The Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute presents a succinct summary of all the kidney cancer clinical updates you need to know from ESMO 2024.
For everyone who's joining us. This is the Geo oncology review of the conference highlights from ESMO 2024. For this part of our discussion, we'll be reviewing the kidney cancer updates from ESMO 2024. My name is Vincent Xu medical oncologist at Dana Farber Cancer Institute. And joining me as a discussant is Doctor Tony Shuwei asthma 2024 kidney cancer abstracts. We saw that there is no benefit for adding the volume to Tavo zib. After prior immunotherapy in metastatic advanced RCC. We also saw that I bil had a 12 month overall survival benefit among a randomized trial of patients with RCC and divergent Testo. We saw yet another phase three IOTK I combination in RCC and we have some important updates on hip two alpha inhibitors and novel mechanisms. We'll start with the TVO two study. This was a randomized trial of Tavo nib plus nivolumab versus Tavo nib monotherapy in patients with RCC who had received prior immune checkpoint inhibitor. We know from the prior contact three study that Kantin plus A Tazi was not superior to Kalin in patients who had received prior immunotherapy. The TVA two study asked a similar question but with a PD one inhibitor instead of a PDL one inhibitor patients with locally advanced or metastatic RCC and who had progressed after prior immunotherapy were randomized to Tava and the volume or Tavo NIB alone. Of note, the dose of Tavo NIB was different in the two arms and it was higher in the monotherapy arm. This was due to potential concern for hypertension with combination therapy. Patients were stratified by part by prior therapy including by whether the most recent line of therapy was immune checkpoint or not. Adjuvant immunotherapy was allowed on this trial going straight to the results. Centrally reviewed. PFS was not different between the two arms in the I TT population hazard ratio was 1.1 for PFS with a P value of 0.49. And looking at subgroups, PFS was not different among any of the subgroups consistent with the PFS. Overall survival was also not different for Tevas nib plus nevala versus Tevas nib with a P value of essentially one and it has a ratio of 1.00. Looking at the adverse events, it was interesting to point out that the Tavo nib related adverse events were more common in the monotherapy arm, which is consistent with a higher dose of Tabas nib among patients uh receiving monotherapy. In summary, TEO two is the second trial that shows that there's no benefit to adding immunotherapy after patients have progressed on prior immunotherapy. There was no benefit for adding nivolumab to Tava Nib. Consistent with prior results. We should not be using IOTK I combinations of patients who recently progressed on immunotherapy. This trial does show that Tava Nib is a reasonable option in refractory RCC with a 20% overall response rate after prior IC I. Although um it's hard to compare this trial directly to contact three, but for the record contact three, Kanty had approximately a 41% overall response rate. Next, we have a potentially practice changing trial. This was the Sunni forecast trial, a prospective randomized phase two trial of it be evil versus standard of care in nonclear cell RCC. Sony forecast randomized patients with divergent histology RCC, which consisted of predominantly papillary RCC with a significant minority of patients with chromophobe RCC. Patients were randomized to either it be nil followed by Nebo maintenance or to standard of care. In this trial, standard of care was mostly single agent TK I uh some patients received SUNItinib, uh fewer patients received cabals anin and a very few patients received IOTK I combinations. This trial was the first randomized trial to evaluate Eppel in nonclear cell RCC. Again, I want to point out that close to 60% of patients had PR CC and almost 20% of patients had chromophobe RCC. There was about 4.5% sarcomatoid features. This trial met its primary end point and I apologize for the Typo. It's 12 month OS not 21 month. OS 12 month OS was superior for ile compared to standard of care with a P value of 0.01. However, overall survival rate at six months and 18 months and overall did not meet statistical significance. Looking at the subgroup analysis PDL one did appear to enrich for benefit from IIL with more benefits seen among patients who are PDL one positive. There was benefit from IPIL among patients with Chromophobe RCC as well as the overall population. Looking at the Sunni forecast results in context. Eppy evil had an overall response rate in this trial of 33%. This randomized trial does establish a be evil as a reasonable treatment option in RCC patients with divergent histologist and nonclear cell. The 26% overall response rate for pineal in Chromophobe RCC is intriguing and potentially shows that pure ile regimens can work in a subset of chromophobe RCC patients. The bottom table shows this data in context with recent combination therapies and I want to point out that um there were significant response rates seen with other immunotherapy combinations including Cabo Aao, Cabo, Neil and Len. Next, we have a randomized phase three study and LA NIB combined with anti PDL one which is be Melba versus Sunni nib. This is another IOTK I versus SUNItinib randomized trial predominantly was done in China. The background for this is that Bell MENSA start is an anti PDL one and alot NIB is a VEG FTK I both are already approved in China for other indications including non small cell lung cancer. In this study, previously untreated patients with metastatic clears RCC were randomized to the combination or to SUNItinib PFS was the primary endpoint. This trial did beat its PFS end point um with a hazard ratio of 0.53 and a significant P value favoring the combination R, the response rate was 72% for the combination versus 25%. For subit I do want to point out that for an immunotherapy combination, there was a surprisingly low cr rate with a complete response rate of only 1%. Overall survival was not mature but not statistically significant. Although favoring the combination arm at the time of the data cut off. In summary, this new PDL one plus TK I combination shows PFS benefit versus Sunni nib given the existing landscape and the lack of OS benefit. It's very unlikely that this combination is going to see widespread use in the United States or Western Europe, but it could be relevant in other countries and especially in China. And this could sit in a similar space with ait plus to paloma, which was recently also presented. Next, we have some fascinating fecal microbiota data. We uh have preliminary results of the randomized phase two tacito trial. The background for this is that we know the gut microbiome is very important for IC I response in RCC and also actually for other diseases, we have several prior randomized phase one trials showing that this active microbial product CBM 588 seems to improve outcomes when added to Cabo Naval or to IVO. This trial investigated whether transplantation of fecal microbiome from a responding patient might improve responses uh to IC I. In this trial, patients were all receiving axitinib plus pembrolizumab for first line treatment of RCC patients with clear cell or nonclear cell were eligible for this trial. Patients were randomized to ayem in combination with placebo or in combination with fecal microbiome transplantation. The transplantation was done in three steps first by colonoscopy, then with two oral capsule uh delivery regimens. The primary end point was PFS at one year. This trial met its primary end point progression free survival was 67% versus 35% for FMT versus placebo. Looking at secondary endpoints progression free survival and overall survival also favored the combination therapy. The overall response rate was 52% for FMT versus 28% for placebo. This is an interesting study and adds to the literature of several small randomized trials showing the microbiome is active in RCC. There were no severe adverse events from fetal fecal microbiota transfer. However, it is kind of intriguing that there was only a 28% overall response rate in the placebo arm for OXY PBR much lower than expected. This is consistent with prior phase one randomized studies where it seems like the control arm for these microbiome studies seems to fare worse compared to the prior phase three data and does raise the question that this data needs to be confirmed in larger randomized studies. Next, we have important overall survival analysis of light spark 005. This is the final analysis of this uh pivotal data that led to the approval of beza light spark 005 randomized patients with advanced or metastatic clear cell RCC with 1 to 3 prior treatment regimens, patients were randomized to Balzan or to Lymus. The results of this study were previously presented showing PFS and overall response rate superior for Balzan versus Lymus and already led to FDA approval for Balzan in clear cell RCC. In this final data cut off, overall survival benefit was not statistically significant for Balzan. Although the hazard ratio of 0.92 did favor Balzo. With this data. Val Zoen remains an important treatment option in patients with a refractory clear cell RCC. Given the PFS benefit higher overall response rate and overall uh favorable toxicity profile of this of this drug. We have some interesting data from a novel hip two alpha inhibitor NKT 2152. This is a oral hip two alpha inhibitor. And in this first data release, we saw that there was a 20% overall response rate among patients who are heavily pretreated. This drug is different from Balza Fan and distinguished by its extremely long half life, the half life was 38 days, which is potentially double edged sword. Uh In the one hand, this drug can have sustained inhibition of hip two alpha. On the other hand, patients who experience toxicity may have this drug circulating for quite a long time. It remains to be seen to see how this performs in other cohorts. And we did uh accrue a lot of patients to NKT 2152 here at DA FIBER including to a post Balzan cohort. So that data remains to be seen next. And finally, we have some interesting biomarker data uh from Doctor Braun looking at glycoprotein biomarkers in checkmate nine Cabo Neil versus unit. As we all remember, checkmate nine established Kazan and Nevala as a first line treatment regimen in clear cell RCC. In this interesting glycoprotein analysis. Uh Doctor Brown and colleagues looked at glycopeptide and showed that there are some glycopeptide that appear to be associated with enrichment for response on Cabo Neil specifically complement protein free glycoprep tide was associated with improved progression free survival and complement factor H. Glycoprep tide was associated with poor progression free survival. This is a new kind of circulating biomarker and needs to be evaluated in future studies. There are plans to use the same platform which is intervened by corpo analysis in future studies and this could be a new avenue for biomarker discovery. And with that, I'll turn it over to doctor Tony Suri. Uh so um starting with TNO two, I think this is the nail in the coffin of um recalling with PD one PDL one inhibitor. This is a practice that's seen in multiple malignancy. Sadly, there is no trials that is a phase three that has been done in any tumor except in renal cell cancer. So, immune checkpoint inhibitors are used in Melanoma bladder, you name it um lung cancer, but you don't find the trial A plus BD one versus a uh post progression on prior BD one doesn't exist. There's a randomized phase two with Nevo IP. Um actually, um as the experimental arm versus um IP and prior PD one failure, it's a small randomized phase two that is positive but no phase three like that. Melanoma is quite different. Um The biology is quite different for checkpoint inhibitor and CTL A four inhibitors. So this is the second, totally negative waste of resources, increased toxicity. It's possible that the lower dose of pals that we use because of the hypertension, uh you know, led to a uh improvement in PFS in the control arm post PD. Um one inhibitor uh PFS with them um close to 10 months is quite um uh intriguing. Um So that's one, the second study we saw another PD one based study uh repeating what we have done over five years ago from China following the Tolima study which was done last year. Same thing I don't know, these drugs are approved in China with his second opinion from China with this video one inhibitor. Are they interchangeable? I don't know. And they're beating um the TK I we don't use as control arm. Long time ago. We haven't used sin. They're beating it and sometimes having an os uh benefit, which may let me think about the availability of other checkpoint inhibitors doesn't concern us uh a lot but probably concern globally. More patient and China will be treated with renal cell cancer based on the just numbers. Although it's less common overall cancer in China than in the US.
