Welcome back to oncology for the inquisitive mind where Esmo never ends. Today we will be the spark on your drive to work when you're winding down at home or when you're waiting for that patient to come. I'm Josh, that's Michael and this is our ongoing Infinity Esmo Roundup. This week we're talking about neuroendocrine tumors and melanoma. We will be your light spark for the next half an hour, Michael. How are you? I'm good, Josh. The point of contention I would make though is when you're winding down at home, do you really want to spark? Because I feel like a spark just turns it to a house fire. Yeah, true, but you won't be a light. I don't know. This is very, very complex, but I'll spark your imagination, so when you sleep you dream of that molecule that will make you famous in the cure cancer. And then you wake up and you'll forget it immediately because that's how dreams work. But yes, you can also tell that Josh sounds like he's been taking podcast lessons, probably because he has, but we are continuing our voyage into Esmo 2025 and we're going to try this again because last week we did the classic podcast, a mistake of over-promising and under-delivering Josh. And for that we apologize. We've let ourselves down, we've let the team down, we've let the fans down. We're going to complete, we're going to complete and present the content that we wanted to do last time, speaking specifically about neuroendocrine tumors and melanoma. And Josh, as you've alluded to with your express permission, O Dungeon Master, I might lead us off with our first nominee for favorite trial in neuroendocrine tumors. Your request is granted. Please proceed. I was on tender hooks there for a moment without cause. The first study to talk about in the area of neuroendocrine tumors is the light spark 015. Now, you might be thinking, Michael, didn't we do this study? And you would be right. And if you did think that, then kudos for you for paying attention. But light spark 015 was a multifaceted study. And so this is actually a different cohort of neuroendocrine tumors. The previous one was a paragongleomas and theochromocytomas, looking at balsuit of hand. This cohort A2 is the result of a subset of patients with pancreatic neuroendocrine tumors or pan-nets still using balsuit of hand. Background here is that novel treatments are needed for patients with advanced pancreatic neuroendocrine tumors who experience progressive disease on existing therapies and these days. Mainly, somatocatin analogs, and if you're very lucky and have access to a radioisotope treatment with PRT, hypoxia-induceable factors or hips are commonly involved in the survival and progression of solid tumors, including neuroendocrine tumors. And balsuit of hand is an oral hip to alpha inhibitor. If you've used balsuit of hand before, it's probably in the context of someone who is an unfortunate enough to have buvon hippolindow, which frequently leads to manifestations of a very distinct subtype of renal cell cancer, but it can also be associated with pancreatic neuroendocrine tumors as well. So, cohort A2 is of the single-lumb phase 2 light-spark 015 study, evaluated balsuit van in participants with advanced pancreatic neuroendocrine tumors. The first thing that's interesting about this study is that patients have to be greater than or equal to 12 years old, as opposed to your usual 18, which always is a bit of a red flag for me, not in terms of the study itself, but in the patient population to which we are examining. Patients that have locally advanced or metastatic well differentiated grade 1 or grade 2 pancreatic neuroendocrine tumors that had progressed on prior targeted therapy. They received oral balsuit of hand, because there's no comparator arm in this single-lumb study. 120 milligrams, one stately until progressive disease or unacceptable toxicity. The primary endpoint for light-spark 015 was overall response rate by blinded independence and troll review or Bicca. Secondary endpoints included duration of response, the time to response to disease control rate progression for your survival and overall survival and safety. So, in this arm of light-spark 015, a total of 70 patients received balsuit of hand. The median age was 58.5 with a range of 39 to 84, so fortunately no 12-year-olds who had locally advanced or metastatic net, 59% were female, 86 had the slightly more aggressive grade 2 tumor histology by the 2017 WHO criteria, and incidentally, if you want to learn more about the 2017 WHO criteria for neuroendocrine tumors, go back and listen to our short series from a while ago on the subject. Maybe leave us a like, subscribe, I'm getting in before Josh does later in the episode. The median follow-up time from the first Osterdata cut-off was 30.9 months. Overall response rate, still not great, 10%, measly 10%, however, the median duration of response was not reached, range was between 4.7 and 26.7 plus months. A total of 59 patients are 84% of the total 70 had treatment-related adverse events with the most common being anemia. 9 patients had a dose reduction due to an adverse event, and 1, a measly 1%, discontinued bells-event due to treatment-related anemia, and no patients died due to an adverse event. So well-tolerated, but the response time could be better. I suppose in this cohort of patients though, your options are fairly low on the ground, fairly thin on the ground, even perhaps if you don't mix your metaphors like I do, where you'd be looking potentially at observation, surgery, maybe even busting out a chemotherapy of your worry about a more aggressive transformation into a neuroendocrine carcinoma. It's a good treatment option, largely because there's not much there. That's it, there's not much there, so anything that's in this field is welcome. We're now moving on to almost the clinical of this mini-series of Esmo neuroendocrine. We're going to talk about alpha-medics, O2. It's the long-term follow-up of peptide receptor radio-neucleotide therapy, PRRT, with Mike, or mentioned about seven minutes ago, so go and listen to that if you've just clicked on this point. In those that were naive, who had gastroenteropancreatic neuroendocrine tumors, or gap-nets, treated with targeted alpha-therapy, which is the two-on-two Pb-dotum-tate. In the back end, it's an alpha-mitting radioisotope that breaks DNA, which is good because broken DNA means cancels die, which we like, and it spares healthy tissue. It is a novel somatostatin receptor, targeted alpha-therapy, under clinical evaluation, in those with unresectable or metastatic gap-nets. Here they present the two-year landmark analysis of efficacy and safety. So as I said, it was a phase-two-micle, open-label, multi-center evaluating efficacy safety and tolerability. In cohort one, there were 35 patients, and in cohort two, there were 26 patients. First one was the PRRT naive, the second one was PRRT exposed. They would miniscede every eight weeks, up to four cycles. The primary endpoints included objective response rates, and incidence, and some adverse events. So as always, in these rare wonderful things, progression free survival and overall survival. As of the 14th of April, don't know what year, but it's sure it was, maybe this year. 35 PRRT naive patients, the most common tumor type was pancreatic, and small intestine. The majority had, look great, really great one or great two. Twenty of those patients had a confirmed partial response with objective response rate of 57%, stable disease, in another 37%, and one patient had progressive disease, and one wasn't available. 14 of the 20 patients with confirmed response had a duration of response of greater than 12 months. So what's that? That's 70%. Two patients had a duration of response of greater than two years, the two year progression free survival, and overall survival 71% and 88% respectively. Which isn't bad, but it's the only two year follow up. And the most common adverse event was decreased lymphocyte count. So at the two year follow up, this do-tam-tate treatment continues to be associated with frequent, durable responses and survival patterns, and no new safety signals. I look forward to a larger trial. I agree, Josh, with your points. The fact of the matter is that we do need more treatment options in this area. I do find it particularly interesting that one of the cohorts had patients with previously been exposed to PRT. And I think that a large trial would be very interesting. But if you can have patients have somatostatin analogs, PRT, the new do-tam-tate therapy, and Bell Zootifan, all of a sudden you've got a fairly crowded space, which is good, obviously. So moving right along, our next study and our final study in this area is our winner. And the reason that we picked this one is because it is a study of advanced neuroendocrine carcinoma and much like small cell lung cancer. This is a type of tumor that is notoriously difficult to construct a study around. It's in fact in many ways more difficult because it is so rare. This is a study, a Chinese study of ZG005 in combination with the top side and cisplatin for the first line treatment of advanced neuroendocrine carcinoma. Now cisplatinatoposide or carboplatinatoposide, they are the standard of care therapies. If in Australia you're feeling a little bit brave or illegal, you can flood the PBS and say that it's a small cell lung cancer and get a tesolizumab. That's probably a bit of an evidence-free practice. So carboeetop, cisetop, that is your standard of care. Now ZG005 is a recombinant humanized anti-PD1/tigip by a specific antibody, which in this study was combined with EP in treatment-naive advanced neuroendocrine carcinoma. And remember these patients who have rapidly progressive disease over the course of weeks to very short months and it is very difficult, which is why this is a phase one/two multi-centred dose escalation and expansion study. And it was first conducted to evaluate the safety and efficacy of ZG005 in combination with chemotherapy. In part one, patients received escalating doses of ZG005, as you would expect, combined with a fixed dose of EP every three weeks. In part two, patients received the agent either 10mg/kg or 20mg/kg versus +cbo, or combined with chemotherapy. This button was administered for up to six cycles, and primary objective of the escalation was to evaluate safety and figure out the recommended phase two dose. And the efficacy endpoints for part two include overall response rate, progression-free survival, duration of response and disease control rate. So again, very rare cancer. So as of May 6th, this year, Josh, a total of 39 patients were enrolled. Indian age was 61, and two thirds of patients had liver metastasis, and he is a very interesting factoid. Almost 95% of these patients had a key 67 of greater than 50% which speaks to the aggressiveness of the cancer. The most common primary tumor site was the GI tract, but only at 23.1%. So I would be interested, more out of curiosity than anything else, to see what other sites were present. I've seen a couple of very rare pancreatic neuroendocrine carcinomas, but it will be interesting to see from whence-else these cancers come. Median of five cycles was administered, and amongst 31 patients available for efficacy, the overall response rate was 50%. Three out of six patients at the 10mg/kg dosing of ZG 005, 61% with the 20mg/kg dosing compared with 28.6% with EP alone. So you've got significantly higher rates of response. Disease control rates were 83.3, 100%, and 100%, interestingly, respectively. So that's 83 for the lower dose of ZG, 100% for the higher dose of ZG, and 100% for EP alone. So a little bit of uncertainty there. In progression-free survival and duration of response were not reached, and no dose-limiting toxicities were observed in the first part, the dose escalation part. Treatment-related adverse events occurred in 82.8% of patients in the arms with the PDO1 antigen, with great three treatment-related adverse events in 55%. But most of the most common toxicities were hematological, and these are likely the known hematological toxicities one would expect from EP. The other thing to note about the study is the median follow-up is only three months. So it's understandable why the median duration of response was not reached, but that in itself is a good thing considering how rapidly treatments fail for these patients and disease progresses. So we don't have, and look, this is the phase 1, 2 study, so it's still a long way away, but we don't have a good immunotherapy option for neuroendocrine past Sonoma as far as I'm aware. Inevitable immunotherapy in this space is potentially very good news, certainly very encouraging news in an area of great need. That's it. It's an area of great need to anything that shows some form of a substance is quite nice to see. Josh, we are doing well for once in our lives in terms of time. So why don't we just keep on rolling, and we will take an area that you have great experience in, melanoma and skin cancer. So I have that much experience in, okay, sure. More in the ocular melanoma space, having worked obviously with one of the great gurus in this area in Anthony Joshua, but yeah, fair enough. So let's talk about the first trial, which is the clinical outcome and PDL1 expression analysis from the trial of mRNA 4359 plus, I got the short straw, plus M-relosomab in checkpoint inhibitor resistant refractory melanoma. So isn't this the holy grail of oncology? We've got immunotherapy, which works great, but we don't really have much afterwards, especially in the melanoma. You've got the B-Raff inhibitors and potentially some other targetable mutations, but nothing really strong. And obviously not every melanoma is B-Raff mutered. Yeah. So the mRNA, it's an mRNA-based therapy, encoding PDL1 and IDO1-IDO antigens, designed to elicit T cell responses against tumors and immunosuppress cells. This is the background. It's been evaluated in an ongoing phase one, two trial as a monotherapy on combination. They previously reported that this mRNA vaccine was well tolerated across all monotherapy doses, and here they're going to present the clinical safety and translational data from the fully enrolled resistant melanoma cohort treated with this drug and pembrolosomab. As of the 20th of February this year, 29 patients had pembrolosomab and the mRNA-4359, different doses given every three weeks up to nine doses. The primary endpoint was safety. The secondary endpoint was objective response rate, disease control rate, and duration of response. The translational analysis included looking at the T cells, so this is actually created T cell response because that's what we want to know, right? All patients had received more than one line of therapy. The median prior lines was three, ranging up to eight, there were no dose submitting toxicities or death-related deaths, treatment-related deaths that occurred, most of the adverse events of grade one or grade two, the pembrol AEs were consistent with what we knew. Of the 25 patients that were available, the objective response rate was 24%. Disease control rate was 60% and median duration of response was not reached with a median pembrol up time of 70 weeks. Of the 22 patients, with available pre-treatment PDL1 IHC or immunohistakemistry, 41% or nine of those had a tumor portion score of greater than one and all respondents were in the group. So the conclusion is that it demonstrated a variable safety profile. The T cell response is in durable clinical activity in the resistant cohort, in those with a TPS of greater than one, supporting the PDL1 as a potential predictive biomarker in this highly animate population. So I think what it's saying is that if you've got a TPS of greater than one, you're probably going to see some form of response. And if you don't have a TPS of greater than one, I don't think you're going to see a lot. Which is very interesting in and of itself, because obviously we've known about PDL1 TPS pretty much as long as we've known about immunotherapy, but it's really not something that is relevant in melanoma until now. Maybe. Who knows. It is interesting. Yeah, well, I mean, it's also hard to say it's such a small cohort, because it says that 41% had a TPS of greater than one and then all responders, you know, six out of nine and we're in that group. So two thirds of the patients had a TPS of greater than one. But then the question is, is this just incidental because it's a tiny cohort of numbers? I don't know. Do a bigger trial. Thank you. Please. And thank you. I think we would call this hypothesis generating, but it is interesting in the hypothesis that it generates. Moving right along. We have another study for refractory or relapse melanoma, and this is the primary results of the randomized phase two trial of B and T triple one in combination with submittler map with calibrator monotherapy arms in anti PDL1 relapse or refractory melanoma. So the background to this study, B and T triple one is an investigational yearidine RNA-based lipoplex cancer immunotherapy. If you know what that means, please send us an email at
[email protected]. The target's the non-mutated tumor-associated antigens NYESO1, I'm just reading here, MAGE-A3, Tyrosinase and TPTAE. Now there's been a previous phase one trial of this B and T triple one, and there were early signs of clinical activity in the monotherapy and in combination with PD1 inhibition, in heavily pre-treated melanoma. So we are looking at a potential means of overcoming PD1 or PD1 resistance, which as Joshua alluded to, is a holy grail. Now this is data from the phase two study in patients with unresectable stage 3 or 4 non-accural ketaneous melanoma, because we know actorol melanoma bays very differently to its non-accural frequently unexposed cousin. This was an open label, randomized multi-side interventional phase two study, and patients were randomized two to one to one, to either a combination of B and T triple one and semipulamap, and then calibrator arms, so comparator arms, B and T triple one monotherapy and semipulamap, monotherapy. The primary endpoint was objective response rate. We've got a lot of objective response rates in this episode, by blinded, independent central review, with secondary endpoints, including safety, PFS and OS. This is it by far our biggest study so far, Josh. It's 184 patients that were randomized 94 in arm 1, 46 in arm 2, and 44 in arm 3. The characteristics were fairly balanced between all the arms. The median follow-up was 15.6 months. The overall response rate of B and T and semipulamap was 18%, including 11 complete and six partial responses. This control rate was 55.3% in the median duration of response was not reached. The median PFS was 3.1 months and the median overall survival was 20 months, which for melanoamer that would previously have gone untreated is not nothing. Now, compared with this, the B and T triple one monotherapy, overall response rates, disease control rates were similar. The PFS was similar as well, but the overall survival was 7 months shorter at 13.7 months. Again, for semipulamap monotherapy, the response rates slightly lower, the disease control rate also slightly lower, but interestingly, the PFS was slightly higher as was the overall survival. So, you do have, again, as Josh said with his study, you do have some questions about the cohort. Is this quote unquote an incidental finding, but if not, what's the mechanism for these numbers? Why are people who have already received PDO1 therapy and PDO1 relapsed or refractory getting some benefit? It seems from semipulamap when we would expect it to work in the same way. So, look, B and T triple one plus semipulamap in advance melanoamer, that is treatment refractory, indicated statistically significant improvement against an assumed historic control overall response rate of 10%. And this is an assumed control overall response rate, and I'll be honest, I don't really know what they're comparing it to maybe where this overall response rate is coming from, maybe single-agent epilimumab as an example. B and T triple one also indicated clinical activity as monotherapy, but there was no meaningful differences in median PFS or OS. Not try necessarily agree with that conclusion given their seven month difference in overall survival between B and T triple one and the combination as well as semipulamap monotherapy, but it is interesting, there's a fair amount that could be unpacked here and I think it would be interesting and I hope as we do for all of these studies that they go on to a bigger phase 3 trial where we can get more data, more patients and try and unpack or try and reproduce, I guess, first, but try and unpack some of these trends in the refractory melanoamer space. Yeah, I feel like there's always a number of these trials at every large conference and it's like, come on, something bigger and then you just don't really hear much. Especially because you and I, Joshua, are very impatient people and we want things to happen immediately and they're setting up these trials and recruiting patients. It does take a long time. Speaking of which, this trial that you're so kindly switched to me, I actually recruited for so that was kind of exciting. This is called a nucleation prevention and vision preservation in primary UVO melanoamer. This is the preliminary result of the phase 2 study of new adjuvant, Daryl Vessertib, which is great because Anthony Joshua speaking, which was the lead of this trial, so that's kind of fun. I wonder if he presented this adesimo. Primary UVO melanoamer, it's essentially brachytherapy, which is vision compromising and 95% of UVO melanoamer harbored this G-NAC GNA 11 mutation. Daryl Vessertib which can be used in the metastatic setting is a selective PKC inhibitor that inhibits the growth of UVO melanoamer in vivo and it could also be a treatment paradigm for primary UVO melanoamer, but the question with this phase 2 study was looking at the safety and efficacy of Daryl Vessertib as a new adjuvant treatment. With the cohort 1 or PB, which is the brachytherapy as the cohort 2, the primary endpoint was called inucleation prevention, so preventing the removal of your eye and an irradiation dose reduction for cohort 2. Tumus shrinkage, bioproduct of diameter, there's lots of fancy words there and they looked to people's vision. 90 patients were involved to receive Daryl Vessertib twice a day in the 28-day cycle, they were in the 50s, treatment related adverse events mostly with diarrhea, nausea and fatigue, and the only greater than 3 treatment related adverse vent was hypotension. In the efficacy population, which is about 62 and 32 in cohort 1 and 30 patients in cohort 2, which is defined as patients with a tumor assessment after 3 cycles of Daryl Vessertib. In this efficacy population, 19 patients in cohort 1 became eligible for EP, which they defined as inucleation preservation and in cohort 2 patients with available paired simulation, essentially a dose reduction was seen in about 82% and over 10 of those patients or 60% showed greater than 20% in the reduction of 3, a predicted risk of having poor vision. So Tumus shrinkage was seen in more than 20% of the product of diameters, which is just a longer tube normal mathematical formula they did and they were seen in 62% of cohort 1 and 63% of cohort 2. Unlong patients who had inucleation preservation or dose reduction, the majority of this magnitude of Tumus shrinkage. So the summary is that Daryl Vessertib was well tolerated. This is all that confusing, very much like Anthony Joshua, when I used to send him emails, I mean, that in a loving way. And it's the first treatment to show Tumus shrinkage in primary uveomolinoma resulting in in inucleation preservation, radiation dose reduction and potential for vision preservation. So these are really exciting, like, you know, really rare tumor that went out in the taster size. You know, you've got a couple of lines, but it's not great. Well, it is good, better than what it was, but it's not kind of perfect. And so they've got a registration study, which is super exciting, very exciting and well done to you Josh, not just for recruiting a couple of patients to the study and definitely not making a big fuss about it, but also for getting through the retelling of the figures of the study. We do have one more study. And this is our winner for our favorite, our personal favorite Melano Mart study in Esmo 2025. And the reason is that aside from antibody drug conjugates, there is one thing that is very close to our hearts on oncology for the inquisitive mind. And that is a deescalation study. So this is the safe stop trial. This is early discontinuation of anti-PD1 therapy upon achieving a complete or partial response in patients with metastatic melanoma. It's another one of those studies that sort of tries to confirm in a scientific setting, something that we probably in many cases already do or already think about doing. Background anti-PD1 therapy has significantly improved survival for patients with metastatic melanoma, that is probably very obvious. However long treatment duration, which is usually given as greater than or equal to two years, has significant impact on patients. We know about the potential development of immune-related adverse events that impair health-related quality of life. And there's also the resource aspect we do talk about health economics every now and then, and giving immunotherapy for the maximum of two years does take up resources, not just money in terms of providing the drug, but chair time, resources of medical professionals, nursing staff, all of that stuff. And currently there's no consensus on the optimal treatment duration in melanoma. The aim of the safe stop trial was to evaluate whether discontinuation of first line anti-PD1 at the first confirmation of response is safe in patients with metastatic melanoma. Now this was a pragmatic design because, as you can imagine, something that is looking at stopping treatment is going to be very difficult to recruit to. So this is a pragmatic design, prospective single-arm study, in 14 melanoma centers in the Netherlands, and they're used to historical comparator, which is keynote 006. Design and recruitment began in 2017, and so this was based on data at the time, and obviously there have been some changes and advances since then. Enrolled patients had to be willing to stop immunotherapy after achieving a complete or partial response, and they were enrolled when they stopped the immunotherapy. So patients were recruited if they had irresectable, stage three, or metastatic melanoma, and then had a confirmed complete or partial response. In the case of disease progression, anti-PD1 therapy could be restarted, and other salvage therapy was allowed at the discretion of the treating physician. So obviously you've got a B-Raff mutant melanoma, or you've got someone who goes on another clinical trial, theoretically you could do that on this study. That's that pragmatic study design. The primary objective, the primary endpoint, was the rate of ongoing responses at 24 months after treatment initiation, and this was compared to the ongoing response rate. This is the historical comparator of 39% at 24 months, and this was in the keynote 006 trial. So between February 2019 and August 2023, they recruited 200 patients in all 14 Dutch melanoma centers. The median treatment of duration with anti-PD1 was 24 weeks, so 24 weeks to achieve a significant response. At inclusion, 58 patients had a CR, and 10 patients were known to have brain metastasis. So 29% had a CR when they were enrolled in the study. Now this is where it gets good. The ongoing response rate at 24 months in the study was 81.8%. Confidence interval was 76.7 compared to 85.8, and you should compare this as they didn't study to the historical control rate at 24 months of a shade under 40%. Overall survival at 24 months was 95.9%, and melanoma specific survival was 97.4. Obviously no p-values, because this is a single alarm study, and the comparisons are probably purely academic, and the hypothesis generating. But this is a prospective trial, and it's a multi-center trial admittedly in one cohort. There is a significantly higher response rate at 24 months, compared to what they took as a historical control. Now a lot has changed. The big question from this study is why is the response rate in this study so much higher than the historical comparator? 40% compared to very close to 82%. Obviously lots of things have happened since then. Our understanding of melanoma biology has improved. We know that in many other tumour types, the degree of response is a predictor for ongoing response. We know sort of how melanoma responds to treatment on an ongoing capacity as opposed to just an initial capacity. So it could just be that we know a bit more about the disease as opposed to the treatment changing, because obviously the treatment hasn't changed. I think that is the big question. As with all of our studies in this episode, I would love to see a big prospective study. It's going to be very, very difficult. But perhaps this is just a little bit of confidence, a bit of a confidence boost, Josh. If you have a patient who has a major response, a complete or partial response to immunotherapy with metastatic or unresectable melanoma, they're getting a bit sick of it, or they've had some minor toxicity. It may be, I'm not willing to go the full hawk, but it may be safe to finish their treatment early. It might be my quiet. As we continue our Esmo crusade for the ages, Esmo crusade for the ages, where we go through upper GI, hepatobleric cancers, and colorectal cancers on next week's episode. Yeah, just call Josh Indiana Josh and call me Sean Connery. And we are on the last crusade. You're not Sean Connery. I'm Sean Connery. Actually, I'm Harrison Ford. I'm happily Harrison Ford. You saw a lot. Are you seriously bypassing Harrison Ford right now? When I was thinking about it, I'm like, no, no, I'm good. I'm good. I've got my whipping case. You annoy me. I think this is a debate that can happen offline. So let's let everyone get on with their day. Thank you for listening to this episode of oncology for the Inquisitive Mind, produced by ADC Productions with the assistance of education grants from Pfizer, Gilead Pharmaceuticals, and the Merck Pharmaceuticals. As always, these companies do not receive early previews or editorial input of any kind. The opinions expressed in this episode are our own, and the facts are, well, the facts. If you liked this episode, please consider subscribing to be among the first to hear our latest forays into the ever-changing world of medical oncology. You can find previous episodes of our show, including coverage of major conferences, interviews with world-renowned experts, and much more at inquisitiveonc.com. If you would like a particular subject covered on the show, drop us a line at
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