FDA Approval of Tislelizumab - RATIONALE 305 and 306 in Upper GI Cancers

Intro Hello and welcome back to the Oncology Brothers Podcast. I'm Rahul Ghosain here with my brother and Co host Rohit Ghosain. Today, we're diving into the recent approval of tisalizumab, another checkpoint inhibitor in the upper GI malignancy space to touch on this agent and unpacked the studies that led to its approval in esophageal squamous cell cancer, G junction and gastric cancer. We're joined by Doctor Anwar Saeed, Chief of GI Medical Oncology at UPMC. Anwar, thank you so much for being here today. Speaker 2 You, Rahul and Rohit, it's my pleasure to be here. Thank you. Speaker 3 Thanks so much again for joining us, Anwar. Well, diving into the space of tisalizumab where this has been approved based on RUSH now three O 2, three O 5 and now three O 6 as well. Where we first heard about tisalizumab was back in 2022 where it was presented in nasopharyngeal cancer space with chemotherapy as part of ASCO plenary session. Since then, we have seen other studies mature in gastroesophageal space, whether that's for squamous or adenocarcinoma. Anwar, before we dive into the studies and the data itself, could you please touch on the makeup of this drug and how tasulosumab is any different in terms of mechanism of action? Mechanism of Action of Tisalizumab Yeah. Speaker 2 So is monoclonal antibody that binds to the PD 1. So from I would say grand scheme of things when it comes to mechanism of action, it's a PD1 inhibitor. However, when we dive deeper a little bit on how it was made, it is somewhat different in terms of the binding pockets on the PD1 protein. And so it has a, it binds on a different binding site on the PD 1 and it binds with a higher affinity, meaning it stays that the the binding stays longer than what we would envision for nivolumab and pumprolizumab. And this may lead theoretically to better progression free time, which would result in better overall survival and and and some tumors or subgroups. Speaker 1 Anwar, thank you so much for laying that foundation. So coming to the data in hand, Tysilizumab first got approved in second line esophageal squamous cell cancer based off rationale 3O2. Role of PD1 in Esophageal Squamous Cell Cancer But now we're awaiting approval in frontline settings with chemotherapy based off rationale three O 6. Given there's overall survival benefit here, can you please start us off with rationale three O 6 study and it's findings? If and when this gets approved, what does it really mean for us out in the community? Speaker 2 The rationale three O 6 trial is our phase three trial that was tailored to the population with unreceptable or stage 4 advanced metastatic esophageal squamous cell carcinoma who are treatment naive for targeting the frontline population with a good performance status PS zero to 1. Those patients were treated with either the Teslasmab, the 200 MG IV every three weeks in combination with chemo versus placebo plus chemo. So I would say pretty much similar design to the other trials that was done in the frontline setting testing checkpoint inhibitors like the Checkmate 649. The difference here is that this trial is purely tailored today esophages squamous carcinoma population and looked at provision free survival and overall survival in this population. As you see here, this is the provision free survival slide showing great separation of the care, very early separation of the curve confirming the efficacy of this PD1 inhibitor when combined with chemo as opposed to the control arm. The hazard ratio is also impressive considering this is an all common population regardless of PD1 expression. Looking at the overall survival as expected for both the top score and the CPS one score, CPS is more than viable when identifying the subgroup with higher PDS PDL one expression because it goes through an equation that considers the tumor micro environment. The top score would not consider that as it will look at the tumor as well. And you know more and more data suggesting that the tumor micro environment, particularly when close to immunotherapy needs to be considered when when sharing and decision making. And so I typically rely on the CPS when it comes to analyzing subgroup analysis in those large trials. If we look at the lower myocards here in the lower part of the screen, as we go from CPS one to below 5 to the group of five to lower than 10 to CPS 10 and the benefit goes higher and higher with the most benefit being seen in the CPS 10 and above with a hazard ratio of .64. Otherwise, the hazard ratio doesn't look bad, but it doesn't meet the statistical significance for the patients with CPS lower than 10. And so I think the interpretation of this is that this also confirms the efficacy of the subgroup, which is in line with what we've seen with the other PD1 inhibitors, both nabolimab and piprolizumab. When it comes to pulling up the data and running meta analysis, we've seen similar outcome from those analysis, confirming that patients with CPS 10 and above are the group that will benefit from immunotherapy. Speaker 1 And we're coming back to our clinical application. In your practice, if this is available, are you going to use this in all comers or are you using it in anyone with CPS one and above or only for 10 and above? Because we've seen the PFS and all comers as well. Speaker 2 And many of those trials and this is not specific to tested as a mouth and all the PD1 inhibitor trials that was done in the frontline setting. I think when it comes to positivity that we're seeing in the old Comer population, I would have to highlight and emphasize that the positivity is driven by the group of patients with high PDL 1. And most of those trials, more than 1/3 of the population, I would say more than 50% of the population on those trials belong to the subgroup that benefit from immunotherapy and that's what's driving the overall positive outcome. So when we interpret, particularly if we are not deeply diving into the data, we can be misled. But when you look at those large subgroup analysis and those very large trials that have a population of 700 to 2000 patients, those subgroup analysis in itself are in my opinion enough powered to to give a take home message that the group of patients that benefit other patients with higher CPS score. And I think this is actually what led the FDA to revisit the decision. As far as the label for those agents in the frontline setting. I would say in my real world practice, we also have to acknowledge that the marker we have is not a perfect marker. There is a lot of nuances to PDL. One CPS measurement, the measurement that was done on those large trials were standardized process in real world practice. There is, you know, issues with reproducibility related to pathologist related to the antibody used the stain, a lot of things. And so we have to acknowledge the nuances. And so for me and real world practice, anyone with PDL 11 and above, if I don't have any, you know, any targeted therapy based on the molecular testing that I could utilize, then I I consider using immune therapy for for those with absolute 0, I'd like to shy away. Speaker 3 I couldn't agree more. Until we have a better marker, this is the only one that we have to rely on. Patient shared decision making is the key here. Besides squamous cystology, recently in December 2024, we also saw tisalizumab expand its approval in GE J and gastric cancer with chemo for PDL 1 positive based off of rationale three O 5 study. TIL-131 Expanded for Gastric and EJ Cancer Can you please touch on this study and its findings So. Speaker 2 The rationale 305 trial is another trial that tested Tesla lismap in the frontline setting. This one is purely tailored to the adenocarcinoma population, both gastric and E junction adenocarcinoma and has similar trial designed to the 306. It's just a different population, the adenocarcinoma population, similar agent logistics, the 200 milligram IV every three weeks used in combination with chemo versus the control arm of placebo plus chemo with the primary endpoint of overall survival. They did subgroup analysis and looked at secondary endpoints as well by the top PD1 expression, PFS and other survival outcome endpoints as well. Speaker 3 Well, thanks for going over the study design. Before we dive into the survival data on WAR, With regards to the regimen which is Q3 weeks based regimen, if one is utilizing 5 a few based approach which is to be administered every two weeks, are you relying on tisalizumab every three weeks or switching that on a different dose for every two weeks? Speaker 2 The rational trials that tested tesizumab pretty much tested the Q 3 weeks dosing real world practice, particularly in the US because we rely heavily on Paul Fox, almost more than 95% of my patients with gastric and esophageal adenocarcinoma in the front line setting around Paul Fox. We favor Paul Fox as opposed to Zalox, particularly I would say in the upper GI population because a lot of those patients might come with dyspagia and issues related to the pedals. And so we favor the pump. And keeping that in mind logistically the Q 3 weeks dozing is challenging. And, and you know, we face those questions all the time that OK, why pembro? Why nivo versus pembro? And though we don't see any difference then Nivo provides convenience being something that we could get once a month and, and, or every two weeks. And so lines very well with with the Paul Fox scheme or regimen. Speaker 3 Thanks so much. If you don't mind going over the results now. Survival data So in terms of the results seen in the rationale three O 5 trial, the provision free survival was significant in the overall randomized population as well as in the subgroup of patients with top score 5% and above. When we look at the months, it's in line with the Checkmate 649 data when it comes to PFS being around seven months overall and slightly better in the in the group with higher PDA one expression, the hazard ratio is .78 and all all comers and .67 and the subgroup with higher expression. I think this is positive data. In my opinion that RUG is working. The overall outcome again I would say driven by the PDL 1 positive population. The overall survival here is when looking at overall population was positive with the hazard ratio of .8. The hazard ratio is much better for the subgroup with PDL one top score 5% and above with hazard ratio .74. This I would say also in line with the published data. I think we might find, you know, some people who do comparative or historic comparison looking at the actual months saying that oh, the median overall survival in the all Comer is 15 months here and then seventeen months in the in the subgroup with higher PDL. One expression which looks more favorable than those numbers when we look at the Checkmate 649 and the other PD1 chemo trials that was done in not my setting. And I would say we also have to be cautious in interpreting those numbers because it's not a head comparison of TESLE versus nivo or TESLE versus pembro. One thing to keep in mind here is the control arm performed really well. The control arm with the chemo is crossing the 12 months mark, which tells me and this is similar, similar kind of arguments we have when we look at the frontline trials in the SEC population. The frontline population is doing better as we go. Does this mean that the chemo is doing better? No, I think this is related to the salvage therapy. We have more salvage therapies for this particular population like more hair to targeted therapy that's showing effect. Trustees about the oxygen is in the market. We have a lot of clinical trials available and keeping in mind that those are trial patients, meaning a lot of them have access to second line and third line therapy. So when we analyze frontline trials, survival and frontline trials, we just have to be cautious on what are we comparing, how the control arm is doing and what that means. Speaker 1 This is all good news. That means our patients are indeed living longer and coming back to be a rationale series or checkmate series for PDL 1 positive patients. Adding immunotherapy with chemotherapy is now the standard of care. That is because there's overall survival benefit here. Anwar, you had touched on the mechanism of dyslizumab, particularly it's higher binding affinity. Side effects of Dyslizumab Are we seeing any different side effects because of that? Or is it very similar to all our other available checkpoint inhibitors? Speaker 2 I think the side effect profile is actually more appealing to me. When you look at comparing the grade one and two side effects seen on this table to the grade one and two side effects seen with placebo and chemo, it's very much comparable. Doesn't look like the PD1 inhibitor or adding the PD one is amplifying the side effects. Similarly, when you look at the grade three grade 4 significant side effects, it's not significant and there's almost not much there to mention on the grade 5 toxicities. And so it looks appealing to me at least from a side effect perspective. But overall, whenever I refer to side effects, I'd like to remind people in reward practice, our community partners, that I think it's good to practice caution when deciding about utilizing immunotherapy because one way to avoid this is to spur the patient toxicity when it's not leading to a benefit. And so getting that PDL 1 score before deciding whether or not to add immunotherapy is very important. In the old days, just within the last few years when we got the blanket approval, we've seen every one of those patients going on immunotherapy even before the PDL 1 testing results comes and they decide later on to stop it or not to stop it. And I think there is a shift now because there is a revisit to the criteria limiting the use to PPL 1 positive population. But the shift is not complete. There are still community providers and colleagues who would use it in a blanket fashion. I would encourage that we wait, maybe give a cycle or two with just chemotherapy before deciding on what to do. I think nowadays we're moving more to our president oncology, particularly in patients with the adenocarcinoma population. It might be less pertinent to squamous, but more pertinent to adenocarcinoma. We're going to cloud an 18.2 now being in the market. We're going to maybe if you are the marginal was making its way so it might come to the markets in the near future. We're dissecting those those patients into the subgroups and also trying to decide what to do with immunotherapy in the front line setting and what to do, where to place it even in second line setting. And so throwing a blanket of kind of regimen on those patients kind of limits their ability to access normal agents in the second line setting just because they receive that those are two of video one inhibitor before stopping it. And so I would encourage using caution, waiting for those markers to come back before deciding which regimen and what to do. Speaker 3 Indeed, exciting times, especially when you mentioned zolbatuximab with recent approval and now tisolizumab. PD1 inhibitors in squamous and adenocarcinoma And as Rahul stated earlier, this is a good problem to have as we have more agents and more discussion with our patients and their families, more choices available on were whether be it squamous or adenocarcinoma, we have few immunotherapy options available, that is pembrolizumab, nivolumab and now tisolizumab. Should we be relying on one or the other agents? Any final thoughts before we close? Speaker 2 I think all of those agents have confirmed their efficacy and phase three trials which have led to their approval and the three are in the market. We can consider any one of them decision making will lie on logistics of giving the the PD1 inhibitor. I think, you know, the chair time now is getting more valuable because we have a lot of agents, a lot of patients are, you know seeking intervention and and so that chair time becomes precious. Also keeping in mind that we're seeing unfortunately and sadly more and more patients who are at younger age with cancer, a lot of those patients are working and so giving them less chair time with similar efficacy might be more valuable to them and more convenient and I think those are important factors. Another thing point to keep in mind is we always look at you know, what to do in the second line setting. I think there is a huge open gap right now in the second line setting of what are we going to do with that immune checkpoint inhibitor, The patient progressed. Do we continue the immune checkpoint inhibitor and add second line therapy or switch to second line? It's an open question. I would like to shine a light on a SWAG intergroup study that I'm leading. It's called SWAG 23003, a power immune trial looking at continuation beyond progression in combination with paclitaxel ramasurumab versus paclitaxel ramasurumab in the second line setting for patients who are progressing on PD1 chemotherapy regimen and frontline and and have APD one, CPS one and above. I think it will address a very important question in the field and direct us to where are we going to head with the new checkpoint inhibitors in the second line and who are the responders. There might be a subgroup of patients who may benefit from continuation of immunotherapies. Speaker 1 And as we close, I want to reiterate that all our immunotherapy options at this time in frontline settings, upper GI malignancy are based off PDL 1 positive status. So checking for these biomarkers including her two including Platin 18.2 is so critical. We just wrapped up our discussion on zolbateximab with Doctor Shatera. Outro Doctor said, thank you so much for taking the time to walk us through all the data that led to the approval of tisalizumab in esophageal squamous cell cancer, G junction and gastric cancer for and listeners, let us go over a quick recap. Speaker 3 Well, we saw close to 50 new indications and approvals in hematology and oncology in 2024. Speaker 1 Rohit, it is mind boggling and exciting how fast this field is changing. Speaker 3 I know antisalisemab was one of the drugs in this approval list. It was first approved for second line esophageal squamous cell cancer and then more recently in December 2024, we saw tisalizumab get approved in GE junction adenocarcinoma and gastric cancer with chemotherapy in frontline. Speaker 1 In today's discussion with Doctor Anwar Saeed from UPMC, we had a chance to touch on the studies that led to the approval of tisalizumab, but wrote that during this discussion, whenever we've touched the topic of upper GI malignancies, we continue to reiterate the importance of biomarker testing. Rahul. Speaker 3 Couldn't agree more because the fact of the matter is all IO options including tisalizumab in frontline settings are approved for PDL 1 positive status. With any new therapy, we have to learn how to manage the toxicity that comes along with it. But the good news is we have been using iOS extensively in our community settings in multiple cancers and are rather comfortable managing some of these side effects that come along with them. But importantly, never forgetting that some of these side effects can in fact be life threatening. For now, tisalizumab is approved in gastric and GEJ adenocarcinoma. We will await its approval in frontline settings for squamous cystology. For now, it is approved in that setting in second line. Thanks for joining us. If you feel like these conversations have helped you, please share this episode with a friend or colleague who might also enjoy it. Leaving us a review helps us increase our visibility and expand our reach, essentially helping more oncologists provide the best cancer care close to home. Continue Follow us along for more practice changing discussions in the cancer world. We are the oncology brothers.