Sam Klempner, MD, addresses what has changed in immunotherapy and targeted therapy in upper GI cancers, and reviews barriers that are preventing improvement. Dr. Klempner recalls a new option using Trastuzumab-Deruxtecan for HER2+ patients, and also explains how incorporation blood-based assays (ctDNA) may speed accrual and access.
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our next speaker this morning is Dr Sam Klempner from the Mass General Cancer Center. He will be speaking to us on immunotherapy and targeted therapy and upper GI cancers. Dr. Klempner works in a multidisciplinary team to optimize and individualized treatment using molecular characterization across all stages of GI cancers. We're pleased to have him speaking with us this morning. If you have questions for him, please use to ask a question chat function and we'll be collating questions for the panel discussion later. Please, everyone welcome Dr Sam Klempner. Hi, My name's Sam Klempner. I'm a G I medical oncologist at Massachusetts General Hospital in Boston, Massachusetts. And today I have the privilege of speaking to you about immunotherapy and targeted therapy and upper GI cancers. Here are my disclosures and grant funding. So while I was preparing the slides, I was thinking about how much the treatment of these two tumor types has changed since I started practice. And, you know, the answer used to be full fox and, uh, for every esophageal and gastric cancer patient, and that's changing. So to maximize really the practice utility of this talk, I'm restricting our discussion to agents that are currently approved or anticipated to be approved in esophagus and stomach. I also use gastric and esophageal cancers to highlight some key concepts and barriers that we need to address to further move care forward. So there is much to be done to achieve the levels of success of targeted therapies and immune therapies enjoyed by our thoracic and melanoma colleagues. But we are making a lot of progress, and the pace is actually increasing. This is an excellent slide from a cohesive Tara at Asco G I in in January of 2021 showing the current landscape and timeline of approved, targeted and immunotherapy agents in GI Cancers. We obviously don't have time to focus on all of these drugs, and we'll be selecting a few to highlight the paradigm here. I'm showing you how they approved agents are currently fitting into practice. I think the really the take home message here is that although these agents represent small pieces of the molecular pie in each tumour type, we're getting much better at slicing up the pie. And this is really partly due to the advent and more routine clinical incorporation of broader genomic profiling, which allows for identification of multiple biomarkers from a given tissue or blood sample, which facilitates patient selection and funneling patients towards the most appropriate therapy. We're going to spend a fair amount of time talking about her two story because I think it really highlights both the successes and the limitations of targeted therapy and upper GI cancers. As you all know, the 2010 toga trial demonstrated an overall improvement in survival by adding trust US A mob to five F U and platinum therapy in her two positive gastric and esophageal patients in first line setting the overall survival. Improvement, however, was relatively modest at about 2.5 months, and this is shown in the upper left on the right. What I'm showing you is a table of all the other negative phase three attempts to continue targeting her to in gastric and esophageal cancers. And really, this immediately calls to question Why did this happen? How come we have been unable to build upon trust us a mob as of yet? So we saw the first clues in the TCG, a sequencing efforts where they sequined gastric cancers and in the lower left what I'm showing you is here in the second row, we see her two amplification is recurrent in about 17% of patients, mainly in the CNN subgroup. And if you look vertically, what you can see is there's a fair amount of overlap between her two amplification and amplification or alteration of other aka genic targets, suggesting a fair amount of heterogeneity in this population. This is a really nice review that summarizes the concept of heterogeneity, which are really central to why targeted therapies may not achieve greater benefit in gastric and so fragile and probably multiple GI cancers. Honestly, this might be the most important slide of the whole talk, so I'm going to spend a little bit of time here. So we learned from several studies looking at primary tumors and metastatic tumors that the diff they often differ an expression of a given my own biomarker like her to, for example, and this can clearly impact the chance of success of a targeted therapy. If we take a look over here and the right at the bottom, we see the differences in biomarker A and B between the primary and metastatic site. This is called Inter Legionella heterogeneity or often terms, um, inter temporal or spatial heterogeneity, where you have different biomarker expression between two sites of disease and the same patient. However, the same metastatic site may actually have regions within it that have differential expression of a given mile marker, and this is called intra lesion. All heterogeneity, or intra temporal heterogeneity, has shown down here the table over here on the right highlights how inter temporal and intra temporal heterogeneity may play into the chances of success for a given agent. Take the top row up here, where we see that there is concordance between the biomarker and the primary tumor metastases and, in this case, the circulating tumor DNA as well. This is a patient whose tumor is very likely to respond to a targeted agent directed against this biomarker, say her two or F G f R. Two or other targets in other GI cancers. Unfortunately, the majority of our patients actually represent more like rose bottom two rows down here and here. We see there's pre existence of multiple populations in which the biomarker is expressed at various levels between metastatic metastatic sites and the primary, or within the primary or metastatic site, therefore, is captured at various bull degrees in the circulating tumor DNA, and these patients either have a very short lived response and then progress or are intrinsically resistant to show you that this actually bears out in clinical practice. I call your attention to this recent cancer discovery publication from from just last month, January 2021 by a friend and colleague, Dan Catenaccio. So the top figure over here on the left is just showing the concept of using a targeted therapy during out the continuum of care. So the biologic was continued through lines of therapy. The choice of targeted agent here was based on a pre specified ranking, with a biopsy from the metastases taking priority over biomarkers taken from the primary tumor. And this is mainly because most of our patients die of metastatic disease, not from changes in the primary tumor. The upper right here is actually showing you, um, comparisons between the primary tumor and the metastatic tumor. In terms of biomarker assessment, the red lines here represent patients who were reassigned to therapy based on differences between the primary and the metastatic tumor. And, as you can see over here. This affected about 35% of patients. So this is spatial heterogeneity at work in the clinic, which differences and biomarkers between two sites of disease. To get a temporal heterogeneity, you can see in the lower right what I'm showing you as a swimmer plot in this plot. Each figure each color bar represents a targeted therapy the patient received, and a change in color represents a change in a group assignment over time based on our evolution. And what's really interesting is you can see that almost all the patients here who had a target and these are all the colored patients, the majority or nearly or half of them changed therapy during the course of the trial. Whether this was from first line to second line or second line to third line, half of patients were changing therapies. Really. The take home here is that assessing and adapting to heterogeneity may improved outcomes, and the survival for this Phase two trial was actually quite encouraging, significantly improved upon historical controls, keeping with the her two story. I'm just providing some additional examples here, showing that more concordant to us here in the upper right panels where we have concordant tissue and plasma are identifying patients more likely to respond. And then in the lower right, a patient with discordant results who had no significant benefit on the left, we see a series looking at her to resistance. So baseline and at progression and what you can see. Is there several mechanisms by which to us evolved and may explain why several of the large trials targeting her to have been negative because they're looking at populations after Herceptin, whereas it quite a hetero, heterogeneous group of patients. So bringing this back to the clinic, you know, how do you get around this problem? It's quite a daunting problem to overcome heterogeneity, and we have clearly now established that most of our patients actually look like the bottom left figure here where you have a tumor, her two positive population and more positive population and then a completely negative population. So there's some cells or clones in the tumor that are completely devoid of the target, for example, in this case, hurt too antibody drug conjugate like trust us, A mob directs the can offer a potential mechanism to address this problem. So by using her to as an anchor for the ABC delivery. There's actually enhanced drug delivery to the sites of disease and then by conjugating to a potent side of toxic Asian that has the ability to kill some cells that are negative for the biomarker of interest. These are populations that would be resistant to pure her to inhibition. You may be able to address heterogeneity, and this is called the Bystander effect and may account for some of the observations we see with this drug. In fact, the strategy was actually born out in this phase two trial Destiny Gastric A one. These are patients who progressed on prior therapies, including Herceptin, where other trials have been previously negative. And as you can see, this four month survival improvement actually lead to a January 18th 2021 FDA approval for trust us. Um Abdurixit can, um, in patients who have progressed on Herceptin containing therapies. So we discussed her, too, And heterogeneity, I'm going to briefly spend a few minutes talking about Kalandia carcinomas to show you that heterogeneity extends beyond gastric and esophageal cancer and also highlight a recent approval there. So as you all know, F g f R two fusions or rearrangements, are common, Um, and almost exclusively found in intra hepatic Colangelo carcinomas, where they're seen at about 10 to 15%. Prevalence, maybe enriched for young patients, particularly young women and Obama got nib. Among other small molecule inhibitors is a selective and potent oral inhibitor of F G F R 12 and three mhm. So this is the data that supports the recent approval of Penny. Got a name for FGF two FGF two fusion positive Kalandia carcinomas who progressed on prior therapies. So originally there was three cohorts, but it became quite clear that the biologic activity was greatest in the Fusion cohort, which is as suspected in this group. The response rate to Oral Penny got mono therapy on a two week on one week off schedule was about 35%. And this is a population where, as you all know, second line therapies have been largely inactive, with full fox perhaps being the standard of care based on a placebo controlled phase three trial. What's impressive here is a mediating duration of response of about 7.5 months, and this, in my mind, is a substantial improvement upon what would be expected from second line or later chemotherapy. And this is what led to the approval in April of 2020. So this is just some pre clinical and translational work to show you that just like her to patients, F g f R two patients have baseline tumor heterogeneity, both intra to moral and inter temporal heterogeneity. And as you can see in the upper left panel, this is a patient who initially responded and then progressed. And you can see the difference in the mutations that were picked up on the biopsy and in the blood, suggesting some inter inter lesion all heterogeneity, some that were only seen in tissue, some that were only seen in blood and blood, capturing some that were not seen in the tissue, reflecting their likely origin from other metastatic sites. The lower left figure just shows in Tralee regional heterogeneity looking at different regions in a single area of the liver, showing that the differential expression of some resistance mutation and then the other two figures are showing tracking these variants in the blood over time. What really this shows is that there's some pilot evidence for the idea of using resistance tracking as a way to inform your next therapy. So although not all these drugs are approved, we can see that, for example, Task 1 20 is able to overcome some of the resistance mechanisms to integrate NIB. And that's shown by some of the audio frequencies here, going down and then rising and then coming down with the initiation of task 1 20. Our lung cancer colleagues are well ahead of us in this, where they often routinely use E g F R resistance mutations and out resistance mutations to decide what is the next Alcor E jafar inhibitor to use. And we may get to that point with targeted therapy and GI cancers as well. We don't have time to cover all the additional targets and biliary tract cancers, but I th one or two and be wrath have clearly demonstrated action ability. And I. D. H one inhibitors were approved a little over a year ago. Based on the Phase three clarity trial, I've just put some updated results here from ASCO G 2021 primarily for reference and interest, and put the references below for you all. So now we've discussed her to F G F R two and heterogeneity as barriers to targeted therapies and upper GI cancers. In the second half, I'm going to talk about immunotherapy. So like other us, there's always been interested in extending immunotherapy to upper GI cancers. However, later line trials and later line therapies have suggested only limited activity. So single agent activity in the 10 to 15% range for checkpoint inhibitors in gastric and esophageal patients. I actually think it's important to think of immunotherapy as a targeted therapy and therefore most active and targeted populations. And so what I'm showing here on the left is a series of trials that have been largely negative, save for the attraction to trial in, um, advanced patients on the right. However, if we think about immunotherapy as a targeted therapy and we take Keynote 61 Keynote 62 which was a 1st 2nd line and first line trial, respectively, we see that in a targeted population, for example, the CPS of 10 or higher or the EMC high patients, there is a clear favoring of the PMR alarm over the comparator arm in the trials. Again, if you have designed this trial to be exclusively conducted in that population. You probably would have seen a positive study again, just highlighting the idea of using immunotherapy or conceptualizing it as a targeted therapy ideally suited to targeted populations. And this will be a theme that we come back to discussing the first line data, so there's less evidence here. But spatial and temporal heterogeneity may play a role in underlying the mixed response to single agent checkpoint inhibitors and gastric and esophageal cancers. Certainly on the left here I'm showing you introduced us to different sites from two different areas, from a biopsy showing differential expression by a couple different antibody clones and then on the right here. These are comparisons between both pre and post treatment and primary and metastatic sites, showing that there is often discordance in up to 40. Want 40% of patients between these two things separated in time or geography? Certainly in the higher the higher PD l one positive populations like CPS 10 or greater, we do tend to see a greater concordance, suggesting that maybe there's a more shared biology that's central to those patients. So what does this actually mean for our patients? Uh, well, it meant that we need to do a little more to expand beyond the limited activity of PT one monotherapy in these diseases. And so combining chemotherapy with immunotherapy did offer some potential advantages. Chemotherapy. If we think back to that picture of the her to where there's a low and medium and a negative biomarker population, you can envision chemotherapy as addressing the biomarker low or absent population and could prevent that rapid progression that happens after i o mono therapy and the majority of patients. Chemotherapy plus immunotherapy also has some more favorable features in terms of driving a more immuno responsive tur. And this has centered along the idea of ImmunoGen IX cell death and decrease in myeloid derived suppressor cell and T regulatory cell activity, as shown graphically here. If we look at the key data sets that are going to be changing practice in the near future, I'm highlighting a couple over the next few slides so we don't have time to dive into all of these important studies individually. So I'm going to focus on checkmate 577 which is the upper two panels here, and this is the data that supports an anticipated upcoming approval for an Ebola mob in adjuvant setting after people with esophageal and G Junction cancers have had residual disease after try modality therapy. So chemo, radiation and surgery. So this was a randomized placebo controlled double blind phase three randomizing patients, 2 to 1 to achieve in Nevada map for a year or placebo. These were all patients who had chemo radiation, followed by surgery and had residual disease at the time of surgery. So this is going to be about 80 80% of our population, perhaps a little bit less than that. The primary endpoint here is disease free survival, and what you see is that the disease free survival was nearly doubled with the addition of one year of adjuvant novel a man from 11 to 22 months. That's a hazard ratio of 0.69 and a clinically meaningful endpoint. Certainly, we anticipate an approval based on this I'm not showing here is that if you look at the subset analyses, thinking back to immunotherapy as a targeted therapy, it seems that the greatest magnitude of benefit here is in the squamous cell populations over the G junction at no carcinomas. Perhaps the most relevant trial to our routine practice is checking 8649 And so this was presented at EHSMOH in September of 2020 and certainly is anticipated to alter the landscape of first line therapy for our patients. So here they compared Z locks or full Fox Standard first line therapy for newly diagnosed, advanced or metastatic patients versus Nivola Man plus Z Locks or full fox, again keeping with the theme of targeted therapies and targeted populations. Uh, we see that the dual primary endpoints of overall survival and progression free survival were restricted to a CPS greater than or equal to five population. So if you look at this group shown here in the lower right, the median overall survival improved by about three months from 11 to 14.4. And that was a hazard ratio of 0.7, Um, and a statistically significant improvement. This is actually important. It's the first phase three study outside of her to patients outside of Asia to establish a survival of greater than one year. So this is an advancement and what we expect to underlie an approval for the FDA in my personal opinion. I think the FDA will probably restrict the label to CPS of five or higher, but that remains to be determined in the lower left. I'm just showing you that this was a primarily gastric and G junction trial with very limited esophageal patients here. Paralleling checkmate. 649 There's some some data in a sophomore esophageal. This is Keynote 5 90 Again. This is standard five F U plus platinum versus five. A few platinum plus, Pemberley is a mob again. What you see on the right panels is that if you look at the shape of the curves and particularly the green curve representing embolism plus chemotherapy, you see the greater separation for the targeted populations. So pd l one CPS greater than or equal to 10. And the squamous populations are driving the greatest magnitude of benefit here. But we do see benefit across really all of the subsets again. This is also expected to lead to approval in esophageal cancers in the very near future. In the bottom left, I simply call your attention to the idea that this trial was primarily Asafa deal and a lot of squamous cell patients just to compare 2649 testing slightly different populations. So, really, the point of this slide is simply to give you some hope. Um, so there's a lot more targets coming, and there's clearly a lot of trials here that may further change the practice. And in the last few minutes we're going to talk about sort of the future and how we can get there and expand the benefit. So the studies we've reviewed offer a lot of hope for our patients, but there's clearly still a lot of work to be done. Two of the major themes demonstrating some promising early results, uh, and potential synergy are the idea of combining monoclonal antibodies with checkpoint inhibitors and the idea of targeting immune checkpoint pathways along with VHF pathways. So here in the upper left, I'm showing you with the putative mechanism for monoclonal antibody plus checkpoint inhibition, where there is cooperation around, um, the monoclonal antibody mediated A, D, C, C and C D. C, and then enhancement of the anti tumour response to that by immune checkpoint inhibitors inhibitors and reinvigorating those exhausted T cells and the cooperation resulting in enhanced um, our clearance immediately below that is a panel that's trying to convince you this actually happens. And so this is pre clinical evidence where you see the curves. The lowest curves here are look to be more than just additive between her two and p d one. It looks synergistic, and we see that here in two different transgenic mouse models to extend this to the clinic. We have some early data. So on the right and on the left are two trials looking at the idea of combining monoclonal antibodies with immune checkpoint inhibitors. The trial on the left is a first line study comparing testing Z locks, plus Herceptin and Pebble is a mob in a single institution setting. And here we see a dramatic waterfall plot with a response rate of about 90% in this population. And this is supporting the ongoing Phase three randomized trial comparing Z locks plus Herceptin plus or minus P embolism app called Keynote 8 11. On the right side is a chemo free regimen showing activity after criticism and failure. And here again we see biomarker enrichment. So if you look at the her to I f. C three plus and PDO one positive, the double positive patients. We see they're getting the greatest benefit from this combination. This combination is now being extended to the frontline setting in a trial called mahogany. So certainly some interesting further results coming for our her two patients. Finally, I'm trying to talk about the intersection of veg F and I o So our kidney cancer colleagues like Dr Monte Paul who spoke earlier today have pioneered this approach with significant success. Um, and a Tesla is, um ab InBev is is, um I'm also represents another example providing some orthogonal support to the idea of combining veg F and i o here. I'm just showing you two promising future strategies combining multi kinase inhibitors. In this case, Len botnet plus Pebble is a map and in this case, regular offensive and Ebola mob showing that and these trial settings again, these are slightly different populations. Between the two, we saw significant activity response rates 84% in the biomarker and rich. So the targeted population, but still activity in the negative population. Similarly, for the regular Nevo trial. So we're looking for ways to expand the benefit to the PD one non responders, potentially by targeting the VHF io axis. Finally, uh, just to call your attention to the idea of expanding our biomarker testing and how genomic profiling and genotyping is enhancing our appreciation of target and access to targeted therapies for patients. This is a really excellent paper from our Japanese colleagues, recently published in Nature Medicine. The authors are comparing plasma genotyping so essentially circulating tumor DNA against tissue based genotyping. And how did those translate to better patient enrollment into targeted therapy trials and better access to targeted therapy drugs? And clearly, what you see in the comparison between the tissue based screening and the plasma based screening is that there doesn't appear to be any drop off in the activity of the targeted therapies. So we're not doing the worst job at selecting the patients. What we're doing a much better job is speeding a cruel and increased decreasing the time from results to getting patient on trial. And so this really supports the idea of considering, um, c T D N A. As a validated mechanism to identify biomarkers, to select for targeted therapies. So we put this all together, Um, we really talked a lot about biomarkers and immune therapies and targeted therapies and how we can maximize their utility to improve the outcomes for our patients. I really think of this as an iterative process. In the top panel, we see what is currently arguably the standard where patients with newly diagnosed gastric or esophageal cancers are tested for standard biomarkers, her to microsatellites stability and PD L one and then there never tested again. Um, they progress through 1st and 2nd line therapies and get what they're going to get. Um, in a perhaps more biologically informed approach and what I and many people envision to be more along the lines of the future and even now is the same profiling at the beginning. Perhaps look for additional targets. Use that information to guide. Maybe that's a chemo Plus I Oh, maybe that's a chemo. Plus I o plus her two. We'll see. Ideally, if you've done well, the patient will do better. And then you repeat this process at each time a treatment decision needs to be made. This is the actually the same concept that was underlying the Pan JIA trial that I showed you where the biologic was continued throughout the lines of therapy based on serial assessment. So I hope this was informative and left you with a sense of hope for our patients with upper GI cancers. I'll leave you with these take home points. So again, what we talked about improved diagnostics This is tissue based in plasma based genotyping are making target identification more routine. We're understanding heterogeneity and polyclonal resistance and how we may target that. And again, we used DS 80 to 1 or transfers amount directs. Taken as an example, we now have several new FDA approvals that are here or coming trust is, um, Abdal. Rex Duncan was approved in January of 2021 for her two positive patients who progressed on trees. Susan, mob age of an immune checkpoint and chemo plus immune checkpoint inhibitors are expected in the near future with FDA approvals, and this will certainly change our practice and then incorporating CT DNA can speed trial and cruel and access to these agents for our patients. Here's my contact information. If there's any future questions and I look forward to the live panel discussion, thank you for your time
