Good afternoon. I'm Pia Banerjee, Head of Investor Relations at Arcus Biosciences. Thank you for joining us to discuss the results from the fourth interim analysis of our and Gilead Sciences phase II ARC-7 trial. We and Gilead issued a joint press release last night highlighting the data from the ASCO Plenary Session abstract, which can be accessed in the investor sections of our websites. In addition, the full results were presented today at 3:00 P.M. Eastern Time at the virtual ASCO Monthly Plenary Series by our lead investigator, Dr. Melissa Johnson, Director of Lung Cancer Research at the Sarah Cannon Research Institute at Tennessee Oncology. That presentation and discussion are available for viewing on the ASCO website. For this afternoon's call, you'll be hearing from Arcus's CEO, Dr. Terry Rosen, and Chief Medical Officer, Dr. Dimitri Nuyten , as well as Dr. Bilal Piperdi, Vice President of Gilead Oncology, Lung Franchise Head.
The Q&A portion will be moderated by Jacquie Ross, Vice President of Investor Relations at Gilead, and we will also be joined by Arcus's Chief Operating Officer, Jennifer Jarrett, along with Dr. Bill Grossman, Senior Vice President, Therapeutic Area Head, Gilead Oncology. Our discussion today will contain forward-looking statements, including statements regarding future data disclosures and presentations, the development of current and future programs, and the efficacy and safety of domvanalimab, zimberelimab, and etrumadenant. All forward-looking statements involve known and unknown risks and uncertainties and other factors that may cause our actual results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. A description of these risks can be found on slide three and in the latest SEC filings filed by Arcus and Gilead, which we encourage you to review. I'll now turn the call over to our CEO, Terry Rosen.
Thank you very much, Pia, and thank you all for joining us today. We're really very excited to discuss the data presented earlier today from the fourth interim analysis of our phase II study, ARC-7 in first-line PD-L1 high non-small cell lung cancer. These data represent the largest and first prospective randomized dataset to be released for an anti-TIGIT combination in this setting and reinforce our confidence in our late-stage domvanalimab development program. Starting with slide five, and a quick reminder of our collaboration with Gilead, our partner for the molecules another ARC-7 study. We're fortunate to have a unique 10-year partnership. This is hugely enabling and allows us to pursue significantly more molecules, studies and opportunities than we'd be able to do on our own.
With Gilead's support, which has included $1.3 billion of capital to date and 50% cost-sharing for five of our clinical stage molecules, we now have an extensive clinical pipeline, including four phase III studies, all targeting billion-dollar opportunities. On slide six, I'd like to remind you how domvanalimab or DOM works. We engineered DOM with a silenced FC region, optimizing its ability to fully leverage the fundamental mechanism of action for this target, blocking the TIGIT receptor on immune cells and reversing TIGIT-induced immune suppression in tumors. In contrast, FC-enabled TIGIT antibodies also tagged certain immune cells bearing TIGIT on their surface for destruction, which can potentially result in negative consequences. These include reducing the peripheral Treg cell population, which could contribute to immune-related events.
As Dimitri will discuss, the emerging clinical safety data from ARC-7, including low rates of immune-related events and infusion-related reactions, suggest, in fact, that DOM may have a differentiated safety profile. Briefly, slide seven provides the key takeaways from today's data presentation. We saw improvement for the DOM-containing arms over monotherapy for every outcome measure we evaluated. Today, we'll focus on ORR, and importantly, PFS, where we saw an impressive 12 months and 10.9 months median PFS for the doublet and triplet arms, respectively. We're gonna review all of these points in detail today. On slide eight, I'll start with an overview of the study. ARC-7 is a randomized, phase II trial that enrolled patients with first-line metastatic PD-L1 high non-small cell lung cancer and included three arms.
Zimberelimab or ZIM, which is our PD-1 antibody and active comparator arm, dompluszim, which we refer to as the doublet, etrumadenant or ETRUMA, our adenosine two receptor antagonist, plus DOM and ZIM, we refer to as the triplet. Each arm enrolled 50 patients. Study recruitment completed in August. PD-L1 testing was performed locally using either the 22C3 or SP263 assay. The primary outcome measures for the study are objective response rate, ORR, and progression-free survival or PFS. Before I hand things over to Dimitri, I really wanna make three essential points. First, we've seen an impressive efficacy signal with domvanalimab with median PFS for both the doublet and triplet, each surpassing anything seen historically for anti-PD-1 monotherapy, and in fact, surpassing even anti-PD-1 plus chemotherapy. That's KEYTRUDA plus chemotherapy in KEYNOTE-189.
In fact, more recent studies looking at anti-PD-1 plus chemo in PD-L1 greater than 50 patients. GSK's PEARLS study, which also included KEYTRUDA plus chemo. Secondly, this is the first and only prospectively randomized data set, and it's the largest data set for an anti-TIGIT, anti-PDX combination in the setting. Lastly, as you heard during Dr. Johnson's presentation today, we believe that the Fc-silent configuration could be an important differentiator for DOM. I'm now gonna turn the call over to Dimitri to review the data.
Thanks, Terry. I'm excited to review today's efficacy and safety data. I spent a significant part of my career in immuno-oncology drug development. It's unusual to conduct a randomized phase II study of this size. Oftentimes, the 11 are based on data. It's a pleasure to review the data set of this nature. The data gives me strong confidence in our anti-TIGIT program. I'll begin on slide nine with a review of the study population. At this interim analysis, our efficacy population is randomized as of June 2022, who are therefore eligible for at least two tumor assessments as of the data cut-off date of August 31st, 2022. A minimum who's provided at least an opportunity for patients to achieve a response and to confirm the response. This ITT-13 population had approximately 44 patients per arm.
The ITT-13 population included both efficacy valuable patients and any non-valid patients who discontinued prior to represent. This latter point is important. The analysis of patients who were randomized as of June 2022, including one patient who did not receive any study treatments and patients who did not make it to the first scan independent of the reason why. The baseline characteristics are shown on slide number 10. The three arms are generally well-balanced, including with respect to PD-L1 status. However, we noted a greater population of patients over 65, as well as an higher prevalence of patients with squamous cell histology in the combination arms relative to ZIM monotherapy. Both of these represent prognostic characteristics that might have negatively impacted the combination arms relative to ZIM monotherapy. A few key points I want to make on our population relative to earlier PD-1 studies.
First, ARC-7 may have been impacted by contemporary treatment landscape with an anti-PD-1 as standard of care. This differs from historical anti-PD-1 trials that included chemotherapy as [chemo] control, which may have resulted in an overall healthier patient population in the older studies. Also, as Terry mentioned, as phase II study, local PD-1 testing was used in ARC-7, and this is in contrast to central testing, where the longer turnaround times may also have impacted the nature of randomized populations in other studies. Secondly, the study population was slightly older than historical anti-PD-1 monotherapy trials in the first-line non-small cell lung cancer setting, with most of them having a median age around 63. Third, ARC-7 also had a higher percentage of patients from East Asia as compared to most other global PD-1 studies.
Overall, we believe the population heterogeneity observed in our study is highly representative of the real-world practice today. In fact, ARC-7 included more than 70 sites across seven countries in larger community settings. Turning to the efficacy data on slide 11. I want to start by re-emphasizing that every outcome measure we evaluated for the ITT-13 population favored the combination arms over ZIM monotherapy arm. Confirmed overall response rates in the ITT-13 population were 41% for doublet versus 27% for ZIM monotherapy for a 14% differential. Overall response rate for the triplet was similar to that of the doublet arm. It reinforces the results observed in the doublet arm. The separation of ORR across subgroups is consistent, which gives us even greater confidence in the potential for anti-TIGIT therapy to provide benefit for a broad patient population.
While the doublet and triplet arms appear similar to this analysis, we do remain excited about the adenosine pathway, and we will need to continue to monitor progression-free survival and overall survival as the data matures, as well as additional data emerging from other proof-of-concept studies that are underway evaluating the adenosine pathway. Based on our analysis to date, what is known about immunotherapy in general, response rates for some patients may continue to improve with greater maturity of data. Approximately 30 of patients who responded in our study did not respond until the third scan or later. Some patients ongoing with stable disease right now might become responders as the data continues to mature. As of the data cut off in the doublet arm, there were six patients in the ITT-13 population on therapy with stable disease.
Moving now to slide number 12 for the PFS results. We observed a median PFS of approximately 12 months for the doublet arm, relative to 5.4 for ZIM monotherapy. For the doublet arm, this translates to an encouraging and clinically relevant hazard ratio of 0.55. As you can see in the Kaplan-Meier curves shown here, the doublet separated from monotherapy before month two, and the separation was maintained. If we move to the next slide 13, we've overlaid the triplet arm here, which again is consistent with the results observed in the doublet arm and further strengthens our results in the overall study.
Although early, these data were very encouraging with the doublet and the triplet median PFS surpassing historical benchmarks, both for anti-PD-1 monotherapy and for anti-PD-L1 chemo combinations. At this analysis, the event rate is 61% for monotherapy, 43% and 51% for the doublet and the triplet arm respectively. While the PFS analysis and the median PFS are still immature, our confidence is driven by the consistency of the signal across both DOM-containing arms and across efficacy metrics, including landmark six-month PFS. Importantly, this latter metric, landmark six-month PFS, is relatively mature given the median follow-up of 12 months, and we observed 65% and 63% for the doublet and triplet arms respectively, versus 43% for the monotherapy arm at the six-month time point.
As demonstrated by the overlay on the Kaplan-Meier curves, these numbers put the doublet and triplet regimen in the same range as the landmark PFS re-reported in CITYSCAPE. The swim lane plots on slide 14 illustrate that 11 patients, or 25%, had progressive disease as their best overall response on the ZIM monotherapy arm. In contrast, only two patients, or 5%, and six patients, or 13%, had progressive disease as their best overall response in the doublet and the triplet arm respectively. This is important, suggesting that the addition of a TIGIT antibody to anti-PD-1 brings the disease under control more quickly. The swim lanes also illustrate a much longer duration of treatment observed to date for the combination arms relative to monotherapy. Slide efficacy results. The overall response rate and PFS data showed substantial improvement for the combined arms over anti-PD-1 alone.
ARC-7 represents the largest data set reported for a randomized trial of any TIGIT plus anti-PD-1 combination. The efficacy data clearly supports our investment in a broad DOM-containing clinical development program. Turning to slide 15 for safety now. In general, no unexpected safety signals were observed, and both DOM-containing arms were generally well-tolerated. The incidence of grade three and higher treatment emergent events was well balanced across the arms, despite longer time on treatment for the doublet and the triplet arm. As we noted earlier, unlike DOM, Fc and able TIGIT antibodies can deplete TIGIT-bearing cells, which includes T regulatory cells, as well as other immune cells contributing to immune-related events. As shown on slide number 16, immune-related AEs were similar in both of the combination arms as compared to ZIM monotherapy.
Specifically in the doublet arm, we saw no increase in the incidence of rash, pruritus, or pneumonitis. For the triplet arm, we saw an increase in incidence of grade one and two rash and pruritus, which tended to occur early in treatment and resolved with treatment of topical steroids and generally did not lead to dose reductions, interruptions, or discontinuations. Additionally, a 4% incidence of infusion-related reactions observed for the doublet arm was noted on the prior slide. This compares favorably to rates observed for competitive anti-TIGIT plus anti-PD-1 combinations. Infusion-related reactions are uncomfortable for patients and may result in more intense patient monitoring and treatment. If these observed rates continue to stay low, this could be an important differentiator for our regimen.
To conclude, I couldn't be more excited about the data and the potential impact of these findings for the field of lung cancer medicine and for patients in need. We are thrilled to have had the opportunity to present these results in the medical forum today, and I'm grateful to Dr. Johnson for all her support. For now, I'll hand it back over to Terry.
Thanks very much, Dimitri. With the current ARC-7 data set that Dimitri shared in hand, we, along with our advisors, are extremely excited about realizing the opportunity to further advance a potential novel IO backbone treatment for patients with PD-L1 high non-small cell lung cancer. While we did review the data on this call, we're also encouraged by the intriguing responses that Dr. Johnson presented today in the ASCO Plenary Session for patients who had progressed, confirmed progressers on ZIM monotherapy and crossed over to the triplet arm.
As Bilal will address, we and Gilead are progressing DOM plus ZIM across four phase III trials, including three in lung cancer settings, as well as phase II platform studies, all of which are addressing large patient populations with multi-billion dollar opportunities. Finally, I wanna thank the employees as well as the physicians and patients participating in our studies. We're looking forward to advancing our portfolio as efficiently as possible and to bringing improved treatment options to cancer patients worldwide. I'd now like to ask our collaborator, Bilal, to say a few words.
Thanks, Terry and Dimitri. First I want to acknowledge and extend our sincere appreciation and thanks to all the colleagues at Arcus and Gilead who worked tirelessly to get this important data set up. We are very pleased and excited to have this opportunity to share this important randomized data set and finish the year on a high note for our program, for TIGIT as a mechanism, and most importantly, for patients. Moving to slide 18, I want to take a moment to put ARC-7 trial into context. As Dimitri mentioned previously, ARC-7 is a prospectively randomized, phase II study evaluating two DOM-containing regimen against anti-PD-1 monotherapy in PD-L1 high metastatic non-small cell lung cancer.
The study was designed as phase II proof of a concept study to estimate safety and potential treatment benefit, rather than to conduct a formal statistical testing, and is not powered to show statistical significance. ARC-7 IA4 data give us full confidence in a joint DOM-ZIM clinical development program and the TIGIT pathway. We are excited by the efficacy results seen in both DOM-containing arm. Notably, both doublet and triplet combinations demonstrated clinically meaningful improvement in all efficacy measures compared to ZIM monotherapy. We are encouraged by the consistency of safety and efficacy data for DOM-containing arm across multiple analysis in the ARC-7 study. Anti-PD-1 monotherapy is the current preferred treatment option in first line PD-L1 high metastatic non-small cell lung cancer.
Although the point estimates of efficacy measure vary from trial to trial, even for the same anti-PD-1 antibody, the median PFS ranges from six to eight months. Basically, it means that more than 50% of the patient would have a disease progression or death within that time window. The observed median PFS of 11-12 months with DOM-containing doublet and triplet is quite remarkable and have not been seen with any anti-PD-1 monotherapy or anti-PD-1 in combination with chemotherapy in this patient population. As an oncologist, being able to tell advanced non-small cell lung cancer, lung cancer patients that they could potentially have more than 50% chance that they would not need a second-line treatment like chemotherapy for about a year is a remarkable advancement.
Of course, these data need to be confirmed with longer follow-up and in the ongoing phase III registration studies that we are planning. With respect to safety, we have seen low rate of infusion-related reaction in both DOM-containing arms. This compare favorably to rates observed with competitive TIGIT molecules. Based on the totality of the data seen to date, we are very confident that domvanalimab with the Fc-silent design has the potential to be differentiated compared to other anti-TIGIT molecules in this space. We are moving very quickly with our partners in both proof of concept studies as well as late-stage trials, including three ongoing phase III trials in non-small cell lung cancer. Our goal is to establish DOM-ZIM regimen as the IO backbone for combination with chemotherapy and other novel agents.
Before we open up for Q&A, I will move to slide 19 and briefly highlight a broad collaboration portfolio of Gilead and Arcus across the four assets. Notably, we are rapidly advancing and executing a large late-stage clinical program for DOM. We have three ongoing phase III studies targeting different indication and setting in advanced non-small cell lung cancer. ARC-10 will be a confirmatory study of ARC-7 data in the first-line PD-L1 high setting where ZIM and DOM will be compared to single agent pembro. STAR-121 is the first line PD-L1 all comer patient population where DOM plus ZIM plus chemo will be compared to pembro plus chemo. In PACIFIC-8, DOM in combination with durvalumab is being compared to durva alone in Stage III PD-L1 positive non-small cell lung cancer in post-chemo RT setting. This trial is being operationalized by AstraZeneca.
The proof of a concept data from ARC-7 IA4 that you saw today reassure our expectation and excitement from this important investment. These phase III trials are important pillars of our overall lung cancer strategy. In addition, we have initiated STAR-221, a phase III trial evaluating DOM plus ZIM plus chemo in first line gastric, GE junction, and esophageal adenocarcinoma. This study represent the first phase III trial of TIGIT combination in upper GI adenocarcinoma, an area of huge unmet medical need. DOM, ZIM and chemo will be compared to nivo plus chemo in STAR-221. All four of our phase III studies have standard of care anti-PD-1 and PD-L1 antibody in the active comparator arm to maximize the competitiveness of our data sets. Thanks to our partnership, we are maximizing the speed of execution to get these promising combinations to patients.
To summarize, ARC-7 IA4 results show a substantial and clinically meaningful ORR and PFS improvement. Excuse me. ORR and PFS improvement for our anti-TIGIT and anti-PD-1 combination over anti-PD-1 monotherapy in PD-L1 high advanced non-small cell lung cancer. We are excited to be working alongside Arcus to accelerate the development of this robust portfolio of molecule with the goal of substantially improving cancer outcome for patients. I'll turn it over to Jacquie Ross, GS Vice President of Investor Relations, to open our Q&A session.
Thank you, Bilal and our Arcus colleagues. As we move to Q&A, I am pleased to welcome Jen Jarrett from Arcus and Bill Grossman from Gilead to the panel, ready to address your questions. If you'd like to ask a question, there are two ways to do so. You can raise your virtual hand in Zoom, and I'll call on you to ask your question live. Or if you prefer, you can submit your question in the Q&A in the tool, and I can ask the question on your behalf.
Again, please raise your hand if you'd like to ask your question live or type and submit it through the Zoom Q&A tool. Please limit yourself to one question so we can accommodate as many analysts as possible on today's call. Just taking a look here. Our first question will come from Robyn Karnauskas from Truist. You need to unmute, Robyn, if you can.
Yes. Okay, thanks. Sorry. learning Zoom for the first time. So for some of us asking about how could ORR and PFS change over time given the median follow-up was around 11.8 months, how do you see that changing over time, especially given less frequent scans? Lastly, you mentioned specifically you're excited about the re-triplet. You remain excited. The presenter said the two arms will not look different. Are you seeing deeper responses with the triplet?
Yeah. Maybe I'll take the first question. you know, what you see here with the median PFS, median follow-up, about 10 months is, you know, clear separation of this curve. I mean, we're really encouraged by the median PFS that we're seeing with both doublet and triplet. I mean, I think median PFS of, you know, 12 to 11 months that you're seeing here is not something that you're seeing with any IO monotherapy trial in the past. I mean, the data is maturing. It's hard to predict and speculate where the numbers are going to go. Generally speaking, with the IO therapy, you know, the responses are durable, and these numbers tend to improve over a period of time. you know, we'll present the data when, you know, it matures.
Maybe I'll take the question about the triplet. Take a first shot at that. I think this is something we talked about actually at IA 3. Clearly both the doublet and the triplet individually are performing well beyond what we see with the monotherapy. It definitely at this point it's difficult to distinguish them, as you saw, you know, particularly when we talk about that PFS on the order of 11-12 months. What we've recognized is that we're looking to wait to see more mature and OS data sometime in 2023. With that said, today Dr. Melissa Johnson shared for the first time our data set on an initial 12 patients that yeah, were confirmed progressors on the monotherapy and then went on to the triplet.
We actually saw, while, you know, this is an exploratory data set, we saw intriguing, a couple of confirmed responses. That, again, is something that we'll both continue to monitor, as those data mature, as well as we have more patients that progress that go on to that therapy. That's something that we'll also update on, at ASCO in June.
Maybe I'll just add on. The only other thing to maybe comment on around the adenosine pathways is this is one of several proof of concept studies that we have ongoing evaluating the adenosine pathway. Obviously a tumor for this one, and we have also several proof of concept trials evaluating quemliclustat, the upstream CD73 small molecule inhibitors. We're looking forward to those data sets, you know, emerging over the next year to two.
Thank you. We'll go next to Umer Raffat from Evercore ISI. Umer, can you unmute please?
Thanks so much. It's actually Jon on for Umer due to a time zone difference here. I'd like to ask about the appropriate benchmark here, because KEYTRUDA trials have a really a wide range of ORR and PFS benchmarks depending on where you look. In your mind, what's the appropriate comp for ZIM monotherapy? At this point, how confident are you that ZIM is the strongest possible backbone for your TIGIT combos? Would you consider running combination studies on top of other PD-1s?
Well, thanks for the question, and maybe it's like [I] said, you really, you know, hit it on the nail here. As you said, I mean, that's why we do the randomized studies, right? I mean, that's why we randomize, particularly in our registration studies, to actually look at what the contemporary numbers are going to look at. If you look across the trial, you know, KEYTRUDA, you know, from KEYNOTE-024 to KEYNOTE-042 to KEYNOTE-598 to, you know, even recent data that GSK presented with the pembrolizumab in combination, the number varies quite significantly from that aspect. We're very confident with ZIM in a combination. As you know, ZIM is approved for Hodgkin disease in China.
You know, the data that we are seeing with monotherapy across the program, we've treated hundreds of patients with ZIM. It's, you know, it's pretty compatible with any other PD-1 in this setting. And, you know, very importantly, I mean, I think what's really important here to note, is that, you know, ZIM is in the both doublet and triplet arm. And the number that you saw from simplest arm is pretty impressive. You know, we are very confident. And, you know, phase III registration study, you know, in ARC-10 will be comparing ZIM and DOM directly to pembro. Hopefully that will definitely answer the question, as we move into it.
Just maybe add on to Bilal's comments again. You know, as both Melissa Johnson and Solange Peters mentioned too, that this ZIM is performing right in line. There's no discrepancy with what has recently been presented by Solange at SIO from where we'll data set too, and has highlighted the majority of these are community-based centers for ARC-7 as well. We have no doubt full confidence in ZIM as a part of the backbone, as Bilal mentioned.
We'll go next to Brian Abrahams at RBC. Brian?
Hey, thanks. It's Leo on for Brian, actually. Congrats on the data. I guess my question is, ARC-7 was run largely ex-U.S. Could you elaborate a little more on the geographic differences in patients and the diagnoses or the treatment paradigms? Or you know, the patient health that could account for the differences between your results and what some other trials have shown with TIGIT's and with ZIM's performance. I guess with the population shifting somewhat away from Asia-PACIFIC for ARC-10. You know, I guess, what are your expectations for how the population differences might affect the likelihood of success in that trial? Are there any adjustments you might make to either powering or comparator arms?
Maybe, I'll start it off, and Dimitri, obviously feel free to chime in on it. As you know, ARC-7 is a global trial, and I think just to answer to your question directly, I think ARC-10, again, is going to global trial. You're right that, you know, we have a little higher percentage of patient, with, from APAC region, in the ARC-7 compared to the other studies. Again, when we look at the subgroup analysis, I think the benefit is seen across all the groups. I'm not really concerned about that. I mean, to be very honest, as you know, Dr. Johnson and Dr. Peters discussed today, you know, ARC-7 really reflects what's really going on in the real world with what you expect to see from, you know, IO monotherapy.
I think, you know, we are very confident that, you know, what we see here in ARC-7 is going to be capitulated in the ARC-10. Okay. Also to note, I mean, you know, this is like a two-to-one randomization. I mean, you see the, you know, similar effect from both doublet and triplet, which actually reinforces, you know, our belief in the DOM moving forward. Dimitri, do you want to add anything on that?
Yeah, no, Sure. I can add a few things, right? To emphasize again, this is the important reason why we do the randomized trial, why we really focus on the comparison between the different arms and the different trials. I think, again, like we've made multiple comments about the comparability to real world data sets. Also if you look at other trials that move through different regions, there's difference in performances. We can speculate on what it is, there's many reasons behind it, between smoking history, perhaps histology, there could be genetic factors.
Most importantly, again, within the trial where you randomize, you really compare over the active standard of care. In ARC-10 we are comparing to pembrolizumab as active standard of care. With the, let's say, the performance of the doublets, both with the DOM-containing doublets, we really feel that the absolute readouts there for specifically the median PFS, let's say that gives us a lot of confidence in the chances of success for ARC-10.
Thank you. I'll go to the Q&A, chat. We have a question from Salveen Richter at Goldman Sachs. There's clearly impressive added benefit from TIGIT here, but the ORR for the doublet is lower than the 50% you previously guided to. What do you attribute this to? Did ZIM perform below expectations or did you expect even more benefit from TIGIT?
Yeah, I mean, again, we select, as mentioned, this is a phase II study, and I think it's a proof of a concept study. What we are really looking for is the delta that we see between the arms. I think, you know, the delta that we saw from both doublet and triplet is pretty much in line with what you'd expect from adding TIGIT over anti-PD-1. More importantly, I mean, you know, the PFS results that we are seeing here are, you know, are fairly impressive. You know, we're pretty happy with where we are. I mean, I, you know, could afford to Bill or Terry to add anything on, in term of, you know, prior expectations and stuff on it, but this data is, you know, proof of a concept for us to move into our registration studies.
Yeah. I think you covered it pretty well, Bilal. I mean, the gold standard here is again, randomization study, which we did for proof of concept. Then the consistencies with both DOM-containing arms is what's leading to our conviction here. You can see, as mentioned, but worth mentioning again, it's, you know, both the doublet and triplet are performing well above expectations for what you'd expect for a PD-1 monotherapy or even PD-1 plus chemo in this, in this population, when you look at recent data sets from both historical as well as contemporary, as mentioned.
You know, the one other thing I would add, Salveen, when you talk about sort of response rate, the way we look at all these is they're surrogate. You got response rate, then you have PFS. Ultimately, what you're looking for is that gold standard for approval, which is OS. Clearly, now we've moved into the realm of PFS being the big driver. What we would also note when you think about response rate, and how that translates, what you'll see in certain cases, and, you know, we'll see this in our study as well, is that you'll actually have patients that have stable disease that benefit enormously. In fact, you know, you might have someone that had a 25% reduction in tumor volume that's classified as stable disease.
You might have someone who's 35%, they're classified as a partial response. Now as you move into the realm of PFS, they both be maybe contributing and in fact, benefiting greatly from the therapy independent of just whether they were classified as a responder or not. Hence, the importance of the survival endpoints as the trial moves along.
Maybe just one other thing that I'd point out, going back to the patient populations, there was three areas of difference, particularly between the doublet arm and the monotherapy arm. First was age, where we had that median age of 69, which was higher than mono arm, probably higher than any PD-1 mono study you could find. The second thing was, percent of patients with squamous cell carcinoma. I don't know if you guys remember the data that Solange put up, but it showed that clearly patients with squamous cell carcinoma don't do as well as patients with that are non-squamous. It's a different amount a month in terms of PFS. 5.5 versus 4.5 based on the data that she put up there.
The third thing that I would highlight is the percent of patients that had greater than 75% PD-L1 expression was also lower in that doublet arm. You had less of the super high PD-L1 expressers in that arm.
Thank you. All right, let's find out who is playing the role of Peter Lawson at Barclays this afternoon. Peter?
Hey, thanks so much. Thanks for taking the questions. Just as we think about ARC-10, when do we get the initial readout around ARC-10? Does that give us a better idea of kind of the comparability of ZIM and pembro?
Yeah, maybe I'll take that and maybe have others coming on. You know, we announced recently that, you know, ARC-10 was redesigned and, you know, trying to compare ZIM plus DOM to pembro based on changing regulatory landscape and a standard of care. I think we'll provide some updates on the trial as we move along on this. The trial is up and running and accruing right now. You know, don't have specific dates for you at this point.
You know, I'll just comment. I think we. Again, we've seen a lot of data, as was, I think Dimitri highlighted in the, you know, in the discussion, that we, you know, whether it's at the molecular level, the characterization of the antibodies, whether it's, you know, in the clinic, you know, ZIM is approved as a monotherapy in China in CHL, compared very favorable to the data that you would see with pembro in that setting. In fact, just recently, a study described in cervical cancer where it even exceeds. We simply have no doubts about ZIM as an anti-PD-1. I think, you know, Solange also made that point in her presentation. Based upon everything that's, you know, already known, ZIM is performing just as you would expect any anti-PD-1 to perform.
Yeah. Terry, I just want to add one point here, too. I mean, you know, the point estimate that we are seeing here from ZIM monotherapy arm is within the 95% confidence interval of what you expect from anti-PD-1s to perform in this setting. I think we are pretty overall confident with the data that we are seeing here.
Great. We'll go next to Evan Seigerman at BMO. Evan, you need to unmute.
Evan playing Evan today.
Thank you.
Excellent. Thank you for taking the question. two questions from me. Do you need monotherapy data from ZIM to really get a DOM plus ZIM double approved? I can't help but to make the comparison and kind of, you know, square with KEYNOTE-024, how should I square away these response rates? I know I'm probably the fourth person asking the question a different way, but when I look at a 27% response rate versus high 40s from KEYNOTE-024, that's a big difference for me. I'm just trying to make sure I'm not interpreting this wrong and, you know, kind of figure out what to expect as we go forward. Thank you.
I'm not sure I hear the exact both questions, but I think the later part, I think you're trying to reconcile that 27% response rate a little bit.
Yeah.
Yeah, just to, you know, you know, probably just repeating myself a little bit here, you know, the point estimates, you know, of what we saw from ZIM monotherapy in ARC-7 is sort of like within the range. I mean, there are a couple of differences here. I think, and Jen mentioned a few of these, and I'm just gonna outline. You know, ARC-7 is done again in a predominantly in a community setting. You know, the enrollment on the trial is based on local PD-L1 results, you know, which is, you know, a little different than the initial, you know, pembro studies or other studies where you require central PD-L1 confirmation for patients to get on the trial.
I think there's, you know, a certain level of natural selection to try and get those patients on the study. Really to be noted, I mean, the initial registration trial, whether you look at atezo, cemiplimab or pembro, those are comparing IO to chemotherapy. I think there's a natural patient selection there. The patient will have to be fit enough to get, you know, chemotherapy to get on some of those trials. You know, with IO monotherapy approved now in first line setting, you know, many physicians in the community are putting a wider range of patients on these trials. I think some of these numbers erode and evolve over a period of time. I think that's something that Dr. Peters was alluding to today.
If you actually look at the real world data, I mean, what you're seeing here with ZIM is what you expect from a PD-1 monotherapy to perform in that setting. Again, I hope, you know, answer some of your concern on it. I think for me the most important thing is this is a randomized data set and, you know, what we are really seeing here from ZIM and DOM, in term of the, you know, progression-free survival that we're seeing here is not something that we're seeing with, you know, IO monotherapy in that setting, and we are really excited about it. Obviously these need to be confirmed in the phase III study.
Yeah, no, I can add a few things. It's something we also mentioned before, let's say the recent publication of the Taylor study, it's a GSK run study where pembrolizumab plus chemotherapy is the control arm, just like it was the experimental arm in KEYNOTE-189. That's a more contemporary trial that ran years later in different parts of the world. And the performance of pembro is shifting in that trial, closer to the real world data, as we also have alluded to. That gives us a lot of confidence. When you look at trials that were run five, six, seven years ago, patient selection was very different because the standard of care in those days was chemotherapy. As Bilal already mentioned, patients getting onto those trials had to be fit for chemotherapy.
In our trial, one of the things we noted, and I mentioned in my part of the presentation is the median age in our trial is older and older. It's probably a surrogate of the fact that patients who might not have gotten onto original trials earlier on because they were not eligible for chemotherapy, and now they are able to get onto the trial because there's no longer a chemotherapy control. The first part of your question was hard to understand. I think you were asking about ZIM as combination of the regimen and the approval. We would refer to that as the contribution of components discussion. We've generated a very large data set of ZIM, not just in this trial, of course, specifically in this population, but we treated more than 600 patients with ZIM.
We have large data sets in cervical cancer, in classical Hodgkin lymphoma. All of that data is used to, let's say, show the contribution of components, when we have discussions with the regulators. All our trial designs are discussed with the regulators before we start them to make sure they agree with our approach for approval.
Thank you.
Add on to what Dimitri said about the age of the patient population shifting. That's exactly what Solange Peters did also highlight in the real world data set from ESMO IO as well, you know, for the monotherapy PD-L1 high population and treatment. Just to reiterate, as most people get back from the health authorities, the primary endpoint for frontline non-small cell cancer is still OS in the end of the day, and we're taking on the standard of care in all of our studies.
We'll go next to the line of Zhiqiang Shu from Berenberg.
Great. Thanks very much for taking the questions. I have a two-part question. The first part of question is around the one of the points that the discussion raised around the need to change the standard when they can change the standard of care is, have a definition of the CD226 pathway biomarker. I just wanna hear from you some of the ongoing biomarker work that is being ongoing on ARC-7. The second part of the question is around for me, and PFS of 12 months in a doublet arm, is quite impressive relative to other PD-1 monotherapy. I guess we've been hearing some comparison of this number to a PD-1 chemo performance. I was wondering your thoughts on that comparison. Is it relevant at all in today's world? Thank you.
Yeah, maybe I will tackle your second question first, and then maybe we get to a biomarker question a little bit too. As you know, if you remember, I think last ASCO, I think, you know, FDA presented the data set looking at IO plus chemo versus IO and TPS more than 50%, you know, a setting. Basically, what it shows is it's both are pretty much the same when they look at things together. I think, you know, Dr. Peters today also show in her discussion that point. You know, yes, there's use of, you know, IO monotherapy as well as IO plus chemo in that setting. You know, majority of the use in this setting is, you know, IO monotherapy in that setting.
That's an acceptable standard of care, in that setting, you know, to design the trials. In terms of the biomarker question, maybe I'll hand it to Dimitri and Terry on it. I think there's extensive plan in ARC-7 to look at the biomarkers, and we'll report some of those, you know, as the data emerges in the future.
Yeah, I can say a few words. We are looking at TIGIT, CD226, CD155, CD73, and there's a number of other things, but those are the first things we'll be looking at, that will be part of the future presentation.
Just to go back to your point about looking at IO plus chemo as a comparison, one of the things that we're so interested about our data is, at least based on the data that we've generated here, you know, there's a possibility that we're even better than PD-1 plus chemo. There is a percentage of patients, as Bilal was referring to, that do receive PD-1 plus chemo, even in that PD-L1 high patient population, because they've got really aggressive disease. We didn't show the spider plots, but when investigators see the spider plots, that's one thing that catches their eye. There seems to be fewer rapid progressors.
Something that we've heard repeatedly from them is, you know, maybe there's a potential to capture that percentage of the patient population that has really aggressive disease and today would receive PD-1 plus chemo based on what we're seeing so far in our results.
Great. We'll go next to Mohit Bansal from Wells Fargo, please.
Hey, this is James Shin. I'm promoting. Thanks for taking our questions. During Dr. Peters's discussion, she showed ARC-7 sharing some of CITYSCAPE's positives and negatives. That said, is there anything from ARC-7 that gives you confidence that ARC-10 will not end up sharing SKYSCRAPER-01's outcome? Secondly, I think it's mentioned that as DOM moves into a larger phase III trial, there's likely to be some PFS erosion. Can you share how much PFS erosion you anticipate? I only ask this because CITYSCAPE seems to have a large PFS cushion, perhaps larger than ARC-7, yet it still missed in SKY-01.
Again, I still like seem to be taking these, but thanks for another question, and maybe I'll take. Like, you know, by design, ARC-7 and CITYSCAPE are different, right? I mean, CITYSCAPE was designed with TPS more than 1% and TPS more than 50% was a subset analysis in that. I mean, that's one select distinction here. I mean, ARC-7, you know, this is a prospective randomization, you know, in TPS more than 50% patient population. The other one, I mean, obviously, the sample size, which make us a lot more confidence. I mean, we are much larger, you know, compared to what you saw with the CITYSCAPE.
The third point for me is, you know, we have two arms here, doublet and triplet, which are independently evaluated, and I think the data looks pretty consistent on this. You know, that give us a lot more, you know, confidence in that setting. Again, as you know, I've been in oncology long enough. I mean, these erosions do happen phase III, but also, you know, if you appropriately conduct phase II, some of the data phase II can be recapitulated phase III. we saw that with some of the pembro data.
You know, a lot of the stuff in phase II get phase III and get it. I'm not gonna completely count on the fact that there's always going to be that erosion. I think it really depends on the sample size, how you conduct these trials, and we're pretty confident what we saw in ARC-7. I don't know, Bill, do you wanna chime on anything I've hit?
I would just add that, you know, SKYSCRAPER-01 is still not done, right? It's marching on towards OS endpoint, which is the primary endpoint required for approval in the setting. I know that the PFS in the first interim was a potential disappointment to some. They've as mentioned, have already, you know, they did mention they have a clear numerical enhancement, you know, with their addition of TIGIT. We'll have to wait and see how the rest of the study plays out.
You know, I'd just like to comment on the delta, because what you're talking about is comparing CITYSCAPE to SKY-01 . You're talking about comparing ARC-7 to ARC-10. I think at the highest level and the most simple answer is what was described, the fact that CITYSCAPE was a post hoc analysis, and then going to SKY-01 , whatever that outcome. To Bill's point, we don't really know the answer. The one thing that if we just take everything that Genentech says at face value, probably a quantitative difference. I think one of the key things to note is that they're such different experiments.
CITYSCAPE clearly pointed to the qualitative advantage of adding anti-TIGIT to anti-PD-1, and I think that's gonna be borne out time and time again. In going from CITYSCAPE to SKY-01 , it's a very different experiment. To expect them to be, you know, quantitatively in the same range is probably a stretch. Whereas ARC-7 to the points that were made here, in fact even the patient population very phase III light. It is a randomized prospective trial and looking very much like the design of ARC-10.
We feel very confident that you really couldn't have had a better progenitor to a phase III trial when you think across the landscape, not only with the two, the two arms that had, the DOM in them, but just the overall design, about as good as you can have in going from phase II to a phase III setting.
I'd like to add one more sort of commentary on that is, you know, we also have different TIGIT antibodies, right? That I think Jed covered it nicely in the presentation, that depending upon the target, how you wanna engineer the SC for a component of the antibodies. We'll see in our phase III trials and how that plays out too. We know that TIGIT, you know, expression is upregulated upon activation in T factor cells. As a reminder, we, you know, we had two antibodies that we've been watching the data emerge. You know, one is an Fc competent IgG1 wild type antibody, and DOM is the FC silent. As we've seen the DOM data continue to progress, we've taken that into the pivotal trials for a reason. We'll see how they play out.
We'll go to Matthew Harrison at Morgan Stanley. Matthew?
Great, thanks. Good afternoon. I guess just following sort of on the theme of some of the last questions, how does the outcome of SKYSCRAPER impact your view on the program? If it doesn't hit on OS, does that change your outlook at all, just given these data and how you think about investment in the program? Thanks.
Yeah, I'll answer this from the clinical development perspective and have others chime in on it. I mean, you know, we design a lot of these trials, you know, at risk because we believe in the pathway. I think the data that you're seeing today, from ARC-7 for ARC-7 really reassure us that the investment that we are making is the right one and that's gonna be important for the patients. I think for me, from the clinical development perspective, you know, really moving forward is really the execution to get these trials executed. Obviously, external landscape change. I mean, I've been a IO business for a while. I mean, if we all waited for CheckMate 026 to read out and change the law, that didn't happen. You know, each company's program is a little different.
There are subtleties within how things are conducted. At least for me from a clinical development perspective, I don't think those results will change. Obviously hope that those are positive, so that'd be good for the patients and believe in a pathway, we'll see how it play out.
Great. We'll go to Yigal Nochomovitz from Citi. Yigal?
Yeah. Hi. Thanks for taking the question. Just one on ARC-7 trial design. Obviously it was an open label trial. Just curious your thoughts on that. Some people are highlighting that to discount some of the findings, but actually I would argue the opposite, that since the triplet didn't behave better than the doublet, that result would seem to substantially limit criticism around inherent bias. Would you agree with that interpretation and any further elaboration with respect to the fact that ARC-7 was open label? Thanks.
Yeah, I can take this question. I think that there's always discussions about open label versus placebo controls. I think you really have to think about what is the ultimate thing you try to achieve with that. If there's a specific, let's say, idea about a, let's say a tolerability profile, safety issues, that is probably a very good reason to blind the trial. We did not have that. As we presented in the safety analysis, we're very confident about our safety profile with limited edit toxicity. If you look at, let's say, a registrational trial perspective, if you have an overall survival endpoint, there's really no, let's say no, let's say reason for efficacy bias to have a blinded trial. The other thing that's a consideration is the patient perspective.
If you actually have, let's say, multiple agents, you have to give the patients a placebo infusion, placebo tablets, so it does put a significant burden on the patient. Overall, I believe for every single trial you need to make a, let's say, an assessment. Is it really beneficial with the burden you put on the patients additionally? Do you get more of an unbiased answer out there? I think for the ARC-7 trial, that was definitely not the case. Something, a point we've made before, the fact that we have two experimental arms comparing to monotherapy gives us more confidence in the overall assessment. I hope that answers your question.
Great. We have just a few minutes left, we're gonna try and squeeze in a few more. We'll go next to Tyler Van Buren, please, at Cowen. Tyler?
Thanks very much, guys. For the STAR-121 study, can you discuss what gives you guys confidence in the study design which tests the DOM-ZIM chemo triplet versus pembro chemo, and particularly as we think about the contribution of DOM on top of PD-1 chemo in the lower PD-L1 expressing subgroups. I guess specifically, how much data do you have in the lower expressing patients, and did you do dose ranging with chemo?
Maybe I'll try to tackle this. I think the general belief now, and I think you heard from Dr. Peters today too is, you know, the way the T-cell is behaving is very, very similar to what the anti-PD-1s behave in the early days. I think one of the main reasons why we're trying to combine, you know, domzim together with the chemotherapy is really to broaden that, you know, patient population in the larger data set. As you know, we will generate some data. There are some ongoing platform study that we are looking at different, you know, combinations in this setting.
You know, based on what we have seen, so far, we're pretty confident that, you know, STAR-121 was designed, to, you know, definitely answer that question, in that setting. Particularly, I think, you know, as you know, the IO plus chemo is, you know, have a place in TPS less than 50% population, and it's an all-comer study. You know, yeah. I mean, I'd love to see what others want to add on it, but I think we are pretty confident in the study design, and we actually have interacted with the regulatory authorities to get to where we are.
Richard?
You know, I think that what's interesting is if you think about proof of concept, the biggest proof of concept that we have as a field is what we're talking about here in the frontline patient population. What the biology points to is really the way you want to think about this is anti-TIGIT is turning anti-PD-1 into super anti-PD-1. When you start to think about your proof of concept and what's the most logical biologically and hence clinically, going right down the line and going at that pushing the PD-L1 lower and doing that with chemo, but then bringing on what essentially becomes a single entity, that super anti-PD-1, that's anti-TIGIT plus anti-PD-1, is probably right down the middle of the fairway when you think about where you'd want to go next. We love that trial. It's a great trial.
It's going right directly at KEYTRUDA. We've got an arm in there where we'll have direct side-by-side data of ZIM chemo that we can look at qualitatively versus KEYTRUDA chemo. It's a great trial in terms of enrollment. It's a great option for patients. We think that's as exciting of a trial as we can really conceptualize on all fronts, clinically, market need, etc. It's a trial that we think is really well supported by the data that are out there.
Great. We're at the top of the hour, unfortunately. We'll take one last question from the chat. It is, "Can you discuss the depth of response over time from both the DOM combo arms?
Yeah, I can say a few things about that. I think looking at, let's say, the swim lane plug we provided, you can see, I would say an more area under the curve when you go from single to double to triplet, meaning, more tumor shrinkage for, let's say treatment, more intense treatment. One important thing that we've made before is about the dynamics of response. We know that for PD-1, response occur relatively fast, but it can take some time. We have seen in our study, as I highlighted, that 30% of our responders doesn't respond until the third scan. That gives us confidence that part of what we see is not only deepening of response, but also an additional, let's say timeline of response.
It's goes both ways because the other thing I mentioned, is that we see fewer primary progressions, something that is often seen with other treatments. When you intensify treatment, you have multiple mechanisms, acting on the tumor. You tend to see fewer primary progressions, which is a pretty, let's say, important finding as well. That means also, let's say a faster response for some patients. More importantly, primary progression is a very poor prognostic sign when patients primarily progress, on a treatment. It's really hard to give them any benefit from a subsequent treatment. I think these are all important observations in the trial, and hopefully it will, let's say, pan out to, let's say, provide, even more benefits, in the long run.
Super. Well, clearly we have more questions than we have time to cover. Please don't hesitate to reach out to Pia at Arcus or to the Gilead IR team if you have additional questions. Thank you all for taking the time, and we wish you a very happy holiday season. Good afternoon.
Thank you, everybody.