Jazz Pharmaceuticals plc (JAZZ) Earnings Call Transcript & Summary

Good day, and thank you for standing by. Welcome to the ZIIHERA GEA Investor Webcast Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to turn the call over to your speaker for today, Rob -- John Bluth, Head of Investor Relations. Please go ahead.

Thank you operator, and thank you all for joining us. We're excited to discuss the FDA approval in U.S. commercial launch of ZIIHERA in first-line HER2-positive metastatic gastroesophageal adenocarcinoma or GEA. The slide presentation accompanying this website is available on the Investors section of our website, and you can also reference the press release we issued regarding the FDA approval of ZIIHERA. Also on our website, you can find a link to the approved label. On Slide 2, I'd like to remind you that today's webcast includes forward-looking statements, such as those related to our future financial and operating results, growth potential and anticipated development, regulatory and commercial milestones which involve risks and uncertainties that could cause actual events, perform and results to differ materially from those contained in these forward-looking statements. We encourage you to review the statements contained in our slide deck and the risks and uncertainties described in our SEC filings. . We undertake no duty or obligation to update our forward-looking statements. Joining the call today are Dr. Rob Iannone, Global Head of R&D and Chief Medical Officer, who will discuss the approved label, Semi Khurana, Head of our Oncology franchise; and Sam Pierce, our Chief Commercial Officer, will discuss our commercial launch strategy. Then we'll open up the call for Q&A. The approval of ZIIHERA is a pivotal moment for Jazz and represents a paradigm shift for the treatment of first-line HER2 metastatic GEA. This approval is a powerful demonstration of our corporate strategy in action as we continue to transform Jazz into a highly innovative rare disease focused biopharmaceutical company. ZIIHERA demonstrated an unprecedented survival fit. -- with median overall survival surpassing 2 years and is the first and only bispecific HER2-targeted antibody combined with a PD-1 inhibitor in chemotherapy proof for all HER2-positive advanced GEA patients regardless of PD-L1 status. These results give us high conviction that the ZIIHERA combination is positioned to significantly improve outcomes and be established as the new standard of care for this patient population. Importantly, the approval marks a major steward in establishing ZIIHERA as a multibillion-dollar foundational asset in our oncology portfolio, backed by robust clinical data and our plans to expand the zanidatamab development program, we are updating our view of the Sahara peak sales potential to a range of $3 billion to $5 billion. This updated range reflects our confidence in ZIIHERA's clinical profile, its potential as a foundational therapy across multiple HER2-expressing tumors and supports our plans to expand zanidatamab's development into new tumor areas. With that, I'll turn the call over to Rob to discuss the approved the ZIIHERA label and the meaningful impact we believe that ZIIHERA can have for patients with GEA.

I'll begin on Slide 7. I -- the FDA approval of ZIIHERA represents a transformative shift in treatment options for patients with TA and their families who now have access to a therapy delivers a median overall survival of more than 26 months when combined with tizolizumab and chemotherapy. These data from the Verizon GEA01 trial demonstrates the remarkable advance in patient care and survival benefit that ZIIHERA provides. It's based on these clinical outcomes, along with the FDA approval that we believe every eligible HER2-positive first-line metastatic PEA patient should receive ZIIHERA in combination with chemotherapy plus a PD-1 inhibitor regardless of PD-L1 tumor status. . These comes to drive our motivation and dedication at Jazz. I will now quickly speak to the label and supporting data. ZIIHERA has indicated irrespective of tumor PD-L1 status in combination with tisolizumab and fluoropyrimidine and platinum-containing chemotherapy has first-line treatment of adult patients with unresectable locally advanced or metastatic gastric, gastroesophageal junction or esophageal adenocarcinoma for patients with either IHC 3+ or IHC 2+ and is positive disease as detected by an FDA-authorized test. In addition, ZIIHERA is indicated with fluoropyrimidine and platinum-containing chemotherapy. For patients with HER2-positive IHC3+ disease as first-line treatment of adult patients with unresectable, locally advanced or metastatic GEA as detected by an FDA-authorized test. ZIIHERA is administered as an IV infusion in combination with chemotherapy, with or without [indiscernible] . Dosing is weight-based, with patients weighing less than 70 kilograms receiving 1,800 kilograms of ZIIHERA every 3 weeks or 1,200 milligrams every 2 weeks. Patients weighing 70 kilograms or greater. We'll receive 2,400 milligrams on ZIIHERA every 3 weeks or 1,600 milligrams every 2 weeks. The optionality of Q2-week dosing aligns to FOLFOX administration as the flexibility allows for physicians to choose the best chemotherapy for their patients. Herceptin efficacy results from the Phase III Horizon GEA trial that appear in the label are outlined on Slides 8 and 9. Both investigational treatment arms containing ZIIHERA demonstrated a statistically significant improvement in PFS, corresponding to a median PFS exceeding 12 months reducing the risk of disease progression or death by 35% compared with the tislelizumab control arm. Likewise, both combinations contain ZIIHERA exceeded 2 years of median overall survival, setting a new benchmark for survival in this disease. The ZIIHERA-plustizolizumab and chemotherapy arm demonstrated a clinically meaningful and statistically significant improvement in OS with more than 7 months improvement in the median OS, reaching 26.4 months and a 28% reduction in the risk of death versus the tislelizumab control arm, Nearly 40% of patients treated with the triplet regimen were estimated to be alive after 3 years. Again, the benefit was observed ireffective of tumor PD-L1 status. In the intent-to-treat population and is published in the New England Journal of Medicine, ZIIHERA plus chemotherapy showed a clinically meaningful survival benefit a median OS of over 2 years, a strong trend towards statistical significance at the time of the first OS interim analysis. The top line results from the second interim overall survival analysis from the Horizon TEA-01 trial doublet regimen are expected this quarter. As outlined in the label, subgroup of patients treated with ZIIHERA plus chemotherapy whose tumors were IC3 for HER2 showed a median overall survival of 25.5 months, and a hazard ratio of 0.74, with an upper bound of the 95% confidence interval that did not cross 1. We are very pleased with the approved label and we believe the unprecedented benefit supports the use of ZIIHERA as the new HER2-targeted agent of choice in HER2-positive first-line metastatic GEA. And we expect that ZIIHERA in combination of metezolizumab and chemotherapy will become the new standard of care for these patients, irrespective of PD-L1 tumor status. Turning to Slide 10. I'll review the important safety information. ZIIHERA has a box warning for diarrhea and embryo-fetal toxicity. ZIIHERA in combination with fluoropyrimidine and platinum-containing chemotherapy with or without pizolizumab can cause severe diarrhea, including life-threatening cases. Physicians should prescribe antidiarrheal prophylaxis during the first cycle when ZIIHERA is given in combination with these drugs and supportive measures should be implemented during treatment as clinically indicated. For modifying the dose of ZIIHERA, it is recommended to evaluate, modify or discontinued drugs contributing to diarrhea in accordance with their respective prescribing information. Treatment-related diarrhea that led to ZIIHERA discontinuation in the Horizon DEA-01 clinical trial was uncommon, occurring in less than 5% of patients across both experimental arms. Based on clinical trial experience and input from treating physicians and patients, we view these AEs as manageable with prophylaxis and active management considering the significant antitumor and survival benefits of ZIIHERA. In addition, physicians have the option to use FOLFOX in combination with ZIIHERA a chemotherapy regimen more widely used in the United States relative to CAPOX, which was primarily chosen as the chemotherapy backbone in the HORIZON clinical trial. Other warnings and precautions related to ZIIHERA administration include left ventricular dysfunction and infusion-related reactions. The most common AEs with ZIIHERA in combination with tislelizumab in chemotherapy or there, nausea, decreased appetite, hypokalemia, vomiting, fatigue, peripheral neuropathy, rash, and infusion-related reactions. The most common adverse reactions with ZIIHERA in combination with chemotherapy or diarrhea, nausea, vomiting, peripheral neuropathy, decreased appetite, fatigue, hypokalemia, infusion-related reactions and rash. I'll cover zanidatamab's unique mechanism of action on Slide 11, which gives us conviction to expand our development program into areas where we think math can outperform historical benchmarks for HER2-targeted agents. As described in the Nature publication illustrating zanidatamab mechanism of action. We believe its design is fundamentally different from other HER2 antibodies by binding 2 distinct sites on the HER2 receptor simultaneously. Zanidatamab cross-links neighboring HER2 proteins, leading to receptor clustering. The unique geometry and binding effectively blocks HER2 dependent cancer growth signaling. Additionally, zanidatamab activates the immune system to attack the tumor including activation of ADCC, ADCP and CDC. We believe complement cascade activation is unique to zanidatamab among HER2-targeted therapies. -- sub data from the HORIZON GEA trial presented at ASCO shows PFS and LS benefits were consistent in patients across PD-L1 positive and PD-L1 negative disease. We believe the complement and other immune activation and new pizanidatimab further enhances the efficacy of immunotherapy and explains the efficacy we see irrespective of PD-L1 status. We believe the combination of its unique mechanism of action, along with impressive clinical efficacy and a manageable safety profile for this molecule to date are supportive of investing further in zanidatamab. Sam will discuss our expanded view on the value zanidatamab may offer to HER2-expressing cancer patients later in the call. I'll now turn the call to Tumi for a discussion of our commercialization plans.

Thanks, Bob. The FDA approval of ZIIHERA is a landmark achievement and our team is ready to deliver this transformative therapy for GEA patients. I will start by outlining the significant unmet need for GEA patients on Slide 13. GEA, which includes capital sema, facetoesophagus junction and esophagus is the fifth most common cancer worldwide. Almost all GEA patients, about 90% of are symptomatic and usually present to a primary care provider or in the ER which complaints such as difficulty swallowing, painful following unexplained weight loss, blood in cost or abdominal pain. . Because the vast majority of GEA patients are diagnosed at an advanced stage, immediate intervention is critical. Approximately 20% of patients are diagnosed with HER2-positive disease, which translates to an annual incident of about 8,000 cases in the U.S. HER2-positive GEA is associated with time of BBM mortality, there remains a high unmet need for new treatment options. The overall prognosis for patients with GEA remains poor with a 5-year survival rate of less than 10% for metastatic GEA. This combination of high morbidity, mortality, prognosis and limited first-line treatment options underscore the surgeon for new therapy for these patients. The annual incidence of 8 poster GEA cases translates to a highly defined treatable patient population. When we look to patients who have unresectable disease, those who are eligible to receive treatment in the first line and those who received pertain reach a market of 3,000 to 4,000 patients on an annual basis who are excellent candidates to receive ZIIHERA. Our commercial investment strategy is focused on patient identification and GE ensuring no patient is left behind. On Slide 14, I will highlight how we expect the treatment paradigm to evolve beyond legacy standards of care and we shape the management of HER2-positive GEA. For more than a decade, trastuzumab-based therapy has a foundation of treatment for HER2-positive GEA and ZIIHERA represents a meaningful advance for these patients. In prior standards of care, which are shown on the left side of the slide, patients would need to be tested for PD-L1 status. Those who tested positive for PD-L1 were eligible for the newer regimen known as PM11, which added an IO to the TOGA regimen. While patients reflected negative for will continue to receive the trainimad-based total regimen. Now with ZIIHERA, once patients have confirmed HER2-positivity the treating position is able to begin treatment with the horizon regimen without testing for patients PD-L1 status and without Clint. Given the unprecedented survival out from the Horizon GEA trial, we expect the ZIIHERA [indiscernible] regimen to rapidly become the preferred clinical choice for eligible HER2-positive GEA potion. Moving to Slide 15. Our launch strategy is built on rapid execution and operational leverage designed to swiftly establish ZIIHERA as a definitive HER2-targeted seen. Critically, our success in DTC to a powerful commercial foundation for our next major growth phase in GEA. Because there is a significant direct overlap rig existing BTC and GEA treating accounts our commercial infrastructure is fully primed and highly optimized. With over 90% target physician overlap, our team will rapidly generate clinician excitement and demand. This enthusiasm is in danugetumab exceptional clinical data, specifically an unprecedented median overall survival exceeding 2 years. Due to the high overlap across our solid tumor ounce our field force has already established relationships with the highest volume prescribers. Artemis life side to capture the larger G&A market without requiring commercial expansion. The key component of our launch strategy leverage Java strength as a rare disease company, including identifying specific patient populations and building a precise commercial infrastructure to serve them. Our launch model is based on the blue print for how Jazz successfully commercializes therapies for rare and complex is. The key component of ZIIHERA launch is identifying the right patient at the right time to accelerate adoption of Bihar. The HER2 testing infrastructure is already mature with 80% to 90% of patients undergoing biomarker testing at diagnosis, anywhere from 60% to 80% of HER2-positive patients for amtreceive HER2-target therapy depending on where the patient is being true. While academic centers to lead in a biomarker-driven therapy, we are actively closing the staff in the community see. Our launch in second-line BTC established a foundation for us to rapidly increase our presence in the community count and layer adoption in GEA. By executing our high-touch commercial model across academic and community networks, deploying life care educators and dedicated support systems to ensure seamless treatment initiation and long-term patient appearance. To complement direct engagement, our nonpersonal promotion and digital campaign will increase awareness of ZIIHERA as a new presentation. To support immediate clinical adoption at launch, we have submitted this data to key oncology pathways. Ordering is available for customers who leveraging our established permanent J code and is also backed by our robust Jazz care patient support program. Rounding out the foundational components of our strategy is an emphasis on creating exceptional patient initiation and treatment experiences, which I will describe on the next slide. We have made strategic investments that support sustained patient adherence to treatment, including the nurse educator program and patient starts. Details on these programs are outlined on Slide 16. The nurse educator program is comprised of oncology certified nurses who provide peer-to-peer proactive education on the dosing and administration of ZIIHERA. Starter kits include educational resources around Ades event management with common or with the counter for aramid. By supporting education around long-term adherence, we can help patients achieve the best possible outcomes. These materials will develop with feedback from patients, caregivers and advocacy groups and are designed to improve patient safety, comprehension and satisfaction. We remain committed to empowering patients and caregivers through every step of the treatment journey and are so excited to bring a therapy with such dramatic vibrant movement to them. I'll now turn the call over to Sam to review the commercial opportunity for ZIIHERA.

This approval is transformational for patients with HER2-positive GEA and marks an important inflection point for ZIIHERA, with approvals now in both BTC and GEA. ZIIHERA develops from a promising pipeline asset into a commercially launched medicine with the potential to become a foundational HER2 targeted treatment across multiple tumor types. Our previous $2 billion-plus peak sales potential is based on the foundational indications of first-line and second-line BTC, third-line metastatic breast cancer and our pan tumor program. We worked diligently over the last 2 years to launch the registrational clinical trials that you can see outlined on Slide 18. One of the most exciting areas is breast cancer, the largest HER2-positive solid tumor market, we believe zanidatamab has the potential to play an important role following progression on HERIZON-GEA-01. We're evaluating this opportunity in our ongoing MPOWER-303 trial, which we expect top line data from late next year or early 2028. At the same time, we are actively expanding our ambitions into earlier stage breast cancer where the opportunity is substantially larger through the mPOWER breast cancer 208 trial, which was initiated over a year ago and the IP program. We're also actively engaged in combination strategies that could further enhance the value of zanidatamab. These include collaborations such as our ongoing study with Bohringer Ingelheim, ones as well as continued development in our registrational pan-tumor program about multiple HER2-expressing cancers. With the zanidatamab clinical development program well underway, the question is, where will we take zanidatamab next to unlock its full potential, which will I'll cover next on Slide 19. We have greater confidence in the molecule's ability to deliver meaningful outcomes across a much broad set of HER2-driven cancers, including earlier lines of therapy and larger genotypes. The Horizon GEA results significantly stricken our conviction in zanidatamab potential demonstrating unprecedented survival outcomes in a large Phase III randomized clinical trial provides important validation of both the molecule and its underlying biology, reducing development risk as we expand the program. Based on the strength of the Horizon GEA data and the growing body of evidence supporting zanidatamab's unique mechanism of action. We are increasing our peak sales expectation for ZIIHERA to $3 billion to $5 billion, up from our prior estimate of $2 billion plus. Beyond breast cancer, we are advancing registrational opportunities in colorectal cancer and evaluating potential pathways in non-small cell lung cancer. Early clinical data have been highly encouraging, we look forward to progressing the program. Taken together, we believe ZIIHERA the potential to become a foundational HER2-directed therapy across multiple tumor pipes. Our updated peak sales range reflects both the progress we've made and the significant long-term opportunity we see ahead as we continue to expand the clinical and commercial potential of this asset. I'll conclude on Slide 21. As we look ahead to the next decade and beyond, we see significant opportunity for growth driven by ZIIHERA's potential to redefine what oil across HER2-expressing cancers. The approval as ZIIHERA in GEA proves our ability to identify, develop and bring highly differentiated, high-value assets to market, driving both clinical progress and long-term shareholder value. In addition, it's a validation of our vision to build a leading biotechnology company focused on innovative, life-changing medicines for rare diseases. As we expand the validation or development program, we will explore both gas sponsored and collaborative clinical trials to realize the full potential of this unique medicine. We are laser-focused on delivering a strong launch in GEA and realizing the increased ZIIHERA peak sales opportunity of $3 billion to $5 billion through continued data generation, thoughtful global expansion and disciplined commercial execution. I'd like to take a moment to acknowledge and thank the patients, physicians, caregivers and Jazz team members for their commitment and dedication to bring ZIIHERA to this point. It's been an incredible effort over many years to reach FDA approval for GEA patients. And with that, I'll turn the call back to the operator to begin the Q&A session.

[Operator Instructions] Our first question today is coming from the line of Jessica Fye JPMorgan.

Congrats on the approval. I'm curious of the new $3 billion to $5 billion peak projection for ZIIHERA, how much of that is accounted for by BTC and GEA and how much of that is from additional indications? And then if I can as for forgiveness in advance, I'm asking a second question. Can you talk about how you get to that 3,000 to 4,000 eligible frontline patients in the U.S. for Zane, what cuts do you take to get to that number?

Yes, obviously, over the last couple of years, we've learned a lot about potential for ZIIHERA, and we're very excited now with the approval of to upgrade our peak potential ZIIHERA it to the $3 billion to $5 billion. As you may recall, the original estimate of $2 billion plus included both in PPC, the GEA approval as well as the metastatic breast cancer and tumor the new $3 billion to $5 billion range, obviously, goes beyond that now with the approval of GA. We're excited about taking ZIIHERA into other HER2-expressing cancers, such as colorectal cancer, non-small cell cancer early-stage GEA and early breast cancer. Whilst we're not providing a split between those indications that makes up the sheet $5 billion at peak. What I can say is that the BTC and GEA are a significant contributor to that. And we're obviously now with the label, we're really excited to get going in GEA and hence start to deliver on the potential there. Just to the second part of your question, we've obviously talked about the 8,000 patients before. Now as we look at the FDA-approved label, we're able to provide more specificity on what the exact kind of addressable patient population is of Von and to get to the 3,000 to 4,000 and -- we're obviously looking at the unresectable disease patient population as well as those that are eligible to receive treatment in the first-line setting and those who receive HER2 testing. So from that, we go from the 8,000 to 3,000 to 4,000.

[Operator Instructions] Our next question is coming from the line of Mark Goodman of Leerink.

Anything on the label that was a surprise to you? The commentary around the diarrhea, probably not. What about the IHC 3+ doublet kind of restriction? Anything there or that commentary?

Mark, this is Rob. Thanks for your question. To the labor is very, very favorable. We're really pleased to have approval of zanidatamab is now the preferred regimen for HER2 GEA approval with tizalizumab and irrespective PD-L1 status. We really feel that the triplet is appropriate for every patient unless there's a specific contraindication. On the diarrhea has been addressed already. This is a known toxicity of zanidatamab when combined with certain chemotherapy. And we found in the conduct of the clinical trial that is very manageable with very few patients actually discontinuing ZIIHERA due to diarrhea. Tommy touched on the education that's planned around this, which will be very important. And we think that some of that diarrhea is driven by capecitabine may even be more manageable with FOLFOX in the U.S. when given appropriate prophylaxis and attending to onset of diarrhea. We're very pleased that the triplet is approved, again, irrespective of PD-L1 status. And of course, that is for both IHC 2+ and 3 plus. Again, I think that -- this is a very poor prognosis disease. Many patients don't make it to second line therapy. It's clear that the addition of tizolizumab benefited patients, which is consistent with prior PD-1 therapies in gastric cancer. And so we think the triplet is really the new standard of care. With regard to interpretation of data on IHC 2+, it's a very small subset. It's true from an epidemiology perspective, most patients who are HER2-positive or 3 plus, is in the trial was a very small subset. We think that the data are probably confounded by other factors as evidenced by overperformance of the control arm where even in the control arm 2 pluses did better than 3 pluses. So overall, very favorable label from our perspective, and we think that zanidatamab is now a HER2 agent of choice in this setting. And the triplet really should be the standard of care for everyone.

[Operator Instructions] Our next question is coming from the line of Gregory Renza of Tru Securities.

Great -- My congratulations on the approval as well. For Rob and Sumit, just circling back to the change in the your belief in that peak sales opportunity, certainly, a decisive statement on going from, as you noted, ZIIHERA 2 plus to $3 billion to $5 billion. We appreciate the color you provided. Just to add on that, just curious if you could comment a bit on how you're characterizing perhaps any change in the time horizon to peak or the time to get into that peak potential to the $3 billion to $5 billion. Also, are there any maybe alterations in how you're looking at the geographic spread that has also informed your conviction today on those numbers. Congratulations again.

I can, first of all, comment on the peak sales potential Yes, we've already always said $2 billion plus. And now we're being more concrete around what that plus actually represents. Obviously, with this GA approval, it discharges some of the risks around some of the other studies that we have ongoing. We know that we have our development program in breast cancer, which is obviously one of the largest opportunities that we're now very excited about. Rob can speak a little bit about some of the timing associated with that and obviously moving into early breast cancer as well, which will be a significant contributor to the overall peak potential for the program. So maybe, Rob, if I hand over to you to kind of say a little bit about the time horizon for some of those to bed.

Yes, happy to. I'll just very quickly maybe give a broad description. So remember, we're approved in second-line BTC, but we have a frontline BTC that's ongoing and progressing very well, where there's no HER2 therapy approved in that space. So combining with PD-L1 in that setting, we think the prospect of tapping a positive study are very, very high. We now have definitive new standard of care in frontline GEA. We're very interested in exploring other aspects of gastric cancer. I think there is the potential in early-stage gastric cancer, where, again, there's no approved HER2 therapy. As Sam mentioned, we've made meaningful progress on a Phase III trial in the later-line breast cancer setting post in HER2, which was kind of an obvious first place to go. -- with zanidatamab in breast cancer, given how in HER2 is changing that treatment landscape and there won't be any -- this will really be the only pivotal trial that looks specifically post in HER2 and there down it's a head-to-head comparison. With Herceptin, but we had broader ambitions in breast cancer as Sam mentioned, we have ongoing Phase II work in neoadjuvant breast cancer and our Study 208 as well as collaborations with ISP and MD Anderson. And we'll look to interpret those data and potentially move to a pivotal trial in midranadjuvant press. We have collaborations with both Boehringer Ingelheim as well as Ambic, on novel TKI combinations with zanidatamab, starting in breast cancer but potentially in other settings. And the importance there is that, that combination is quite powerful allow us to get to even earlier lines in breast cancer and difficult-to-treat population. Such as brain mets. And then we have aspirations beyond that. You may have seen that we have breakthrough designation now in colorectal cancer. We'll be working with FDA to define a path to approval with colorectal cancer. We have an ongoing pan-tumor trial, which ultimately could give us a tumor-agnostic indication. That trial is also enrolling non-small cell lung cancer patients who are overexpressing HER2 and there may ultimately be a pack there as well. So a lot of opportunity now given the results that we have so far with data.

[Operator Instructions] Our next question is coming from the line of Annabel Samimy of Stifel.

It was good to see the broad label. I was curious about the extent to which ZIIHERA could be used with pembro rather than fiscally. Do you think there's going to be any kind of interchangeability in the marketplace and how do physicians approach when they've been using pembro. Just a curiosity about that. And then also, the 3,000 to 4,000 eligible patient population, is there an opportunity to moving it towards the 8,000 or is the 3,000 to 4,000 quite set.

Yes. So the study was conducted with tizlizumab, which is already approved in the U.S. And so we think there's little obstacle to combining with tizolizumab. However, as you said, multiple other PD-1s have shown efficacy in gastric cancer. We do have an ongoing trial combining with pembrolizumab, which would provide some, let's say, safety and preliminary efficacy such that if there were some compelling reason to use a PD-1 agent other than atezolizumab, we think that would certainly be compatible.

And with the net's Sam. The 4 patient population, patient population we're talking about here. That is reflected in that $3 billion, $5 billion peak estimate that we've provided. Within that, obviously, we're looking at the kind of unresectable disease. -- there's also those that are treated with -- that are -- that get a task. We will be closing on ensuring that patients that are tested that are result they're tested for Hersey positive, that's obviously a good team. But those patients that are tested for and are positive for her to then they are treated with Dana. So these are all the areas that we'll be focused on during the launch phase.

[Operator Instructions] Our next question is coming from the line of Jason Gerberry of Bank of America.

Mine was just -- would you expect physicians to prioritize the doublet in elderly patients, some of the language in the label seems to suggest that like the diary profile, more severe cases was less with the doublet. So curious if you -- it's a meaningful size subgroup within GEA if you think the doublet would get traction there? And how you think community docs will navigate some of the prophylactic measures with the diarrhea. I don't know if there's any analogues you can point us to that give you a high degree of comfort that how that will be managed by community oncologists.

Sure. So with regard to the older population, I do think that every eligible patient, unless there's a specific contraindication should get the triplet. Remember, this is still a very lethal disease. It's clear that tislelizumab added to the benefit irrespective of PD-L1 status. And you can even see as you look toward the latter parts of that curve, there's some encouragement there that, that might persist. We believe that the mechanism of action potentially synergizes with the PD-1. And so this is a disease where you don't want to sequence the therapies you really want to give these best therapies upfront where there may be synergy and you get the full benefit. In terms of toxicity as it was observed in younger than 65 or older than 65, interpret that with some caution, you can start to get to small subjects or other factors may be at play. And I would just point out specifically with regard to diarrhea, these are easily distinguished. The zanidatamab diarrhea comes on early, whereas atezolizumab diarrhea is more immune related and tends to be more delayed, there are diagnostic evaluations that really can distinguish the 2. So -- and I'll let others comment potentially on differences in community practice, but as I said, we conduct a very large global trial where we think the diarrhea is managed very, very well. Yes, there's needed education around starting with prophylaxis, ensuring the patients alert doctors promptly if they have onset of diarrhea because more can be done in terms of supportive care in terms of upping the anti-diarrheal therapy the label pretty clearly says to first modify chemotherapy so that you can maintain exposure to ZIIHERA, which is really critical for the survival benefit. And so these various things that we know about how to manage will be subject of education for any new prescriber, whether that be tertiary care centers or in the community. And I think everyone will be well equipped to manage this well. Maybe Sam or Tommy, would want to add to that answer.

Yes. I would just add that, of course, the benefits of using by ZIIHERA patient population are clear from the data that we have that we're familiar with now. And in the clinical trial, discontinuation rates of ZIIHERA, diarrhea was low, less than 5%. So what we want to do now is ensure that those results can be retitrated in the real world. And we will be investing significantly to ensure that patient doctors are supported to ensure that patients can stay on treatment and get the full benefit of ZIIHERA. And maybe I'll just ask Tumi to comment here a little bit around some of the investments that we're making to achieve those goals. .

Yes. Thank you, Sam. So we investment in education around management of diarrhea and we make some strategic investments that support 15 patient earn, which is obviously important -- we have a clinical nurse educator team that will provide support to nurses on patient initiation and management so that they have a first great experience within preoperational programs that are targeted specifically at the community and will proactively educate the evolving treatment paradigm as well as the compelling efficacy on data by supporting this education around alternate we can help patients achieve the best possible outcomes. We were prepared to do that.

[Operator Instructions] Our next question is coming from the line of Leo Timashev of RBC.

On the approval. I wanted to ask more broadly on the development strategy. You guys are running the basket study for potential and you talked about how potentially the registration for tumor elastic label, but you're also exploring a potential registrational study in colorectal and in non-small cell. And I guess those would also be included in the basket study. So I guess what I'm asking is, how are you thinking about the differences that specific studies in colorectal, non-small cell could add the opportunity, I guess, how you're thinking about what those clinical trials would be enrolling in terms of patients? Just any sort of differences in future labels that you'd be aiming more for patient segments.

Sure. I'm happy to take that question. So the basket study or the PAN tumor trial was really meant to allow us to enroll the patients that we would need it ultimately to get a tumor-agnostic label. And we are progressing tour that goal. And we continue to think that, that is potentially a pivotal trial for that purpose. It's a place where we can get additional data in refractory colorectal cancer patients as well as non-small cell lung cancer patients. In addition to any patient across a whole range of rare tumors who overexpress HER2. So there may be an opportunity for our tumor-agnostic indication in addition to having enough patients in any 1 indication such as colorectal or even on small cell lung cancer, where you may get a specific label in that regard as well. Remember, for colorectal cancer patients, we had some Phase I data. I think there were 28 patients in the Phase I. So we're adding to that in the Study 206 pan tumor. And on the basis of the combination of the Phase I and from the 206 study, we received breakthrough designation. And the next step now is to agree with the FDA on path to an approval for colorectal cancer, but you're right, it is an opportunity for a pan tumor or tumor agnostic indication as well as to generate data that could give us specific indications. And then, of course, there's the opportunity to go beyond that. That would be in a refractory setting, but there's always the possibility of then expanding into earlier lines as well.

[Operator Instructions] Our next question is coming from the line of David Amsellem of Piper Sandler.