The Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute presents a succinct summary of all the bladder cancer clinical updates you need to know from AACR 2026.
Yeah. All right. So, yeah, moving on to the next, uh, we're in the bladder cancer space, uh, in AACR there are a few that targeted in ADC and synthetic lethality therapies, which might be useful in bladder cancer space. The first, uh, study that I'm gonna discuss is a phase one trial of TS-8201A, which is transtuzumabdoxican in combination with ollareb and HER2 expressing malignancies. Uh, the result from the dose escalation. Uh, this was presented by Doctor Elizabeth Lee, which is one of our gynecological oncologists, and, uh, uh, this was studied done under CTAP or NIH. Uh, this, uh, study provided a very innovative idea of a combination of this ADC and Olarib. Uh, basically, the TO1 inhibitor trapped the topoisomerase one during the DNA cleavage, generating the, uh, topoisomerase DNA cleavage complexes, and uh after that, the replication fork and transcription complex collide with the top 21 cc. And the cleave DNA templates become misaligned and generating irreversible top one, complexes. So, uh, so there is a synergism of possible synergism of PARP inhibitor and TPO1 inhibitor that occurs strictly due to PARP-catalytic inhibition regardless of the PA trapping ability. There is a historical, historically, this uh uh syn synergy has been tried with the chemotherapy, mainly dopa-1 inhibitor chemotherapy with uh PARP inhibitors, but the main hurdle was, uh, toxicities, uh, high rates of grade 3 or 4 cytopenias or immunological toxicities and GI toxicities as well. So DLTs were a major limitation and therefore the mini trials historically was not able to move forward. This is just like ADC construct of transfuzumabdoxican which we are aware with uh payload, potent payload, and the drug to antibody ratio around 8, and there is a cleavable linker. So the innovative idea is that because in a classical, historically, the chemo and the PARP inhibitors simultaneously have toxicities, the idea was that after administration of dopeP1 inhibitor, dope 1ccC remains in a heavily loaded in tumor cells, while in the normal tissue, it gets cleared, as on the right side in the figure we can see the brown shows the normal tissue where there's a quick clearance of the TP 1 cc. But in the green, there's an accumulation of the 2. CC in the tumor, so we can utilize this physiology, uh, physiology with introducing PARP inhibitor later when it is cleared from the normal tissue. So, uh, so that makes it like a good temporal precision with a gap dosing, um, with uh the PARP inhibitors to mitigate the overlapping toxicities. This is a, a steady designed for the dose escalation. Um, the authors, uh, designed this, the model 12, and 3. Basically, the module 1 has olaporib in a continuous dose from day 1 to 21, and Module 2 olaporib was introduced at day 8 through day 14, and Module 3 olaporate from day 3 to day, day 9. Key eligibility criteria include advanced solid tumors, measurable disease, HER2 IC greater than 1 plus, or ERBB2 amplification. No limitation in the prior line of treatment and prior P PARP inhibitors was allowed. Uh, patients who had a non-infectious ILD and pneumonitis were excluded. The primary objectives of the study was to evaluate safety and tolerability uh with a combination of DSA 201A plus Olareb and to find the recommended phase to dose. Secondary objectives include ORR, clinical benefit rate, TUR, and median PFS. Baseline characteristics include a total of 28 patients were enrolled, mainly endometrial cancer and ovarian cancer, and median prior lines of therapy were 3.5 and 43% of the patients received prior PAARP inhibitors. And also, uh, 32% of the patients had a primary platinum free interval of less than 6 months. And most of the patient, uh, all the patients had, uh, HER2 expression, and, uh, mainly IHC 2 in 57% of the patients, and one patient had HER ERBB2 amplification. And 2 patients in the entire cohort had BRCA2 mutation, 1 somatic, and 1 more had a germline mutation. So, uh, when the trial was designed, when they tried the module 1, it was deemed not feasible because there were dose limiting toxicity in 3 out of 3 patients. Similarly, for module 3, dose limit 1, there were 2 out of 2 DLTs, so it was declared infeasible, and in module 2, it was deemed feasible with olarib dosing from day 8 through day 14. As we can see in this slide, the treatment-related adverse events were attenuated with this staggered or gapped schedule ollarib dosing. On the right-hand side, we can see that there's a decrease in the hematological toxicities and low grade gastrointestinal toxicities with this graph dosing of ollarib, whereas on the left-hand side of the slide, there's increased toxicity with continuous dosing. And also, uh, hematological adverse event where markedly are noted in module 2 compared to the module 1 in this slide. And with the transfuzumabdrotean, we have to take extra precaution than pneumonitis. So, uh, in module one, there were grade 2 and grade 1 toxicities, um, and those were mainly like late events. In terms of the response, there was a good tumor response in combination treatment with overall response rate of 54% and confirmed response of around 46%. 67% had clinical benefit rate and medial duration of the response was around 11 months. One patient had uh complete response. In the swimmer plot, we can see that there's a the median duration of the 8.4 months, uh, the PFS at 6 months was around 88%, and estimated median PFS was 15.2 months. So, my clinical, uh, key clinical takeaway is it's PR catalytic inhibition prevent T1 CC repair, creating high-related targeted DNA damage, and TDHT provides tumor-specific to1 inhibitor. And gaped ollaerative dosing seems to um leverage the, uh, the attenuate, like uh attenuate the toxicities uh as compared to the continuous dosing. So, the main question remains, that is the activity. TD uh is this activity from TDX alone versus TDX plus Olarib, which is an unanswered question in this trial. Given that we have, uh, in the bladder cancer space, the HER2 is highly expressed and there's also frequent DDR alteration, uh, this is a potential trial. This kind of ideas can explode in the bladder cancer as well. Now moving on to the next abstract. The first in human study of a novel novel EGFR targeted ADC in patients with advanced neuropharyngeal carcinoma, SYS 6010001 in NPC. This is a trial that was done in Chinese patients. I thought this trial is important because in some subset of the urothelial or urethral carcinoma or like in a penile cancer, there's a high EGFR expression, so there's a potential of exploring this kind of Targeted uh treatment in, in GU space. Again, this is EGFR ADC construct, which has a DA of around 8 and the payload of topoisomerase 1, topoisomerse 1 inhibitor, and excellent specificity for EGFR with high endocytosis rate in the cells. Trial design uh includes mainly NPC nasopharyngeal carcinoma, and there was no restriction on EGFR expression in this patient cohort. And most of the patients were heavily pre-treated with the platinum and immunotherapy. Uh, the study was designed to give in the two doses from, 4.2 mg and 4.8 mg per case. Primary endpoints include safety, tolerability, and recommended phase two dose. Secondary endpoints include overall response rate, duration response, disease control rate, PFS and OS. 56 patients were enrolled and cut-off time was the median follow-up time was 11.5 months. So, as we can see from this uh slide, uh, the mainly Asian patients were enrolled in this, uh, trial, and uh there was a small subset of squamous cell carcinoma, uh, and, uh, stage 4B was mainly in higher proportion in 4.8 mg per kg as compared to 4.2 mg per kg. Most common grade treatment emergent adverse events were hematological toxicities, as we can see in this slide. And uh in terms of the response, 32% of the patients achieved the objective response with 1 CR in 4.2 mg per kg cohort, and overall response rate of 28% in 4.2 versus 36.4 in 4.8 mg per kg. In terms of duration of response in the swimmer plot, we can see that 4.8 mg per kg seems to have uh more better duration of response as compared to the 4.2 mg per kg. And PFS there were no difference in the PFS, uh, all median, uh, PFS was around 7.5 months, regardless of the dosing. When, uh, uh, analyzed based on the EGFR pre-treated versus NI, as we can see here, there is a higher overall response rate in the EGFR nive, um, antibody NIV patients with 40% OR in 4.8 mg per kg and in uh uh 38% OR and 4.2 mg per kg. So, there were no difference uh in ORR and PFS uh found by EGFR expression level. So, this ADC targeting EGFR showed clinically meaningful activity and sustained uh durable tumor shrinkage and heavily pretreated nasopharyngeal carcinoma. There's a signals, a preliminary signal suggesting that EGFR antibody 9 population tend to have better response with this ADC. And also, uh, the treatment seems to be manageable with safe, uh, in terms of the toxicity profile. Uh, the, the key question in the GU space is that whether this kind of ADC we can apply in some subset of bladder cancer or some rare tumors such as penile cancer, which has high expression of the EGFR. With this, I will hand over to Doctor McGregor to comment more on this abstracts. You're mute. Cancer, um, space as we think about this, but I think as you go to the first one with the HER2 story or HER2 PARP, I mean, I think there's been this long thought about, you know, using the TPA-1, and synergy like that was the idea behind combined with platinum, and now we have a very novel strategy combined with PARP inhibitors. So I think From from where we are right now, I think it's intriguing because this idea that ADCs can be used with other drugs, we have to think of it as a monotherapy. Like we've done this with dad. Um, I think this data here supports the tropion Tropion started looking at platinum Dao DXD versus platinum gem, like what is that role there again. With the platinum being the pooring part, and then the combobas trial is actually open right now with TDXD plus nerapirib for those patients who are HER2 overexpressors. So that can be a way in which we sort of use some of this, what we've seen here and apply it into an ongoing clinical trial that we can be a part of. But I think this is the start of, you know, starting to combine ADCs with other agents that we're not going to be ADCs on monotherapy anymore, but really looking at combinations. In terms of the second half track looking at EGFR, I think. I mean, I agree with your point. I think that as we start to explore ADCs, um, obviously the payload, target link are all important, and so this is sort of very exciting for a very unique cancer with oparyngeal showing great activity of this Melva ADC and can we start using this in other, other cancers? You know, we already have the um the hope that BMS trial with EGFRHER3 ADC that's in development, which is the biomarker are selected was pretty encouraging results and um. Eothelial cancer as we've seen before, but to your point, I think that this is certainly we need to start thinking about looking at some of these more difficult to treat cancers and thinking about novel targets and EGFR certainly that we could think about in penile carcinoma where our response has been quite poor, but I think at the same time you need to make sure you have the payload that's going to be effective in those pure, the pure squamous, but I think Um, again, I think really exciting ways as we start thinking about the future of ADCs that we're going to be starting to look at ADCs in novel approaches, novel situations, but also in novel combinations. Thank you, Doctor McGregor.
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