Hello, and thank you for standing by. Welcome to the zanidatamab KOL Investor Webcast. At this time, all participants are in a listen-only mode. After the speaker presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star 11 on your telephone. You will then hear an automated message advising that your hand has been raised. Please be advised that today's conference is being recorded. It is now my pleasure to introduce Chairman and CEO Bruce Cozadd.
Thank you, Operator, and good evening, everyone. Earlier today, pivotal phase IIb data from the HERIZON-BTC-01 clinical trial assessing zanidatamab in previously treated HER2-amplified biliary tract cancers, or BTC, were featured in an oral session at this year's annual meeting of the American Society of Clinical Oncology. Zanidatamab is one of several late-stage programs in our pipeline that we are advancing on behalf of patients in need of improved treatment options, and we're excited to share these impressive results with you today. I'd like to remind you that today's webcast includes forward-looking statements as outlined on slide two. These statements are subject to risks and uncertainties. If we refer to guidance, that's referring to our first quarter 2023 disclosure made on May 10th. Please see our SEC filings for more information. There is a brief agenda for today's discussion on slide three.
We are very pleased to welcome Dr. Shubham Pant from the MD Anderson Cancer Center to provide an overview of the trial findings. Following Dr. Pant, Jazz Chief Medical Officer Kelvin Tan will provide perspectives on how we view zanidatamab development moving forward, as well as how this novel therapy builds on our existing oncology franchise. We'll then open the call for questions. Abizar Gaslightwala, U.S. Business Unit Head for Jazz Oncology, will join our other speakers for the Q&A session. We are exceptionally pleased that the zanidatamab phase IIb data from the HERIZON-BTC-01 trial were selected by ASCO to be featured in an oral presentation this afternoon. Findings from the trial were also concurrently published in The Lancet Oncology.
In addition, the presentation has been selected for the 2023 Best of ASCO program, which will be held later this summer following the ASCO annual meeting. Now, I'm pleased to introduce our expert speaker, Dr. Shubham Pant. He is a professor in the Department of Gastrointestinal Medical Oncology at MD Anderson Cancer Center, serves on the ASCO GI Guidelines Committee, and is a leading GI cancer researcher. Dr. Pant's bio is on slide five. Dr. Pant serves as an investigator for the Zanidatamab HERIZON-BTC-01 trial and presented data from the trial at today's ASCO oral session. He is also a senior author of The Lancet Oncology manuscript on the phase IIb data from the HERIZON-BTC-01 trial. Dr. Pant.
Thank you so much, Bruce. I'm going to present the results from the pivotal phase 2b HERIZON-BTC-01 study, zanidatamab, in previously treated HER2-amplified biliary tract cancers, and that's the slide six. On slide seven, you can see that this is a background of patients with biliary tract cancers. There are approximately 12,000 HER2-positive BTC cases annually in the U.S., Europe, and Japan. For patients with locally advanced or stage four metastatic BTC, standard therapy second line and beyond offers limited clinical benefit. Chemotherapy in this setting provides an overall response rate of 5%-15% and a median progression-free survival of four months. HER2 amplification or overexpression is observed in a subset of BTC, and it's different in the different subsets. Most commonly found in gallbladder cancer, where it can be found in 19%-31%.
In extrahepatic Cholangiocarcinoma, it can be overexpressed in 17%-19% and in 4%-5% of intrahepatic cholangiocarcinomas. And as we know, HER2-targeted therapies have clinical benefit in breast, gastric cancer, and lung cancer, but there are no approved HER2-targeted therapies for biliary tract cancers. On slide eight, you can see the unique mechanism of action of zanidatamab. It simultaneously binds two domains in the HER2 protein, extracellular domain two and four, and that binding is unique and results in multiple mechanisms of action. Preclinical studies which were published recently demonstrate a greater activity in mouse models than trastuzumab as a single agent or trastuzumab in combination with pertuzumab. And a phase I trial, basket trial, which was done, which was published before in Lancet Oncology, in that zanidatamab showed a manageable safety profile and encouraging anti-tumor activity in patients with HER2-expressing BTC.
And we saw 22. We enrolled 22 patients in that cohort, and seeing activity in that cohort led to this trial. On slide nine, you can see the HERIZON-BTC-01 study design. The key eligibility criteria were locally advanced or metastatic BTC. Tissue was required to confirm HER2 status by central lab. Patients should have progressed after treatment with a gemcitabine-containing regimen or be intolerant to the same. No prior HER2-targeted therapies were allowed, and patients had to have an ECOG of zero or one. We did exclude patients with ampullary cancer. Now, all patients who entered the study did have HER2 amplification by in-situ hybridization. Cohort one was HER2-positive, which were IHC 2+ or 3+, and cohort two were IHC 0 or 1+. Zanidatamab was given at the dose of 20 mg/kg IV with mandatory pre-medication for infusion-related reaction prophylaxis.
We scanned patients every eight weeks. The primary endpoint was confirmed overall response rate by independent central review, with key secondary endpoints being duration of response, disease control rate, progression-free survival, overall survival, and frequency and severity of AEs. On slide ten, you can see the enrollment. This was done during the pandemic, September 2020 to March 2022. We enrolled in 32 sites across four continents: Asia, Europe, North America, and South America. The data cutoff for the primary analysis was October 10th, 2022. We enrolled 80 patients, eight zero in cohort one and seven patients in cohort two. Now, going forward, the focus of this presentation will be on HER2-positive BTC. That's cohort one, IHC 2+ and IHC 3+, as cohort two contained a small sample size of seven patients, and it did not reveal any responses nor any unique safety signals. These are the demographics and baseline characteristics.
65% of patients were Asian. Majority had an ECOG performance status of one. As expected, the most common BTC subtype was gallbladder cancer, which was 51.3% of patients. About 77% of patients had IHC 3+ disease, with close to 90% of patients, 88.8%, having stage four disease or metastatic disease. 76% of patients received cisplatin and gemcitabine as frontline therapy, and 26% of patients received prior checkpoint inhibitor. They could either be a PD-1 or a PD-L1 inhibitor. On slide 12, you can see the disease response in patients with HER2-positive BTC. Now, at the time of data cutoff in October 2022, 16 patients had ongoing response. Now, we assessed response in two ways: by independent central review and by investigator assessment, and they were both the same. 41.3% of patients had a confirmed overall response rate.
One patient had a complete response, and these are patients in the independent central review that I'm mentioning. 32 patients had a partial response, and 22 patients had a stable disease. The disease control rate was 68%, and the clinical benefit rate, and that was defined as complete response, partial response, and stable disease for greater than or equal to six months of 47.5%. This is slide 13. This is the waterfall plot, and as you can see, the majority of the evaluable patients, 80 - sorry, 68.4% - had decrease in target lesions. The asterisks that you see are the patients who have HER2 2+ disease. The rest of the patients had HER2 3+ disease, and as you can see, majority of all the BTC subtypes, which is gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma, seem to benefit from the therapy. Slide 14 shows you the same swimmer's plot.
The little green dots that you see are patients with an ongoing response at the time of data cutoff. The median duration of response for the 33 patients who showed a response, PR or CR, was 12.9 months, and the median time to first response was a relatively short 1.8 months. This is a Kaplan-Meier curve for the progression-free survival in patients with HER2-positive BTC. The overall survival data is not yet mature. The progression-free survival median was 5.5 months. This is slide 16 of adverse events. 96.6% of patients had any treatment emergent adverse events, with 72.4% of patients having any treatment-related adverse events. However, there were two patients who had TRAEs, treatment-related adverse events leading to treatment discontinuation. The most common side effects were diarrhea, infusion-related reaction, ejection fraction decrease, nausea, and anemia. Majority were grade one and two.
There were no grade four TRAEs and no treatment-related deaths. And this is slide 17. We did look at adverse events of special interest. 33.3% of patients had infusion-related reactions. One of them had grade three or higher infusion-related reaction. All the events resolved generally within one day, and most occurred within the first cycle of treatment, and most had no recurrence. There were five patients who had confirmed cardiac events, which was decreased LVEF. Patients were clinically asymptomatic, and the events were confounded by pre-existing or concurrent conditions. One patient had non-infectious pulmonary toxicity, and 43.7% of patients had diarrhea, with 6.9% of patients having grade three or higher diarrhea. All but two events were managed in the outpatient setting, typically with loperamide, which is commonly given for diarrhea. Most events were resolved at the time of data cutoff, and the median time to resolution was two days.
Slide 18 is the conclusions. To conclude, zanidatamab demonstrated anti-tumor activity, including rapid and durable responses in patients with treatment refractory HER2-positive BTC. The confirmed overall response rate per independent central review was 41.3%, and most responses were identified at first disease assessment. The median progression-free survival was 5.5 months, and the median duration of response was 12.9 months. Zanidatamab demonstrated a manageable and tolerable safety profile. Few events led to treatment discontinuation. No grade four TRAEs, no deaths were treatment-related, and the most common AEs were IRRs and diarrhea, predominantly low-grade and reversible, and these results support zanidatamab having meaningful clinical benefit and potential as a future treatment option in HER2-positive BTC, and additional studies are both planned and active, including zanidatamab in combination with cisplatin and gemcitabine.
On slide 19, we sincerely thank all the patients and their caregivers, and to all the investigators, clinical trial researchers, and the research staff. On slide 20 is a slide which has already been shown. It was great for us and the co-investigators that we had a simultaneous publication in the Lancet Oncology. It's published online today, June 2nd, 2023. With that, I want to thank you for listening.
Thank you, Dr. Pant, for reviewing the data that you presented earlier today at a packed ASCO session. This is very exciting news for the field, and most importantly, for patients with BTC. Looking more broadly at the zanidatamab opportunity on slide 21, we believe that zanidatamab has the potential to transform the current standard of care in multiple HER2-expressing cancers.
Given its monotherapy activity across multiple HER2-expressing tumor types, including cases resistant to prior HER2 therapies, we are committed to rapidly advancing our development program to unlock the potential of this molecule. Our initial focus is on BTC and gastroesophageal adenocarcinoma, or GEA. There are approximately 12,000 HER2-positive cases of BTC annually in the U.S., Europe, and Japan, and as we've discussed today, these patients are in need of new therapeutic options. Currently, there are no HER2-targeted therapies approved for the treatment of BTC. The findings in the phase IIb zanidatamab trial showed a significant improvement over the current standard of care in second-line BTC. In particular, I'd like to call out the compelling response rate and PFS data from this trial. Current standard of care for second-line advanced metastatic BTC includes two treatment regimens. One is the chemotherapy regimen, FOLFOX, which includes folinic acid, fluorouracil, and oxaliplatin.
Recent guidelines from the NCCN and ESMO recommend the protocol of FOLFOX plus advanced symptom control, or ASC, for second-line BTC treatment. The other commonly used regimen is trastuzumab and pertuzumab. The literature indicates an overall response rate between 5%-15% and a PFS for approximately four months for these regimens. As Dr. Pant noted in his presentation, patients treated with zanidatamab in the HERIZON-BTC-01 trial had an overall response rate of 41% and a PFS of 5.49 months. In addition to these efficacy findings, zanidatamab demonstrated a manageable and tolerable safety profile. Based on its overall clinical profile, we believe zanidatamab has the potential to significantly advance the treatment of BTC.
We are in dialogue with the FDA regarding the potential regulatory path forward for zanidatamab and BTC, and we believe that the current body of data is sufficient to support a BLA submission. GEA is another area of unmet need and is a more frequently occurring cancer relative to BTC. In the U.S., Europe, and Japan, there are approximately 63,000 HER2 plus cases of GEA annually. At the January ASCO GI Conference, the first zanidatamab overall survival data were presented from a phase II trial evaluating zanidatamab in combination with chemotherapy in first-line patients with HER2 expressing metastatic GEA. The preliminary results showed that the median overall survival had not yet been reached, with an 18-month overall survival rate of 84%.
The overall survival findings in this trial are compelling given historically reported overall survival rate for the currently approved standard of care is a median of 14 months. These results show zanidatamab's potential as a foundational treatment for patients with HER2-positive GEA, and we look forward to additional data from the ongoing pivotal phase three GEA trial expected to read out in 2024, which may support U.S. and global regulatory submissions. Now, slide 23. Slide 23 shows the breadth of our R&D programs, and I'll start by highlighting several programs in our oncology portfolio. Since we acquired development and commercialization rights to zanidatamab last year, our confidence in this program has only grown based upon positive data in both BTC and GEA.
And while our initial focus is on those two tumor types, we believe zanidatamab has the potential to transform the current standard of care in multiple HER2-expressing cancers. To that end, we're excited that zanidatamab was added to the I-SPY breast cancer platform this year. We also have multiple earlier stage trials assessing zanidatamab's clinical profile in a range of tumor types and are actively evaluating opportunities to pursue additional indications. In addition to zanidatamab, we have several other oncology programs in late-stage development. We are collaborating with Roche on a phase three trial to evaluate Zepzelka as maintenance therapy in first-line small cell lung cancer, which is expected to complete enrollment by the end of the year. We also expect a response this year on our MAA submission for Rylaze.
We also have multiple ongoing neuroscience programs with top-line data readouts from our JZP150 program in PTSD expected later this year and from our suvecaltamide essential tremor trial expected in the first half of next year. In total, we expect at least three late-stage data readouts by 2024. Our efforts over the past several years to expand and enhance our R&D capabilities and productivity are being realized, and we're excited to reach these upcoming milestones on behalf of patients who are in need of new treatment options. This concludes the slide presentation, and now I'll turn it over to the operator to begin the Q&A.
Thank you. As a reminder, to ask a question, you will need to press star 11 on your telephone. And we ask that you please limit yourself to one question. Please stand by.
And our first question comes from the line of Joe Thome with TD Cowen.
Hi there. Good evening. Congrats on the data, and thank you for taking our question. Maybe just for Dr. Pant, how quickly do you think this might be adopted in sort of the standard of care in second-line patients? It looks like the response rate, understandably so, was much higher in the three-plus IHC patients. But when you think about those that maybe are 2+, would you use this in everyone there too, or how would you make that distinction? And I guess is there anyone that would not be a candidate that is a 3+ patient?
At least in the data, thank you. The data that we've shown, it seems to benefit both HER2 3+ and 2+ in totality. So I think that's where we would think about using it.
Obviously, in the 0 and 1+, that's where we really did not see any responses. So that's a place where we would not be clinically. I would not be using it, but 2+ and 3+, definitely based on the data.
Thank you. And our next question comes from the line of Madhu Kumar with Goldman Sachs.
Hey, thanks for taking our question. It'd be a question for Dr. Pant. When we look at the ORR kind of differences relative to the PFS differences versus standard of care, I mean, I guess one interpretation is that there's something about patients who respond to those drugs with the real depth of response.
In the kind of work y'all have done from the Horizon trial so far, have you seen certain features of disease or certain biomarkers that kind of predict this kind of depth of response that you don't necessarily that doesn't, on the bulk, translate to changes in PFS, but to get that certain patients are getting a greater impact from zanidatamab?
Yeah, so we have not looked at kind of co-mutations, any other innate resistance mechanisms in the beginning. We've collected blood on these patients, tissue on these patients, so hopefully we can look at that. Progression-free survival is really challenging to interpret in this single arm study because a lot of the patients who have HER2 positive disease are gallbladder cancer patients. Traditionally, those patients seem to have a more maybe aggressive disease.
But that's what the progression-free survival only we can figure out on a randomized trial. It's hard to interpret that in a single arm study. As far as duration of response, yes, we were very – that's what made the study important for us was the response rates, obviously, but the duration of response was more meaningful, is more meaningful to me as a clinician. So that's what we were happy about to see.
Thank you. And our next question comes from the line of Ami Fadia with Needham & Company.
Hi, good evening. Thanks for taking my question. My question is for Dr. Pant. At ASCO, just earlier, data were presented for Tukysa plus trastuzumab. Can you compare and contrast those data with these? And in the real world, how would you think about determining what patients to put on which? Thank you.
Thank you for that question. That presentation was right before mine, so that's when I got to see it. Differences are, and as Andrew Ko, who discussed our session, said that there have been three or four trials which have been done, mostly part of basket trials. So the difference is there were less patients, I don't remember how many, but between 20 and 30 patients. And so it was part of a basket trial. I don't want to describe, but I don't think they had central read. So this was truly like a global trial. So more number of patients, obviously 80 patients, where we did see the benefit with the response rate of 42%. So it was more of a global trial for continents. That's a different flavor than that trial which was a basket study done in Japan.
So at this time, the data has just come out, so it's kind of hard to compare and contrast, frankly, to see. But those are the two big differences I think which I caught when I was on the podium was smaller numbers, and this was global. That was more local. And I think the HER2 testing was central, sorry, central on this trial, and I think it was more local on the other trial. Just add there was good data presented in both presentations on tolerability of the regimens, and I'd look at that as well.
Good evening. This is Abizer Gaslightwala . Thanks for taking our question. Just a quick one, opportunities outside BTC and GEA, in particular, HER2 expressing breast cancer, which is a large indication with a lot of competition.
Could you let us know what's the focus of your BD for breast cancer, given that it is a very competitive landscape and zanidatamab is currently on trial for both first-line and third-line therapy, if I remember correctly? Would it be safe to assume that third-line therapy would be more of a focus for zanidatamab for breast cancer? Thank you.
Yeah, this is Bruce. Maybe I'll start and then ask Kelvin to weigh in. And I'll just start by saying we haven't announced our specific development plans outside of BTC and GEA yet, but we have signaled that we have interest beyond those two initial indications with a real interest in breast cancer. And Kelvin, maybe you can talk about why we're headed that direction and any color you might want to provide.
Yeah, thank you for that, Bruce.
So what's clearly our focus right now is ensuring that we remain focused on BTC and GEA, and in good time, we'll be thinking about where we need to progress next. Given that we know that HER2 is expressed widely, particularly in breast, it is an area of interest for us. I'm very pleased to share that we have been invited by I-SPY to join their platform where they'll be looking at zanidatamab for HER2 expressing tumors in neoadjuvant treatment of locally advanced breast cancer. So we're excited about what that opportunity will look like, and we continue to explore other potential indications for zanidatamab, knowing that the HER2 biomarker is expressed quite widely amongst other cancers as well.
To note on the timing of that, I-SPY, we've been invited to participate in. Patient dosing has already happened.
Absolutely.
So it's moved quickly.
Thank you.
Our next question comes from the line of Stacy Lee with Stifel.
Hi, this is Stacy calling in for Annabel. Thanks for taking our question. One for Dr. Pant. So zanidatamab could be the first HER2 targeted treatment for BTC, but in this study, prior HER2-treated patients were explicitly excluded. Does that mean that HER2 agents are currently used off-label or with only NCCN guideline support? And how does this compare to those patients who have received HER2 with gemcitabine? And I guess to that effect, if it is effective as combo therapy, then why has it never been pursued as an actual indication?
Okay. So I think there were two parts to that question. One was what is being used outside off-label. So in NCCN guidelines, we have trastuzumab and pertuzumab, which is used off-label.
In the HER2 pretreated, the 22 patients with biliary tract cancer who were enrolled in the phase I trial, they were HER2/neu pretreated, or at least a majority of them were HER2/neu pretreated. I don't have the data in front of me. We saw a response rate, I think, in BTC of about 38%. There was also some response rates in that patient population of HER2/neu pretreated. I'll have to look at the whole paper to exactly know, but that was, I think, the case. The second part is, yes, I think it makes complete sense to combine zanidatamab with chemotherapy. It's been combined in upper GI. Interestingly, the same regimen that we use in second line, FOLFOX, for biliary tract cancer is we have safety data with zanidatamab, so it does make sense to combine it.
I think the challenge has been that the patients and kind of running these big trials in a rarer patient population. So that's just my opinion on it.
And if I might just add, zanidatamab has demonstrated compelling anti-tumor activity both as monotherapy and in combination with chemotherapy. And we're pleased to also share that we have some phase one monotherapy data in multiple HER2-positive solid tumors and in cases also resistant to prior HER2 therapies. I know that was a question that was raised.
Thank you. And our next question comes from the line of Jeffrey Hung with Morgan Stanley.
Hi, this is Michael Riad on for Jeff Hung. Thank you for taking our questions. These are for Dr. Pant.
Looking at the waterfall plot for evaluable patients on slide 13, it just seems like patients with gallbladder showed a better response versus ICC and ECC overall. Do gallbladder cancers have a higher HER2 expression level than ICC or ECC, or do they tend to be more responsive? Thanks, and I have a follow-up.
Yeah, so I think if you look at it, I think all subtypes did get some kind of benefit in the trial. And if you look at the asterisk, the waterfall plots, obviously the 3+ patients seem to have higher benefit than the 2+ patients, but it's not that gallbladder cancers have more 3+. They can be gallbladder cancers with 2+ also, but I think it mostly what it depends on is the oncogenic driver.
3+, we think, have a potentially higher response rate than2+ , but the 2+ also seem to respond maybe not as a high rate as the 3+.
Thank you. I'll now hand the call back over to Chairman and CEO Bruce Cozadd for any closing remarks.
All right. Thank you, Operator. Just in closing, we believe zanidatamab has the potential to transform treatment for a number of HER2-expressing cancers, and we are prioritizing its development. Zanidatamab is the newest program in our pipeline and exemplifies our approach to corporate development as we seek to identify and acquire on favorable terms differentiated therapies that improve patient care, enhance the value of our pipeline, and are strategically aligned with our development and commercial capabilities. It also reflects our enhanced R&D capabilities beyond the expanded breadth and depth of our pipeline with at least three late-stage readouts through 2024.
I'm really proud of our expanded capabilities, including enhanced medicinal chemistry and translational biology and differentiated capabilities across cannabinoids and nanoparticle drug delivery. Our oncology franchise is a core component of our efforts to diversify our business, and we're excited about how zanidatamab may contribute to both patient care and our business. Thank you all for joining us today.
Thank you. This concludes today's webcast. Thank you for participating, and you may now disconnect.