Gilead Sciences, Inc. (GILD) Earnings Call Transcript & Summary

Hello, everyone. My name is Marina Chiara Garassino. I am a Professor of Medicine at the University of Chicago, and I am the moderator for today's session. Joining with me are Dr. Jedd Wolchok, who will be the first speaker, and he will set the scene of the abstract. Dr. Melissa Johnson who is our abstract presenter; and Dr. Solange Peters, who will be our discussant. You have the possibility to submit questions by using the question submission form to the right of the presentation broadcast, and we will try to answer all your questions at the end of the session. The first speaker today is Dr. Jedd Wolchok. He is the Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell, and he will set the scene for the abstract #397600. The floor is yours.

Hello. I'd like to thank the organizers for the kind invitation to present at this session of the ASCO plenary series. My name is Jedd Wolchok, and I am here to give an introduction on immunotherapy. I'd like to thank Dr. Garassino for the kind introduction. As many of you know, immunotherapy has emerged as an additional pillar of standard anticancer treatment, and we are now aware that the answer to both of the central questions in the field, is there an immune response to cancer, and can that immune response and the immune system reject cancer. The answer is to both of these questions are yes, and that has allowed for some success in the use of the immune system to treat some cancers. But we are obviously interested in improving both the quality of responses as well as the number of people who respond to currently available immunotherapies. One of the central challenges in cancer immunology is the fundamental self-versus-nonself challenge. And that said, while the immune system is very capable of recognizing and responding to foreign infectious pathogens, some cancers represent more like self than nonself. And they may look very similar to the normal cell from which they arose. While other cancers, such as non-small cell lung cancer or melanoma or cancers in people with inherited deficiencies in mismatch repair, can be heavily mutated, and therefore, present potential neoepitopes because of the altered proteins resulting from those DNA mutations. Those altered proteins may make the cancer appear more like nonself. And so we consider cancer to be sort of an altered cells. And they've agreed to that alteration. As reflected in the tumor mutation burden is 1 feature that plays into the likelihood of immunotherapy being successful in that particular patient's cancer. This has been a very long journey from the time of William Coley and the late 1800s who first hypothesized that there was a connection between patients who had a postoperative wound infection and their cancer outcomes to today and in 2013, cancer was really -- cancer immunotherapy was first deemed a breakthrough of the year by science based upon papers and checkpoint blockade as well as CAR modified T cells. And so we've learned much in the past 10 or 15 years since the availability of truly effective immunotherapies. However, we need to turn the clock back a little bit further to the mid-1980s when Interleukin-2 was first identified as a growth and differentiating factor for T cells. And then employed in a series of clinical trials started at the National Cancer Institute by Dr. Steven Rosenberg. Eventually, melanoma and renal cell carcinoma were noted to be responsive in a small number of patients, the high dose Interleukin-2. And this data on the slide represent work from Michael Atkins, showing a pooled analysis of patients with metastatic melanoma treated with high dose IL-2. And even though the response rate is quite low, just 16%, there is a subpopulation of patients, maybe between 3% and 5% of patients, will have durable 10- to 20-plus years of disease control with high-dose Interleukin-2. So for me, I really believe that Interleukin-2 was the first example that when the immune system is directed toward cancer here through growth and differentiating agent for T cells, there can be control of an otherwise uniformly fatal malignancy. And the next great step forward really was the recognition that there were multiple co-inhibitory pathways which function normally to maintain immune homeostasis that could be perturbed as a way of treating cancer. The CTLA-4 pathway was the first of these recognized. It was noted to be inhibitory pathway by Jeff Bluestone and Jim Allison. Jim Allison then hypothesized that if you block this inhibitory pathway with an antibody, such as ipilimumab in this slide, you would allow for a more robust T cell response based upon the ability of CTLA-4 blockade to induce T cell proliferation and higher activity. CTLA-4, normally, under resting T cell conditions, exist in the cytoplasm. Once a T cell becomes activated as a result of antigen recognition and co-stimulation, CTLA-4 translocates into immune synapse where an outcompete CD28 for binding to co-stimulatory molecules, and begins to shut down the T cell. So by blocking CTLA-4 as a prototypical immune checkpoint, we can see that this higher degree of T cell activation could have a role in controlling cancer. Indeed, the success of CTLA-4 blockade in diseases like melanoma led to investigation of the PD-1 pathway as the next immune checkpoint. PD-1 was identified by Tasuku Honjo as being involved in programmed cell death of T cells. And then the work of Arlene Sharpe, Gordon Freeman and Lieping Chen, identified the PD-1 and PD-ligand-1 interaction as being critical to immune recognition and response to antigens on tumor cells. And so there have now been numerous agents that block the PD-1 pathway that have been approved for different cancers. Our group hypothesized that there could be additional activity when CTLA-4 blockade and PD-1 blockade were combined. This was based upon preclinical data from Alan Korman and Mark Selby and then from Jim Allison and Michael Curran in mouse models. And in human clinical trials, combined blockade of CTLA-4 and PD-1 led to quite high response rates in patients with metastatic melanoma in Phase I and Phase II studies. This led to the design and conduct of a global Phase III study, CheckMate 067, which looked at combined CTLA-4 plus PD-1 blockade, alongside the individual treatments in patients with advanced melanoma. The overall survival at last analysis published which was earlier in this year, which was with 6.5 years of minimum follow-up, showed that patients with metastatic melanoma who were treated, at first, with ipilimumab plus nivolumab had a median overall survival of just over 6 years. And a post-hoc analysis, this was actually higher when we looked at melanoma-specific survival. This is in comparison with nivolumab at 36.9 months and ipilimumab monotherapy at 19.9 months. However, combined checkpoint blockade does lead to additional toxicities. Nearly 60% of patients treated with CTLA-4 plus PD-1 blockade in the CheckMate 067 trial had a high-grade adverse event. Thankfully, very few of these were fatal. But this does represent a frequency of high-grade adverse events that's more than twice what we see with monotherapies. So the decision to use combination checkpoint blockade with ipilimumab and nivolumab is one that needs to undergo a careful and thoughtful discussion between patients and their families and their clinicians. So the results of many clinical trials and translational analyses using CTLA-4 and PD-1 blockade led us to hypothesize that there was a central dogma for cancer immunotherapy. The mutational landscape fuels baseline immune reactivity, primary immune evasion and adaptive resistance, restrained therapeutic immunity, and checkpoint blockade with CTLA-4 or PD-1 blocking drugs may disinhibit this baseline response to achieve regression. However, as you can see, even in melanoma, half of patients do not have a durable response. And so the above is subject to modulation by numerous factors, including suppressive T cells, T regs, suppressive myeloid cells, myeloid drug-suppressor cells, physical barriers to trafficking, deficiencies and antigen presentation and processing, a hostile microenvironment or insufficient co-stimulation. And these all form the basis for some additional steps. One of these steps was the use of an antibody that blocks another immune checkpoint, LAG-3, along with PD-1 blockade in patients with melanoma. This study termed RELATIVITY-047 was recently reported to be positive and was actually presented in a prior ASCO plenary series session by Professor Georgina Long. Now the primary endpoint in this study was progression-free survival by blinded independent review. And you can see that this was a positive study. Secondary endpoint, overall survival, not statistically significantly different. The safety summary, however, did show that as opposed to ipilimumab plus nivolumab, this combination had a lower frequency of high-grade treatment-related adverse events. So we now turn our attention to other mechanisms by which tumor cells may evade the immune response. And that brings us to today's presentation by Dr. Johnson. And so one of these pathways that can be considered for blockade is called the TIGIT pathway, and I will introduce that in a moment, as well as the production of adenosine in the tumor microenvironment, which also can lead to immune suppression. And so the TIGIT access is composed of interactions between TIGIT, CD226, CD96 and CD112 receptor. TIGIT, when it ligates, one of its ligands shown here, leads to an inhibition of signaling in the T-cell or NK cell. And so blockade of TIGIT with an antibody is another way in which the immune response to cancer could be augmented. A second mechanism, which was explored in the trial that you're going to hear about is the blockade of the adenosine receptor or the A2A receptor. And adenosine plays a major role as an immune-suppressing molecule. It has an effect on regulatory T cells, which leads to additional suppression coming from the T-reg onto the T effector cells. Adenosine can also have direct effects on T effector cells. And adenosine can, in addition, have effect on dendritic cells, which under some circumstances, can impair or augment the activity of T cells. And so adenosine is an agent that we are looking at very carefully in terms of how best to impair its role as an immune-suppressing molecule. One way is to block this receptor, which you'll hear about. Other ways are to block the production of adenosine by blocking some of the converting enzymes, CD39 or CD73, which can be found in the tumor microenvironment. So I'd like to finish up there, and thanks again for the presentation, and I look forward to hearing about the data.

It's my great pleasure now to introduce Dr. Melissa Johnson. Dr. Johnson is the Program Director of the Lung Cancer Research at the Sarah Cannon Cancer Center in Nashville, and she will be the presenter of the today's abstract. Please.

I'd like to thank the ASCO Plenary Series leadership and the non-small cell lung cancer track for the opportunity to present our data. On behalf of my co-authors, it's my pleasure to present ARC-7, a randomized Phase II study of domvanalimab and zimberelimab with or without etrumadenant versus zimberelimab in first-line metastatic PD-L1-high non-small cell lung cancer. The introduction of PD-1 inhibitors has revolutionized treatment and dramatically improved outcomes for patients with PD-L1-high non-small cell lung cancer. However, fewer than half of these patients achieved long-term benefit to monotherapy with anti-PD-1. Recent data suggests that targeting additional nonoverlapping immune checkpoints and immunosuppressive pathways in combination with PD-1 inhibition may provide further clinical benefit to these patients. ARC-7 is a randomized Phase II study, evaluating whether the addition of domvanalimab, a monoclonal antibody targeting the T cell immunoglobulin and ITIM domain, also known as the TIGIT receptor; and etrumadenant, a selective adenosine receptor antagonist, can augment the activity of the anti-PD-1 antibody zimberelimab in patients with PD-L1-high metastatic non-small cell lung cancer. Today, I will present the safety and efficacy results of ARC-7 from our most recent interim analysis, the first to include both objective response rate and PFS. The 3 investigational therapies examined in ARC-7 each target a distinct molecular pathway. The monoclonal antibody zimberelimab or ZIM, targets PD-1 on lymphoid cells, blocking PD-L1-mediated immunosuppressive effects. Previous work has demonstrated ZIM activity in multiple tumor types, including non-small cell lung cancer, and ZIM is approved for the treatment of classic Hodgkin's lymphoma in China. The monoclonal antibody domvanalimab or DOM, targets the TIGIT receptor on T cells to prevent its binding to CD155 on tumor and antigen-presenting cells. Notably, DOM is an Fc-silent antibody that does not stimulate ADCC-mediated destruction of TIGIT-positive immune cells. Finally, etrumadenant or etruma, is a small molecule dual antagonist of the A2A and A2B receptors, designed to block the effects of extracellular adenosine on both lymphoid and myeloid cells. Both DOM and etruma achieved full target receptor occupancy at the doses investigated in ARC-7. ARC-7 is a randomized open-label Phase II study of patients with metastatic PD-L1-high non-small cell lung cancer. Patients were treatment naive for metastatic disease, and were eGFR and ALK negative. PD-L1 was tested locally by 22C3 or SP263 PD-L1 assays. A total of 150 patients were randomized equally to 1 of 3 treatment arms: Arm 1, ZIM monotherapy; Arm 2, the doublet, DOM plus ZIM; or Arm 3, the triple combination of etruma, DOM and ZIM. Primary endpoints were overall response rate and progression-free survival. Patients received efficacy scans every 6 weeks for the first 6 months. Scanning intervals were extended to every 9 to 12 weeks thereafter. Of note, patients initially randomized to ZIM monotherapy were given the option to cross over to triplet combination therapy upon radiographic confirmation of progressive disease. As of the data cutoff of August 31, 2022, the median follow-up time was 11.8 months. From May 2020 to August 2022, 207 patients were screened across 7 countries in Asia Pacific and North America, primarily at nonacademic centers. 150 patients were randomized and included in the ITT population. Of note, 1 patient was improperly randomized to Arm 2 and subsequently deemed ineligible for treatment. This patient is included in the ITT population, but not in the safety population, the latter being defined as patients who received at least 1 dose of study drug. The efficacy data presented today will include a modified ITT population of 133 patients, the ITT 13. This population includes those patients randomized before June 1, ensuring at least 13 weeks follow-up. At the time of our data cut, roughly half of the patients in both DOM-containing arms remained on study treatment, compared to 28% of patients randomized to ZIM monotherapy. In the ITT population, the median age was 68, and approximately half the patients were of Asian descent. The vast majority were past or current smokers and had an ECOG performance status of 1 at baseline. Roughly 1/3 of patients in both DOM-containing treatment arms had squamous lung cancer compared to slightly fewer 18% of patients assigned to ZIM monotherapy. All patients were considered PD-L1 high with a median of 70% to 80% of tumor cells staining positive for PD-L1. Following treatment, higher confirmed objective responses were seen in both DOM-containing treatment arms compared to ZIM monotherapy. Overall response rates were 41% and 40% in Arms 2 and 3 respectively, versus 27% in Arm 1. 3 additional patients in Arm 3 have had a response on treatment and are awaiting confirmatory scans. The improved response rates seen in the DOM-containing arms are consistent across multiple subgroup analyses, including PD-L1 status, tobacco use history, race and disease histology. This slide shows a swimmer's plot, including all ITT 13 patients. Patients treated in Arm 1, ZIM monotherapy in red; patients treated in Arm 2 DOM plus ZIM combination in blue; and Arm 3, etruma, DOM and ZIM in green. 31 patients with partial response remain on treatment, and another 14 patients with stable disease also remain in active treatment. Across all treatment arms, the time to initial response ranged from 1.2 to 14.6 months, scored as orange triangles for partial response and purple boxes for stable disease. Notably, there are additional delayed responses in the DOM-containing arms observed, as late as 14 months after initiating treatment. The median duration of response has not yet been reached in any arm. This slide shows the Kaplan-Meier curve estimating PFS across the 3 arms. There was early separation of the Kaplan-Meier curves as demonstrated by 6-month progression-free survival rates of 43% in Arm 1; 65% in Arm 2; and 63% in Arm 3. The median PFS was 5.4 months in Arm 1; 12 months in Arm 2; and 10.9 months in Arm 3. And there was a reduction in probability of progression or death of 45% and 35% for Arms 2 and 3, respectively, relative to ZIM monotherapy. In the safety population, the proportion of patients who experience treatment-emergent adverse events was broadly similar across the treatment arms with the majority of patients experiencing at least 1 AE during treatment. The most common AEs across all arms were fatigue, nausea, constipation, dyspnea, decreased appetite and pneumonia. The frequency of Grade III or higher adverse events was similar across treatment arms, with the most common events reported being pneumonia and anemia at 8.7% and 5.4%, respectively. The rate of AEs leading to study discontinuation was 28% in Arm 1, but less 16% and 20% in the combination arms. Approximately half of patients in Arm 1 and 2 experienced at least 1 immune-related AE compared to 60% of patients in the etruma-containing triplet with the difference primarily driven by low-grade rash. Importantly, the rate of infusion-related reactions remained low across all arms even in the addition of -- even with the addition of DOM. Four fatal adverse events considered related to study treatment were reported. One case of interstitial lung disease in Arm 1; 1 case of myocarditis in Arm 2; 1 case each of pneumonitis and congestive heart failure in Arm 3. Median treatment duration was 9.8, 21 and 24 weeks in Arm 1, 2 and 3, respectively. The most common immune-related AEs are shown here. Pneumonitis was reported at similar frequencies across treatment arms ranging from 8% in Arm 2 to 14% in Arm 1. Most pneumonitis events were Grade I or II. There was no clear increase in the rates of pneumonitis or any other immune-related adverse events in the DOM-containing arms compared to ZIM monotherapy. Incidence of rash was consistent between Arms 1 and 2. However, events were more commonly observed in the etruma-containing arm. All cases of rash were Grade I and II and most resolved with topical corticosteroids. No cases of rash led to treatment discontinuation. As previously mentioned, patients with confirmed progressive disease initially randomized to Arm 1 had the option to cross over to receive triple combination therapy. 12 patients from Arm 1 had crossed over to treatment with etruma, DOM and ZIM. These patients are shown in the spider plot. At the time of our data cutoff, 5 of these patients remain on crossover treatment. Of these 12 patients, 2 or 17% had confirmed partial responses. Crossover patients exhibited a safety profile roughly similar to that of the larger study group, 3 Grade III, and 4 adverse events and 2 serious adverse events were reported. None of these were Grade V. In conclusion, in this interim analysis of the first and largest randomized data set evaluating the Fc-silent TIGIT monoclonal antibody and adenosine receptor antagonist in combination with an anti-PD-1 therapy, data from ARC-7 demonstrated the addition of DOM results in improved objective response rates and progression-free survival as compared with ZIM monotherapy. Patients in combination treatment arms, including anti-TIGIT, experienced an approximately 13% improvement in overall response rate compared to ZIM alone, and approximately 40% reduction in risk of progression or death compared to anti-PD-1 alone, with an improvement in landmark 6-month and median progression-free survival. The clinical activity and safety of ZIM was consistent with that expected of agents in the anti-PD-1 class, and treatment with ZIM, DOM and etruma was well tolerated with similar safety profiles across treatment arms. Low rates of infusion-related reactions were observed as intended with the Fc-silent design of DOM. These data also provide support for further development of DOM and ZIM combinations, including the Phase III studies ARC-10, STAR-121 and PACIFIC-8, all of which are currently ongoing in patients with advanced non-small cell lung cancer. Finally, I'd like to thank our patients, their caregivers, all the investigators and their study staff who participated in the ARC-7 study. I'd like to wish you all a happy and healthy holiday season. This study was sponsored by Arcus Biosciences in collaboration with Gilead Sciences. Thank you.

It's my great pleasure now to introduce Dr. Solange Peters. Dr. Solange Peters is a friend, and she is the Chair of the Medical Oncology at the Lausanne University. She is the President of ESMO, and she will give her discussant presentation.

I would like to thank the organizers for inviting me to discuss this interesting ARC-7 trial. My discussion is titled the promises of targeting TIGIT. Targeting in checkpoints has changed the cancer treatment paradigm with a series of anti-PD-1, anti-PD-L1 compounds having been registered in the last 10 years across a very large number of diverse cancer indications. This is the current algorithm of non-small cell lung cancer treatment landscape in metastatic disease frontline. And as you can see, it's now a must to have immune checkpoints being proposed to the patient frontline being as monotherapy or in combination with chemotherapy, maybe with the exception of the never-smoker oncogene addiction -- addicted non-small lung cancer patients. But all the other ones received checkpoints, monotherapy or combined with chemo. And today, we discuss this monotherapy paradigm, which can be offered in patients with a high T cell exhaustion, a very high PD-L1 expression of more than 50% of the tumor cells expressing PD-L1 where anti-PD-1 or anti-PD-L1 are standard of care. These are the curves on the left-hand side. You have the pembrolizumab in more than 50% PD-L1 against chemotherapy. We had 5 years follow-up in that trial. On the right-hand side, cemiplimab versus chemotherapy. It's a trial dedicated to patients with a smoking history. And on the left-hand side, down the slide, the atezolizumab and anti-PD-L1. Here's the biomarker assessment. It's slightly different, potentially changing a little bit the magnitude of benefit, but still all these 3 trials show very super impossible benefit of monotherapy, I-O over chemo. We had the opportunity to do a real-world data assessment to try to see and to analyze if monotherapy is sufficient or in combination with chemo would be better. And as you can see, in terms of survival or progression-free survival, monotherapy performed as well as combination with chemo in high PD-L1 regardless of the presence of brain mets or of the presence of liver mets. Why we need to rethink what cell lung cancer treatment is due to the fact that on the left-hand side, even looking at biomarkers, at least 1 patient out of 5 will have progressive disease as the best response on the monotherapy I-O in high PD-L1 expression. On the right-hand side, it's also because we have to face this unmet need of addressing immune checkpoint resistance. This acquired resistance, but initially, you have a response, and later down the road, a progression of the disease. All of this represents potential opportunities for improvement of our treatment strategies. TIGIT is part of a complex signaling pathway for the immune response. TIGIT is an inhibitory receptor expressed on multiple immune cells, including T cells and NK cells. And basically TIGIT prevents CD8-positive T-cell activation. Initially, in the beginning, we saw TIGIT's expression was correlated with PD-L1 expression. However, this was not confirmed later on. This is a very simple graph we started to use in the beginning, trying to explain the TIGIT pathway. Unfortunately, the reality is different. It's way more complex with basically 4 receptors, regulatory receptors, being expressed on T cell or on NK cells. It's still quite difficult to exactly decipher the component, which is important on the T cells versus NK cells. But 4 important receptors on these cells and 2 important receptors on the tumor cells regulating this pathway. Here is the study is here also for the nomenclature because what is very important is, over time, across various studies and preclinical studies, there has been different names being used for each of this protein. Maybe you should go back to this graph at some point. But basically, the pathway is this one. CD226 will interact mainly with CD155 on the tumor cells, also with CD112 to a lesser extent, and this interaction will activate the T cell and the NK cells with the immune response and in the killing of the tumor cells. Thinking about this activating pathway, there are inhibitory protein -- inhibitor proteins. TIGIT will inhibit the interaction of CD226 with both CD155 and CD112. PVRIG will inhibit the interaction with CD112, and CD96 will inhibit the interaction with CD155. So apart from TIGIT, at least 2 other inhibitory proteins have to be found, and there are 2 targets on the tumor cells. So that's quite important to imagine that anti-TIGIT is one of the way to reactivate the interaction of CD226 with CD155. The other important point to keep in mind, it's probable that TIGIT is also expressed on T-reg cells. So you have here a mechanism of ADCC, antibody-directed cell cytotoxicity, which would potentially be related to anti-TIGIT monoclonal antibody resulting in the depletion of T-reg sales. Last, but not least, why do we think there is a synergy between PD-1 signaling and TIGIT? So basically, this has been shown that PD-1 signaling, when it binds to PD-L1, results in [indiscernible] and deactivation of CD226 via [ SAC homology 2 -- domain SHIP2 ], which, of course, is another way to inhibit interaction of CD226 with CD155. So a kind of a potential other way to inhibit cancer cell killing. Last, but not least, there are currently kind of a crazy landscape of more than 30 anti-TIGIT monoclonal antibody in development in Phase I, in Phase II, in Phase III with inactive or active Fc region across TIGIT types and many of them being developed in non-small lung cancer. Importantly, in Phase I study, using an anti-TIGIT in monotherapy was resulting in a very low response rate, 0% to 5%, and this was also the case in preclinical studies. Speaking just 2 minutes about the adenosine pathway. The adenosine pathway is about the production of adenosine in proangiogenic niches within the tumor, which is strongly immunosuppressive. The production of adenosine is related to the 2 nucleotides CD39 and CD73. And we also have very important receptors for the adenosine, the A2A receptor, anti-effector cells and dendritic cells, which will be inhibited once the adenosine is binding. It was shown, for example, that high CD73 expression is associated with poor prognosis, which makes sense in that disease. The adenosine pathway is also interestingly upregulated at PD-L1 resistance, and has also been shown to be upregulated overexpressed in eGFR-mutated non-small cell lung cancer. We had early data showing a signal of activity in advance and recently in early non-small cell lung cancer of adenosine pathway inhibition combined with PD-1 or PD-L1 blockades. This is the closed trial, which is consolidation after radio-chemotherapy for radical treatment or locally advanced non-small cell lung cancer. But as you can see, the combination of durvalumab plus the entire CD73 oleclumab was resulting in a very strong improvement of PFS as compared to the standard durvalumab monotherapy, really paving the way of potential adenosine inhibition in lung cancer. And on the right-hand side, we have the list of anti-CD73, anti-CD39 and A2A receptor antagonist being today being developed across diseases, including lung cancer. What do we know about TIGIT inhibition in lung cancer? So the landmark trial is CITYSCAPE. CITYSCAPE is a Phase II randomized double-blinded trial, comparing an anti-TIGIT, tiragolumab plus atezolizumab, an anti-PD-L1, to placebo and atezolizumab. It was for naive patients from any treatment, metastatic disease. These patients were stratified according to PD-L1. It was only positive PD-L1, but stratified to 1% to 49% or more than 50%. Histology and tobacco use and co-primary endpoint was response rate and PFS. The intent-to-treat population graph is on the left. Response rate is 37%; hazard ratio 0.69, in favor of the tiragolumab arm. But the most interesting graph is on the right where you can see that all the benefit is driven by more than 50% PD-L1, the high PD-L1, with a response rate of 66% and the absence of benefit in PFS in the patients with 1% to 49% PD-L1. So really kind of a cluster of patients being high PD-L1 benefiting from -- from -- sorry, from TIGIT inhibition. Importantly, this combination is safe. But there was a doubling of low grade, Grade I and II rash up to 40% and infusion-related reaction up to 30% to be kept in mind. We try to look at biomarkers in CITYSCAPE beyond the PD-L1, so more than 50% PD-L1. We looked at TIGIT immunohistochemistry using a threshold, which was more or less above and under the median expression of TIGIT. And this was not playing a role as being a predictive biomarker of anti-TIGIT strategy. And it was not correlated with PD-1 expression. And on the right-hand side, we looked at PVR. Remember the nomenclature, PVR is CD155. The PVR expression was not correlated with any signs of predictive ability for TIGIT efficacy in that trial. Maybe this is the very early attempts, and the accuracy of testing and the thresholds used were not the good one. I mean, maybe we can work a bit more on these biomarkers, but today, we can't do anything with them. Maybe also, we are doing an incomplete evaluation of the very redundant CD226 pathway, as you have understood in the first slide. SKYSCRAPER-1 is a Phase III trial following CITYSCAPE. Same strategy, tiragolumab, atezolizumab versus placebo and atezolizumab, 2 co-primary endpoints, overall survival and PFS, patients stratified by performance status, histology and region. And as you have probably seen, there is a press release telling that the PFS is one of the core primary endpoint, was not met. However, we are still waiting for the overall survival. And the numerical improvement was stated and was confirmed to be observed in both co-primary endpoints. We still wait, are waiting, expecting to see this data and understand better the magnitude of benefits due to the tiragolumab in that trial. We also have the vibostolimab from Merck, which was combined with pembrolizumab in I-O-naive patients, again, with some signal of activity and a response rate of more or less 30%, slightly higher in positive PD-L1 patients with the PFS also being higher in positive PD-1 patients. You can see in the waterfall plot which conducts now, which leads to the conduct of a randomized trial using also vibostolimab in combination with pembrolizumab in non-small cell lung cancer. The current data today are in line with the previous I have been showing. We have 3 drugs being used. First of all, the zimberelimab, the ZIM. It is part of the China's 6 approved homegrown anti-PD-1 monoclonal antibody. You have all the names on this slide in order for you to recognize them in the future. Domvanalimab is an anti-TIGIT monoclonal antibody. It's one among few anti-TIGIT harboring an inactive Fc as an important feature of this monoclonal antibody. And the etrumadenant, the etruma, is an A2A receptor inhibitor, which has shown signals of activity in early Phase I trial. It is now being explored in multiple combination indications, including colorectal, but also lung and metastatic prostate cancer. The ARC-7 trial has a very simple design. It is an open-label that time, an open-label Phase II trial, randomizing patients with the high PD-L1 expression more than 50% of the tumor cell expressing PD-L1, with a test done locally or essentially using standard assays 263 or 22C3. Of course, not oncogene-addictive. [ Six ] patients are randomized 1:1:1 to the anti-PD-1 ZIM to the anti-PD-1 plus anti-TIGIT DOM plus ZIM; or the triple therapy, etruma, the adenosine inhibition, plus the other 2 drugs. The co-primary endpoints are response rate and PFS by RECIST 1.1. So basically, we have to keep in mind that the study was designed to estimate potential treatment benefits and to evaluate safety rather than to conduct formal statistical hypothesis testing. Thus, neither comparison between arms nor statistical significance can be concluded from this study. And please keep it in mind, the pro of such a trial design is that the randomized nature of the study, all but we saw small numbers, is addressing the selection bias. The contra, the cons of having such a design is that the sample size is not based on statistical design considerations, such as usually pre-specified Type 1 error or the power. There were multiple interim analysis, 3 for response rate and 1 for PFS, but again, without any adjustments in Type 1 error. And overall response rate and PFS are called co-primary endpoints. However, they are also reported equally. However, without any adjustments in Type 1 error. So please keep this consideration in mind before making final decisions about this trial. These are the results of the ARC-7 trial where you can see here the progression-free survival curve, which shows the benefit of adding TIGIT. Adding TIGIT alone always the adenosine inhibitor as compared to the monotherapy of anti-PD-1 with a hazard ratio of more or less 0.5. Very striking difference. You can also see the response rate going from monotherapy, 27%, to double or triple therapy arms -- ranging the response rate up to 40%. This is to be compared with the CITYSCAPE trial, where you can see again the curves here and the response rate and basically with the conclusion that the results are very similar to the CITYSCAPE. CITYSCAPE was highly criticized in the past because of the standard arm PFS of 4.9 months, while in IMpower110, the Phase III randomized trial is the standard arm of atezolizumab had 8.2 months for the double PFS. So just rethinking, the standard arm performance maybe underperforming. Here, in the ARC-7 trial, we have 5.4. So again, quite a low PFS. So on the question of the next time it what does it mean the control arm PFS. A control-arm PFS is reflecting how the trial contract is made, meaning about patient selection, but also how and when the time and the place, depending on the environment where the trial is conducted. And I like these 2 trials are real-world data, about high-PD-L1 more than 50% monotherapy checkpoints. And please look at the number. In non-squamous, 5.4 months; in squamous, 4.9 months; and across histology, 5.8 months. So real-world data presented at the ESMO I-O confirmed that today, this is what has to be expected for a standard arm, and there is no discrepancy in ARC-7 here. Let's look at the safety profile. Interestingly, keep in mind the CITYSCAPE. There was in the trial, first of all, no increased rate in pneumonitis, in the TIGIT-containing arm compared to monotherapy anti-PD-1. The rash in maculopapular rash were reported to be greater in the triple therapy arm, but not in the TIGIT anti-PD-1 arm. So nothing comparable to the CITYSCAPE. And there was no increase in infusion-related reaction like in CITYSCAPE. So my question to you is, is this Fc inactivation potentially reducing toxicity? But obviously, without a very measurable reduction in activity, so that might be the interest. What about adding an adenosine pathway inhibitor? So first of all, there is no preclinical or clinical data showing an addictive or synergistic effect of adenosine and TIGIT, right? There are very scaled data in AML, but nothing really relevant. In that trial, we couldn't see any benefit of adding the adenosine pathway inhibitor, and it's very probable it will change over time based on simulation. However, what was nicely shown in the trial that allowed crossover, a switch to the triple therapy for the patient in the anti-PD-1 arm. And switching to an adenosine inhibitor or switching to a TIGIT inhibitor always combined with an anti-PD-1 or anti-PD-L1, results, at least in that trial and in the hand of MSG on the right-hand side to -- result in some stabilization of the disease [indiscernible] with strong stabilization. And this will be tested for adenosine plus anti-PD-1 or TIGIT plus anti-PD-1 at resistance in ongoing Phase III trial. There might be potentially a way to be better than chemotherapy in second line. So first of all, I think we have all the background to understand why TIGIT is interesting. And at the latest point, we need to see how much the landscape is big. You can see here all the TIGIT inhibitors having an active or inactive Fc to be combined with a backbone of anti-PD-1, anti-PD-L1, various compounds are being used, compared with a placebo controlled or a chemotherapy combination arm in the various disease setting, early disease, in various strata of PD-L1 expression. So all of these trials are currently ongoing. They are all Phase II and III trials in non-small cell lung cancer. An interesting and [indiscernible] combination, trying to complete the blockade of the CD226 pathway, or even combining with anti-angiogenic are ongoing and will give us better insight in the future about how to handle TIGIT. This is a table I invite you to go through quietly of ongoing phase -- ongoing trials using anti-TIGIT in non-small cell lung cancer. You can see Phase I, Phase II and Phase III trials across many clinical scenarios, lines of treatment, and using various combinations, and really showing that we will have more answers and questions in the next months to come. In conclusion, blocking TIGIT consistently demonstrates activity in combination with the backbone of anti-PD-1 or anti-PD-L1 blockade in advanced non-small cell lung cancer. A large number of compounds are in development with ongoing adequately powered and controlled Phase III trials. Some are currently on hold, [indiscernible] overall survival data to reach. A meaningful magnitude of benefit will be needed to change our standards. It is a very, very busy thought. And this meaningful magnitude of benefit will require. First of all, an adequate trial design. Second, I'm convinced it will require the definition of CD226 pathway-related biomarkers. And in accident, it is ongoing with the immunohistochemistry to quantify levels of TIGIT, CD226, CD155 and CD73 being performed on the samples of the ARC-7 non-small cell lung cancer patients. We also will potentially need innovative combinatorial strategies in order to increase the activity and enlarge to target patient population in advanced non-small cell lung cancer. And last but not -- last but not least, I would like to let you with this open question about this trial, about the next one to come. What do you think means and is a meaningful benefit at the era of growing health care systems limitations globally. And this is, I would say, the food for reflection in the whole community of cancer professionals. And with this, I'd like to thank Melissa Johnson as well as Arcus company for answering my 100 questions over time. And more importantly, I would like to thank you all for your wonderful attention.

Nice presentations. I would like to congratulate with all the 3 presenters for the outstanding presentations. I'm sure that we will call forever DOM, ZIM and etruma because they have names that are impossible to be pronounced. And I would like also to thank all the people who sent a lot of questions in the chat.

So I will start to torture Dr. Johnson now. So the first question is, is the ITT 13 prespecified? Or is just an exploratory analysis?

Thanks, Marina. Thanks for that question. Thanks to all of those of you in the chat asking that question. So just to say from the outset, ARC-7 was designed to estimate treatment benefits and evaluate safety, but there was no formal statistical testing or hypothesis. And so the initial 3 looks were all resulted in qualitative press releases, but no data was presented. This is the first presentation of quantitative data. And it includes both a look at response rate and PFS. And to answer the question, yes, it was prespecified. It coincides with the ITT population -- ITT 13 population, where all the patients that were included, 133 of the 150, had at least 13 weeks follow-up. So 2 coincidence scans. So their response could be confirmed. So that's the reason that the population is 133.

And clearly, there are some people that are asking results about the overall survival. If you can comment if there are -- how -- about the maturity of the overall survival and how many deaths on each study in each arm? I don't know if you can comment on that. Maybe it's really too early.

The median PFS is about 50% mature right now. So the overall survival is still quite immature. So stay tuned.

So there is another question that was very reported, and is also my question. Discontinuation rate seems very high. How was duration of treatment adjudicated when there was a treatment discontinuation or progression?

Yes. So the short answer is that in this trial, the -- there was no adjudication committee for pneumonitis, for example. But anything that was scored as an adverse event due to toxicity, the patient was scored and censored, and it was included in the nominator, but not in the response rate -- numerator. The discontinuation rates were a little higher, but surprisingly, they were highest in the ZIM monotherapy arm. And so I guess if there's 1 silver lining to the adverse event rates we saw, it didn't increase with the addition of the DOM or the DOM and the etruma, which is what we saw in the first presentation from Dr. Wolchok and also from Professor Peters with the addition of added checkpoints. So I think we're left to conclude that this was -- there were still only 50 patients per arm, each patient equaling about 2%. And so it may be just the statistical noise, if you will, as to why ZIM monotherapy was -- the adverse event rate was higher and the discontinuation rate higher. Across the whole ZIM program, and of course, ZIM has been approved for Hodgkin's lymphoma in China, plus there's data in cervical cancer, plus all of the non-small cell lung cancer data to date, the safety profile looks the same as other PD-1 agents.

Okay. And there is another question, which is about the cytokine-related syndrome that was recently added as another endpoint to the SKYSCRAPER-1. What is the content for this? And is it common for TIGIT monoclonal antibodies?

Well, that is a good question. The -- in SKYSCRAPER-1, and in particular, in CITYSCAPE that came before it, one of the most common adverse events were infusion-related reactions and we attributed those to the addition of the TIGIT and the Fc-active antibody to the PD-L1 atezolizumab. Now in this trial, the dumvalumab was Fc-silent. And so notably, infusion reactions were quite seldomly seen. So it's an interesting -- it's interesting enough note and cytokine release wasn't something that we saw much in this trial, ARC-7.

There is another question. Does ITT 13 remove the patients who progressed? Let me check. It's difficult to follow the questions here -- remove who progressed prior to 13 weeks?

No. They were scored and included. And in particular, it also -- yes, they were scored. They were included.

Okay. And there is another question. Is the response rate and PFS investigator assessed? Or just that there was an independent review?

No, this -- to Professor Peters' point, this is a real-world data set, and investigators did assess response rate and PFS.

Okay. And I ask something also to Dr. Wolchok. There is a question on, do you expect any impact of LKB1, KEAP1 on the adenosine pathway and also TIGIT? They are genes -- onco-suppressor gene, very frequent in lung cancer, and they are characterized by a very low response to immunotherapy. I'm not sure that we can answer.

Yes, it's a great question. I don't think that we have that information, at least I don't right now. But I think given the knowledge about that particular subset of non-small cell lung cancer, it would be pretty straightforward to evaluate whether there is a higher or lower level of TIGIT or adenosine access members present.

And there is another question again for Melissa. Were there imbalances in PD-L1 such as very high 75% to 90%? Or the same for the never-smokers between arms can justify the results, in particular, in ZIM and in ZIM and DOM?

Yes. That's a good question. So remember, all patients were PD-L1-high that were enrolled in the study. And the median PD-L1 ranged from 70% to 80%. It was a little higher in the ZIM monotherapy, I think, 80% versus closer to 70% for both the combination arms. Never-smokers were included. And that may be an explanation -- one explanation for why this definitely appears to be a real-world result.

And I have a question for Dr. Wolchok. Do you think that the Fc receptor can be important? And will biomarker data help in establishing Fc hypotheses, whether [indiscernible] require directive Fc?

I think the Fc receptor has been deemed important in prior studies. And I think that one needs to consider the presence of the intended target of the antibody on the immune cells as well because -- so for example, if you're blocking the PD-1 pathway, you may not want to use an Fc-competent antibody because you would then deplete activated T cells as well as blocking the dysfunction signal that goes through the PD receptor, the PD-1 receptor. So I think it very much depends upon the pathway. There's a lot of thought about this in the context of CTLA-4 given its presence on regulatory T cells. So I think that it needs to be a case-by-case analysis depending upon the expression of the intended target of the antibody on different immune cell subsets.

And for you, I have another personal question. Clearly, the results of the adenosine receptor was not -- were not so surprising. Do you think that is because we are not using a good biomarkers and maybe this specific population is not the right population? Or do you think that the redundancy of the adenosine system is too much and is not, in general, a good target?

I think those are all viable hypotheses. And I think studies like this, if there were archival pretreatment biopsies available, one could try to look into that to see whether expression of the A2A receptor with -- or CD39 and CD73, which are part of the pathway, are they upregulated in the tumor microenvironment? And obviously, if one could measure free adenosine in the tumor microenvironment, that would be very advantageous. But given the complexity of getting fresh tissue to do that in a reasonable period of time, I think that one would have to go with surrogates for the biomarkers.

I might just make 1 comment to that question. I am fascinated by the 2 partial responses in that group of 12 to 15 patients that progressed on PD-1 alone that went on to get the triplet. So they went on to get PD-1 TIGIT and adenosine receptor antagonist. And they were able to reinvigorate the immune response with the triplet. Now whether it was the TIGIT or whether it was etruma that was the causative agent for that? We don't know. But it is so often in these patients that are PD-1 treated, that come to us for clinical trials, we are unable to reinvigorate a response. So there is hope that we can do it if we can figure out a little bit more about what's going on in the tumor microenvironment, to Dr. Wolchok's point.

Yes. And actually, Dr. Johnson, I think that's a great point. And it's important to also recognize that, at least in the melanoma literature, Dr. Allison Betof Warner published about 1.5 years ago that retreatment of patients with PD-1 blocking drug after they progressed on an anti-PD-1 agent can rarely, but sometimes, result in responses. I think having an adequate number of those patients to dig into in terms of understanding why they respond is going to be very important.

I wonder if that's different melanoma to lung, just seeing some of those melanoma patients in the drug development unit here. I see that there's a difference, lung to melanoma. So that would be another...

Absolutely. Yes. Yes.

Yes. And based -- and I just want to have also your both opinions about the CD226, if you think that this can be included as a biomarker?

100%.

Yes.

Okay. And I have another question in particular for you both. So clearly, now the new companies are building their pipelines, considering the anti-PD-1, anti-PD-L1 that they have as they approve the PD-1, anti-PD-L1. For example, in this setting, we have pembro, atezo and cemiplimab approved. Do you think that we can consider ZIM as a good backbone exactly as pembro? And we will see in the future that they are building everything on what they have in house?

Well, I'll go first. Marina, I think it's really hard to say that these drugs are not the same. Now this small randomized Phase II study did have response rates less than what we would expect with PD-L1-high tumors. But across the ZIM portfolio, the response rate in other tumor types are equivalent to what we see. I think in the future, we will use all of these interchangeably. And I guess we'll just look forward to the results of ARC-10, which is DOM, ZIM versus pembro in a larger data set to show us that, in fact, ZIM is the same as pembro.

And Dr. Wolchok, would you like to add something? Maybe...

I think as Dr. Johnson said, it's a very hard question to answer. And I think that my own bias would be that maybe we stop making similar versions of the same drug and focus our energies on novel pathways, pathway discovery, novel combinations. I just -- I mean, I'm an academic so I don't understand the business constraints. But I just think that there really should be some thought given to additional copies of agents that really block the same pathway when we have agents available readily that we know have response rates.

Okay. So I think that we have finished, unfortunately, our time. There were still a lot of other questions in the chat that we didn't have the time to answer. So -- but I think that we did the most. So we have new results for another subgroup. We will see in the future is the chemo and within Cigna trial will be better or not to the combination of ZIM and DOM. And as it was said, I think that working at the academic level to find right biomarkers, the right strategies, I think that this is the most important thing for our patients. And I would really like to thank you for the participation for answering so many questions. And I would like to -- happy holidays to all of you on the floor and also on the chat.

Happy holidays.

Happy holidays.