting expectations for bar of success perhaps with precedent trials? And then on breast cancer in the previously discussed potential of Zani in multiple breast cancer settings beyond just commercial opportunity, where do you see the lowest hanging fruit in terms of clinical execution.

So in terms of -- I'll start, this is Rob Iannone. In terms of what we expect and what will 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, et cetera, 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 3 months. And if you reference them the data we've generated in that front line either plus chemo or plus tocilizumab and chemo, you can see we're trending well behind 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.

Yes. So I think that the -- 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 a 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 201, 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 in 3, 4 years into the study, which is really kind of president certainly compared to trastuzumab chemotherapy. But even compared to pembro-tras-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 is 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. We're 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.

Your next question comes from the line of Akash Tewari from Jefferies.

[indiscernible] HERIZON GEA, which is expected later this year. Can you talk about PFS and what time you need -- 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 funds for this would be helpful.

Great. Partially I answered some of your question earlier and so 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. We will look at OS at an interim at that time. And the reason to do that is that while PFS would support approval globally, help 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 2 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 -- so overall, 3 analysis points, 1 for PFS and 3 for OS. We haven't gotten into details of how we're splitting alpha or that kind of thing.

Your next question comes from the line of Troy Langford from TD Cowen.

For all the additional detail today. For BTC, how much off-label use have HER2 do you all currently expect in the space. And can you also just walk us through the incorporation of Zani 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 in HER2, but also Herceptin, Perjeta, compelling both in terms of the number of patients we treated, remember, it was 2 separate trials, 1 smaller in about 20 or so patients and then another follow-up trial that was the basis for the -- that was a pivotal trial on 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 meeting that we checked was 12.9 months. But importantly, as a bispecific antibody, not chemotherapy, not a ADC that's loaded with the 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 an HER2 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.

And I'll just jump in to Bill on Rob's point on current use and where we see guidelines. So 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 more outcomes less than 5%. And 5-year survival still in this population. So clearly, there is a need for a new agent. And the 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 the guidelines appropriately in particular for high unmet need areas like this. We've seen that with other places we've been in with lung cancer and other places where we see NCCN a guideline updates pretty rapidly. So we are -- we will submit those as appropriate when the time is ready, and we expect hopefully rapid adoption.

Your next question comes from the line of Jeffrey Hung from Morgan Stanley.

This is Catherine on for Jeff Hung. 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 to 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. Escrivá-de-Romaní a chance to comment first.

Yes. Well, regarding the copy number question, we usually use the ASCO guidelines to define HER2-positive patients. And usually, we know that patients are HER2 3+, usually, they respond better to anti-HER2 therapies. But that doesn't mean that patients that are HER2 amplified would not respond. So I would guess that with the data we have until 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 population of patients that maybe are not HER2 positive, but they have some expression of HER2 and 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 under. I now hand the question to some other KOL.

Yes. This is Sara Hurvitz. There's not been a threshold that's been designed for activity, at least in breast cancer of HER2-targeted agents. This is an area of active research looking not only a copy numbers but also receptor expression level and quantifying receptor expression level needed for activity. This is particularly pertinent for drugs like TDM1 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 this 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 Zani with the clustering of the HER2 is pretty exciting. And I'm not -- I would be interested in seeing it just not only in HER2 over-expressing 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.

Thanks, Dr. Hurvitz. I would only add that something that we're looking at, and we certainly are looking at experimental combinations where you might then target patients with different levels of expression like our ongoing LX trial with anti-CD47. So thanks for those responses.

Your next question comes from the line of David Amsellem from Piper Sandler.

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 and all?

Thanks for the question, David. So just to answer, then we consider all of the above. I mean we look at not only potential in biosimilar trastuzumab, some other 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, as we look at the value drivers and what we continue to see and how we think about pricing the product and think about the outcomes we're delivering, in particular, for this agent, we looked at not only the data we've seen on activity for objective response rate PFS but as we will continue to update the overall survival. And when we increase on the see on this product in biliary tract is the quality of that survival in terms of the tolerability, the safety and the manageability of a single agent Zani in this population, not only a recent really impressive overall survival data, but the quality of those patients and the quality of life on that is pretty compelling. There was an interesting data at a poster of ASCO GI that talks about opioid tapering in the cancer population on Zani. 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 are 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 data set. And I think whether we look at comparators analogs that we always do that, I think what we want to do is really talk about the value drivers. And what we think on Zani, what we're seeing at BTC are some pretty unique value drivers that may have no precedent in the HER2 space because of the way this agent works and what the quality data we're seeing. So we'll take all that into consideration as we think about pricing this.

Your next question comes from the line of Gary Nachman from Raymond James.

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 and 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.

Sure. Let me start and I certainly will 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 the patient population with metastatic disease who are not likely to be cured and need subsequent therapies but also therapies are effective where the great majority tend to progress into the subsequent line of therapy. And 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 great majority of patients beyond that first line setting. And I think that will remain true even in patients who've gotten in HER2 whether that be in second line or in first line. In terms of how quickly this trial will read out, it's -- 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 risk enrollment, and we know from 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 time line, 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.

I'll just go ahead. So this 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 BREAST-03 that is the study that led to the approval of T-DXd a second-line therapy when compared to TDM-1. So if you look at the progression-free survival cures of T-DXd, approximately 25% of the patients were off treatment after 1 year and 50% of the patients were off treatment after 2 years. So maybe this gives you some clarity for the question.

Your next question comes from the line of Charles Duncan from Cantor Fitzgerald.

This is Asfia on for Charles. 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? And additionally, for the Phase III EMPOWER study, what are key next steps you're considering to ensure initiation is on track?

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. And what we're finding is it's generally well tolerated. We know what needs to be managed. So certainly, diarrhea is one of the adverse events that needs to be proactively managed and we do that in our clinical trials. So overall, we think that it combines well with chemotherapy and in the planned Phase III, there'll be an investigator. There will be a set of chemotherapies that investigators can choose from so that it's tailored to patients particular situation. And yes, I think your second question was around start-up activities. We haven't given a specific time line 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 will be running the trial. And so we're pleased with the progress and we're poised to move very quickly into the next study startup stages, and 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.

Yes. This is Geoff. I can chime in. I mean I think, Rob, you identified that I think diarrhea, certainly when combined with 5-FU based regimens [indiscernible] 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 beyond the monotherapy with minimal toxicities for several years actually.

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, Dr. Hurvitz, Dr. Escrivá-de-Romaní and Dr. 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. And now, as you've heard today, we've initiated a pivotal program in breast cancer as we also consider other opportunities of 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.

This concludes today's conference call. Thank you for your participation, and you may now disconnect.