The Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute presents a succinct summary of all the renal cell carcinoma clinical updates you need to know from AACR 2026.
I'll now move on to um some of the exciting abstracts in uh renal cell carcinoma or immunotherapy, immunomodulation space. uh Doctor Sherry is our discussing, discussant for this topic. So, first, I'll discuss about um first in human P phase one study of PLN 101095, a first in class dual alpha-V beta 8, alpha-V beta 1 integrine inhibitor as monotherapy and in combination with pemblizumab in a patient with advanced solid tumors refractory to immune checkpoint inhibitors. This is the common um resistant pattern in our uh RCC patients, so this trial is important in that respect. So, uh, the rationale seems to be quite compelling. Uh, the tumors can use integrane mediated local activation of TGF beta to create immune suppression and stromal resistance. And the PLN 101095 is designed to block this local activation rather than broadly inhibit systemic TGF beta signaling, with the goal of increasing interferon gamma signaling and reducing fibroblast activation and restoring immune responsiveness. So, uh, these slides provides a mechanistic bridge from clinical inhibition to immune effect. In the pre-clinical model, um, PLN 101095 reduced TGF beta associated signatures and increased interferon gamma associated signatures, shift, shifting tumors from uh towards more ICI responsiveness. Um, this is a trial, uh, trial design, uh, a phase one dose escalation study in patients with a prior PD1 resistance, and, uh, there was a short monotherapy leading followed, uh, with PLN 101095, followed by remlizumab. And uh the uh primary endpoint and secondary endpoint includes safety, which includes TEAs, serious treatment emergent um adverse events, DLTs, and pharmacokinetics. Secondary exploratory endpoint includes uh clinical activity with ORR DCR per irists, and some corollary studies, uh, correlative studies include biomarkers. Uh, patient, uh, although this is a small, uh, phase one study, but there's a diverse patient populations, uh, uh, with this advanced solid tumor, including one patient with RCC, uh, and, uh, also there are patients with ICR resistant, which is the key, uh, or important for this trial. So, considering the safety and tolerability, PLN 101095 was well tolerated, with most common side effect is a rash, mainly grade one or grade two. rash was reported during the monotherapy period, otherwise, uh, they were primarily observed within the day two of starting combination treatment. Uh, responses were observed in a patient who had a secondary IA resistance with one complete response, 2 partial response, and one confirmed PR. So, overall, uh, 19% overall response rate in overall study population. In ICI resistant cohort, there were 30% overall response rate. There is a uh a durable response observed in 3 patients out of 4 IC responder with dose greater than equal to 1000 mg BID and the average maximum tumor shrinkage reduction, tumor reduction of around -89%. In terms of biomarker, uh, with, uh, clinical response to PLN 101095 was associated with elevated plasma interferon gamma and PD1 levels after day 14 monotherapy. So, this is kind of potential biomarker to suggest that introduction of immunotherapy at day 15, day 14 or day 15 might be helpful because those are the marker for the immune uh activated condition. So in the key takeaways, the PLN 101095 has successfully demonstrated both biological viability and superiority in dual innovation of integrine alpha V beta 8 and alpha-V beta 1. Uh, there is early indication for anti-tumor efficacy in a patient who has secondary resistance to the immune checkpoint inhibitors and treated with PLN 101095 in combination with premlizumab, showing overall response rate of 30% and disease control rate of 60%. And more importantly, in this abstract, interferon gamma can be a potential early predictor of response uh with the immunotherapy and the combination of this PLN 101095. Uh, currently, those, uh, uh, the authors are planning to do those expansion cohort and expanse and non-small cell lung cancer, clear cell RCC and TI TMBI cancers. Moving on to the next target, this is pre-clinical, which is uh basically drug development in the space with the ENPP3 ADC by Johnson and Johnson. The molecule, the dis discuss was like JNJ 89862175 in advanced solid tumors. As we know, uh, ENPP3 is a type 2 transmembrane protein and has restricted expression in normal tissue with loss of polarization in tumors. It is highly expressed in solid tumors, specifically RCC and lung adenocarcinoma, CRC and helocellular carcinoma. Although we don't have clearly elucidated functional role of ENPP3 in cancer. So the good, it is a good target because there's a negligible expression in normal tissues, and there's a broad and homogeneous expression in the solid tumors. And uh this provided a perfect target for ADC to release into the tumor. As we know, uh, there were some trials, uh, with ADCs targeting ENPP3 in RCC space, which are discussing Dr. Sherry was involved in that trial, uh, almost 8 years ago. And, uh, the, the, the two ADCs that were tried, I, uh, kind of summarized on the right side of the Table, right side of the uh screen with a table with some response, but I think the drug didn't move forward because of uh no efficacy signal in the later phase. So, JNJ 8986217 is humanized IgG G1 backbone targeting extracellular domain of ENPP3, and there's a protea cleavable linker and the, the payload is orestin derivatives. And And uh in pre-clinical studies, JNJ 89862175 showed, showed ENPP3 specific and potent binding to the tumor cell lines and rapid internalization and demonstrated anti-tumor efficacy in vitro and had bystander activity as well. So, it also showed anti-tumor efficacy in patient derived xenograph model of ENPP3 expressing RCC and non-small cell lung cancer. So, uh, this is a small table to summarize what is the difference between prior ADC targeting ENPP 3 versus GNG 2175, which is novel ANPP 3 ADC. So, the prior ADC was humanized IgG 2 and hybridoma, this one is high affinity humanized IgG1. The payload in AGS or AGS 16C35 was non-cleavable microtubule inhibitor, but this novel ENPP3 with GNJ is sin derived payload, which is membrane permeable payload. Linker was non-cleavable in prior trials. This one is cleavable linker. And toxicities uh associated with prior ADC include the chopath, keratinopathy, thrombocytopenia, and some modest activity in RCC only. And this is uh the new JNJ ADC is designed to reduce the ocular or hematologic toxicities with broader anti-tumor efficacy. So, key takeaways, JNJ 2175 is a normal ADC. It has features of high affinity in preclinically and specifically targeting um ENPP3. Uh, it uses normal payload and with a bystander activity. In pre uh preclinically, there's a robust anti-tumor efficacy in RCC and lung models. Although it's uh the, the, the studies also claimed that preclinical studies with a non-human primate, it was well tolerated and shown to have favorable pharmackinetics. Currently, there is ongoing phase one clinical study focused on advanced solid tumors. Now, moving on to the next uh target, which is, which was uh which was uh presented in the AACR 2026 is the discovery and optimization of new 811 1st in class molecular glue degrader of ARNT utilizing structure-based drug design. This is simple schematic for the RCC biology. There's a VHL loss, HI accumulation, and tumor angiogenesis and growth. And uh this is uh clear cell RCC is driven mainly by hypoxia, unchecked hypoxia signaling. So the clinical rationale was that hypoxy inducible factor beta, also called ARNT, is essential for dimerization partner for all HIP alpha subunit. The oncogenic hypoxia signaling cascade collapses without HIP1 beta. So blocking and eliminating ARNT offers a strong barrier against the survival of the clear cell RCC tumors. So, uh, historically, HIP1 beta or ANT was viewed as a difficult drug to, uh, difficult to target the drug because the protein-protein surface infraction remains relatively flat, as shown in the right side of the diagram, and lacks a catalytic pocket where a small molecule is unable to bind and cause inhibition. So, the abstract demonstrated some clinical, pre-clinical evidence that neoE11 has a potent and selective ERNT degrader. So, uh, this molecule does not rely on blocking the active site. It functions as a bridge, recruiting the E3 ibuquineligase directly to ERNT. This induces proximate uh triggers the cell's natural disposition system and ibuination and proteasomal degradation. And in pre-clinical space, the neo 811 showed uh robust efficacy in a zoonograph model. So key takeaways from this abstract, so NO 8811 uh pioneers the degradation of ERNT, unlocking an undruggable target. It represents a novel mechanism where molecular glue technology to eliminate the target, then like compared to the small molecule that inhibit the pocket. So, pre-clinical evidence shows a highly favorable in vivo efficacy and selectivity. So this could be highly primed for the next uh next phase of the clinical study. So currently, there is a phase 1 or 2 study that is evaluating neo 811 in a patient with locally advanced or metastatic clear cell RCC. So the core question is that it can it overcome the adaptive resistant or hypoxic survival network by degrading ERNT in a patient with clear cell RCC. Moving on to more exciting abstract that was discussed in AACR, new adjuvant L1 beta and PD1 inhibition in localized clear cell RCC clinical and correlative analysis of phase 1B SPARC one trial. As we know, localized RCC is highly immunogenic, as well as there's a recurrence rate of 20 to 30% after surgical intervention. So there's a high chance of like systemic micrometastatic disease that likely precedes the surgical resection. There is no currently established role of new adjuvant therapy in clinical practice. So, current treatment, uh, focus for the highly localized clear cells RCC includes surgery followed by pembrolizumab, adjuvant pembrolizumab in high-risk RCCs based on the keynote 564 data. Basically, to target microscopic residual disease after primary tumor resection. There's unmet need for the new adjuvant gap in this space. So there, uh, so we need, um, this trial kind of lay out the idea of new adjuvant to change the tumor microenvironment and how that can be uh potentially feasible for the future trial. As we know, uh, RCC has extensive population of the myeloid debride suppressor cells, which is one of the key resistant mechanisms for immunotherapy. So that these uh tumor suppressive myeloid cells exhaust the cytotoxic T cells, therefore, single agent inhibition often fails and develop the resistance with the treatment. So, this trial basically focused on uh targeting myeloidis required to unlock the deep immunologic response. This was shown in a pre-clinical studies where IL-1 beta inhibition shift the uh tumor uh associated macrophages towards more anti-tumor phenotype and that enhanced the PD1 blockade efficacy. Based on that pre-clinical evidence, Spark one designed the trial that uh hypothesized that untreated localized clear cell RCC, which is suppressive, uh, dam-rich TME, uh, that combined the new adjuvant of uh interleukin one beta plus PD1 blockade to reprogram the clear cell RCCTME from the suppressive myelid state toward the effective anti-tumor immunity. Interleukin 1 beta cannakinuzumab was used and PD1 inhibitorspartulizumab was used in this trial. Which help in suppressing the myeloid signaling and T cell dysfunction. And make those tumor microenvironment less suppressive myeloid program. The study design include high-risk, clear cell RCC, T1B to T4, and N0, TNEN1 or M0. And the NTPD1 was given every 4 weeks, and canekizumab was given every 4 weeks. And primary endpoint includes safety and feasibility of canelizumab and sparilzumab, exploratory endpoints include twelve-month metastatic-free survival, and some immune response correlative studies. Baseline patient characteristics. A total of 14 patients were enrolled in this study. And uh uh interleukin 1 beta NN PDU1 is well tolerated and safe, feasible in the new adjuvant setting. No grade 3 treatment-related adverse events were noted. All patients underwent surgery without any unexpected complications. Uh, 50% of developed patients developed any treatment-related adverse event and mainly musculoskeletal and connective tissue disorder. So pathological characteristics, uh The T3A was uh in um T stage 64% of the patients, and grade 4 were presenting 31 21% of the patients, and grade 3 and 35% of the patients. So, interleukin 1 beta and PD1 blockade reveals promising clinical activity with no recurrence in 12 months' time period. And also, uh, 38.7% improvement in the DFS as compared to predicted at six years' time point with new adjuvant combination. The correlative analysis revealed the distinct modulation of the tumor microenvironment and the uh trial did a mass tissue analysis confirming the successful penetration of the dual inhibition of the agents. Uh, IL-1 blockade corresponds with a measured depletion of the myeloid suppressive signatures and PD1 uh inhibition facilitate the measurable CT cell reinvigoration and infiltration. So, uh, the study shows that TMA shift from the immune suppressive to more immune active state. So this, this shows quite a proof of concept and clinical feasibility with this trial, and new adjuvant intervention did not compromise the timing and safety of the definitive surgery, and it did, uh, the combination did overcome the myeloid resistance and provided a durable systemic control. And there was no safety signals in terms of treatment. And The key takeaways from this study, there's a quite unmet need for the new adjuvant treatment in a high-risk localized clear cell RCC. So this trial successfully bridged the pre-surgical gap for high-risk localized clear cell RCC patients, and there is a, uh, the trial also showed biological resistance overcome with dual interleukin 1 beta and PD1 inhibition that remodels the suppressive myeloid TME to more immune responsive. So this is a really good proof of concept mechanistic where new adjuvant immune priming can modulate and improve the patient outcome. So, and it was well tolerated. So, the core question remains, does the observed neoadjuvant pathological immunologic changes with AL21 beta and PD1 translate into superior PFS RPFS or overall survival with the current adjuvant pembrolizumab. And uh to define the practical biomarker or clinical enhancement strategy to identify which localized clear cell RCC truly need interleukin 1 beta or PD1 inhibition. To, uh, we, our own Doctor Vincent Zu, who pioneered the pre, pre-new shift like new adjuvant sandwich immunotherapy with HIP inhibition and immunotherapy combination. Uh, in this trial, currently, we are enrolling patients where patients are given caststatifan and imbrimab, uh, or catativan uh for 3 cycles and followed by surgery. And uh and there will be a visit after post nephrectomy. This is quite an exciting trial, and we are hoping to enroll patient and see the outcome in this trial. Now I move on to Doctor Sheriff to review on those critical review on the, those abstracts. Uh, hey, um, thank you. Um, do you have by any chance, do you have them listed? Uh, uh, uh, like in terms of, uh, uh, Yeah, one by one to go. Oh yeah, sure. Maybe Vicky, your one of your first slides, you had everything listed one by one. Yeah, I can, uh, Yeah. OK. Now, um, Mm, OK. So, I mean, I'm not, I think the biology of THEF beta and how to uh inhibit uh TGF beta and components of TGF beta, that's the first abstract. It's quite complex and one size does not uh uh fit all. We have work from um David Braun in my lab that showed that there are certain, um, certain population. Of uh T cells that are sensitive to TGF beta 1 inhibition in a context, um, uh, that include immune checkpoint inhibitors. So it's specific to do something like that, I don't know. And the two patients that responded were not clear cell RCC and I also like to um Uh, see, uh, responses from monotherapy, from 101095 monotherapy, which we have not, we have not seen if you look. The ENPP3 is a great target in uh clear cell RC less so in papillary, but still makes sense. Um, we have done a study with an antibody drug conjugate a long time ago, uh, versus exitinib, a randomized phase two that showed exitinib. works actually better. So I think the reason is the payload. With these ADCs is chemotherapy-like and response rate to chemotherapy, regular mitotic uh targeting agent in chemotherapy is near zero in renal cell cancer. So what do you expect, uh, uh, you know, a better delivery to be better. I don't expect it if the core agent does not work. NO 811 is um quite um Interesting. I've been involved in original um study here. We're gonna open it at the MGH. We have our own uh study with uh Steph Berg here with the BMS one. They're both ARMC degrader, ARRNMCT, also known as FO beta, is the partner of FF2 alpha. I think we're seeing significant EPO decrease. And hopefully, we'll start seeing responses. There are limited spots, but it's an important study and important to, um, you know, uh, enroll to this, um, and hopefully, Steph will be, uh, leading, um, you know, this study, uh, nationwide. Um, of course, only it has responses. We will know within the next 6 months. This is Neomorph, it's very similar. Actually, the, um, uh, The founders of that company are from Dana-Farber, 3 out of 4, I believe. Uh, I am not a believer in IL-1 beta signaling for cancer. If you know, for prevention, they did that cardiac, large cardiac uh study and they found, oh, as one of the subgroup, lung cancer goes down, lung cancer, uh, uh, incidence goes down, but I think Um, you know, they start using CI in, um, all sorts of cancers with or without checkpoint inhibitor. There's a trial in lung cancer called COI 2, which is with or without docetaxel post PD1 and chemotherapy, and that was completely, uh, negative. So I don't know, uh, yes, you want to test something as a window of opportunity here. That is fine. At least with PD1 inhibition, you have something that is active. The problem, how do you separate the effect of IL1 beta uh inhibition if you don't have an, you know, a PD1 only uh arm, for example. I'd rather um invest in uh prenatal shift and hopefully in neo shift later. Thank you, Vicky. Thank you
