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 2023.
So for those just joining us, this is the ESMO review led by our colleagues at Dana Farber Cancer Institute. My name is Vincent Shu and I will be leading the kidney cancer updates from ESMO 2023. In brief RCC data from ESMO 2023 the most influential data from a North American or European perspective will be the several updates that we received on Balzan including a pivotal phase three trial in the refractory RCC setting. There was a new IOTK I doublet Tori polya plus AIT which will probably not change the standard of care much in the Western world but is a critical new treatment option in China where there are currently no IO doublets available. And finally, we'll discuss intermittent TK I dosing an intriguing trial showing this treatment strategy. We have for many years been able to target the VHLH I two VEGF pathway but only at the level of VEGF. Now, for the first time, we have drugs that can target H I two alpha including Balzan and other drugs that are in development. Several trials are ongoing. This slide shows some of the phase two and three trials involving Balzan and three of these trials were presented at ESMO this year. The first trial I'll discuss and the most impor important from a practice standpoint is light spark 005. This is a phase three randomized trial of Balzan versus Lymus in patients with previously treated advanced clear cell RCC lights, spark 005 enrolled patients who had unresectable metastatic RCC, who had prior treatment with 1 to 3 systemic regimens including both A TK I and immunotherapy. Patients were randomized to Balzan versus Lymus, 1 to 1 and the dual primary end points were progression free survival and overall survival. The baseline characteristics of this trial were as expected for a refractory RCC population. Most patients had 2 to 3 prior lines of therapy. In other words, most patients were on third to fourth line therapy at the time of this trial and uh cong congruent with that. Most patients had IM DC intermediate or poor risk. So, relatively sick and pretreated patient population, the primary end point of this trial was progression free survival. PFS was superior for Balzan versus evil Lymus with a hazard ratio of 0.74 which remained consistent through both interim analysis. One and two, the progression free survival favored Balza fan in all subgroups including in IM DC, favorable intermediate and poor risk and for patients who had prior veg F or IO, the primary end point was also dual endpoint of overall survival. This end point was not entirely mature. But numerically, the overall survival also favors Balzan over Lymus with a hazard ratio of 0.87. This difference did not reach statistical significance at this point. With a P value of a 0.99 data is still maturing. So these numbers could change over time. There were several key secondary endpoints reported. Overall response rate was also superior for Balzan versus Lymus with 22.7% for Balzan and 3.5% for Lymus. Quite a big difference in the overall response rate. The duration of response also favors Bel Zen over ever Lymus with a median duration of response of 19.5 months versus 13.7 months for ever lymus. This is a really important slide, not only was the progression free survival and overall response rate better for Avril lymus, excuse me, better for Balzan compared to Avril Lymus. But Balzan was significantly better tolerated. The side effect profile for Balza reflected its known activity against hip two alpha. Specifically, there were on target toxicities of anemia, fatigue and also a uncommon but important side effect of hypoxia which was seen in 14.5% of patients. Il Lymus had a side effect profile consistent with prior trials. Another reflection of side effect profile and the response are the patient reported outcomes. The patient reported quality of life as measured by FKS ID RS and by QL QC 30 both favored Balzan over Lymus and the results including the nominal P values were significant in both cases. In summary, Lights Park 005 shows that Balzan was superior to lymus for progression free survival, overall response rate and for quality of life, overall survival trended towards favoring Balza Fan. But the final results and analysis are still pending. H two alpha inhibition with Balzan is active and is a new treatment option for patients with refractory clear cell renal cell carcinoma. This data is being submitted to the FDA and we may hear some news in the next few months. Next, there was updated data presented from lights spark 003, which is a phase two study of Balzac in combination with cabals antony for advanced clear cell RCC. This trial has been previously reported and updated data for both cohort one and cohort two were presented at ESMIL. In this trial, patients with metastatic RCC received cabozantinib plus Balzo. The trial included two cohorts cohort one was treatment naive. Whereas cohort two included patients who had prior immunotherapy with or without prior TKIS. The primary end point was objective response rate, baseline characteristics for cohort one and cohort two are quite different as you would expect from a first line versus a refractory. Cohort cohort one had primarily IM DC favorable risk previously untreated patients. Whereas cohort two had primarily IM DC intermediate and poor risk cohort one was untreated previously. Whereas cohort two had received several 1 to 2 prior lines of therapy. The objective response rate in cohort one was impressive at 70% including a 79% objective response rate in patients with IM DC favorable risk. The response rate in cohort two, the pretreated cohort was lower at 31%. Looking at the waterfall plots impressively. In cohort one, every patient with measurable disease had a decrease in the size of their target lesions. Whereas in cohort 2 88% of patients had a reduction in target lesion size progression free survival. As assessed by the investigators was 30 months in cohort one and 13.8 months. In cohort two, overall survival um is still maturing cohort one did not have many deaths. There were only five deaths in total so far. Whereas in cohort two, the median overall survival was 26.7 months. The treatment related adverse events for this TK I plus Balzan combination was mostly driven by the Cabal Zanten component. As you can see, these are side effects that you mostly see with cabals antony with the exception of anemia which was common and expected with Balzo effect. In summary light, spark 003 showed that cabozantinib plus Buddha is active in clear cell RCC with a tolerable side effect profile. The untreated first line cohort had a really impressive objective response rate of 70% and the response rate was 31% in cohort two, which was similar on paper to the response rates that we've seen with single agent Kal's antonym in the refractory setting for RCC. So it's not clear yet how much Balzan adds to cabozantinib in the refractory setting. But there is an ongoing phase three trial comparing cabozantinib versus lenvatinib plus Balzan in the refractory setting. And that will answer this question a little bit more directly. Third, I will briefly touch on the light bar 013 study which compared two different dosing regimens of Balzan. Comparing Balzan at 120 versus 200 mg daily in patients who had metastatic RCC, all patients were previously treated and objective response rate was the primary endpoint of this trial. The objective response rate was similar in both the lower dose and the higher dose by Zan cohorts with 23% versus 23.7% objective response rate. Waterfall plots are also quite similar and the progression free survival and overall survival were also similar between the two doses of Balzo defen. The treatment related at adverse events were comparable but there was a greater incidence of grade three or higher adverse events in the higher dose level of Buddha. This data overall supports staying with the current 120 mg dose of Balza, which is consistent with the current FDA label for VHL disease and will be used. Moving forward. In summary, we've heard updates from three trials for hip two alpha inhibition at RCC. There are several trials ongoing. I've already mentioned the Balzan plus liat versus cabals antony trial. Phase three. In the 2nd and 3rd line, there is an ongoing randomized trial of pembrolizumab with or without Balzan in the adjuvant setting, as well as an ongoing first line trial building on a backbone of Linda plus pembrolizumab doublet therapy with or without Balzan with or without Quavo leap, which is the CTL A four inhibitor. We expect results from these trials in the next coming years. An additional phase three RCC trial was presented and this was a positive study but probably is going to impact care mostly in China. This was Ror which looked at Tora Halima combined with AIT nib versus unit nib in first line setting for intermediate and poor risk RCC. In this trial, patients were randomized to the novel IOTK I combination of Axitinib plus to Paloma versus SUNItinib. The primary endpoint was progression free survival. The baseline characteristics were as expected for an intermediate and poor risk population. The progression free survival favored the combination arm over Sunni nip with a stratified hazard ratio of 0.65 significantly favoring the combo arm on subgroup analysis. All subgroups did better on the combination arm compared to cit nib. Overall survival also favors the combination arm with a stratified hazard ratio of 0.61 and a nominal P value of 0.02. Adverse events in both arms were largely driven by the VEG FTK I. And we can see there were expected side effects of hypertension, proteinuria, diarrhea and so forth. In summary, this adds yet another IOTK I option to the list of first line treatment options for clear cell RCC in the western world. This will probably not change the standard of care since we already have several IOTK I combinations available. However, in China where the study was conducted, there are no current approvals for IOTK I combinations and this will be an important option for patients in that country. Tide A was a phase two study of a vab plus intermittent Aib, an untreated first line RCC. This was a really interesting study design. It asked the question among patients getting an IOTK I, can you stop the TK I in patients who are having a complete or partial response with the option of resuming the TK I once patients have disease progression. This gets to the question of trying to reduce the TK I toxicity for patients who are having good response. Over 89 patients that were screened, there were 75 patients that were considered for the efficacy analysis. 57 patients had tumor response and 29 patients interrupted exit nib. The primary endpoint was freedom from progression after eight weeks off. AIT nib and 72% of patients met the primary end point. The median progression free survival is 23.8 months and the median duration of avail amount maintenance was 16 weeks. Arguably this was a little bit disappointing that patients didn't stay on avail mab alone for longer than four than about four months. Among the 29 patients who stopped axitinib nine were still ongoing on avail Malone 20 had progression of disease and 19 of those patients. So all but one restarted accin among patients who restarted AIT nib nine are ongoing. Six had further PD and four discontinued ACC accident. NIB again. In summary, this trial demonstrates that the interruption of Axitinib was safe after treatment with OXY bum and some patients who progressed still had benefit from reintroduction of accin after progression, it remains to be seen whether this data can be extrapolated to other Iotkis. So with that, I'm going to move the discussion over to doctor Shuwei who will give us his impressions on the RCC abstracts. Yeah. First, if you have any questions, send them the panel, we have 50 people. I think uh you know, uh all five study uh is an important study. It's gonna lead to the approval of the and post TK I and the PD one, we are the highest recruit uh ACCRU at in the United States at Del Farber. Um It's a clear pfs and response rate signal. I'm not sure if OS is gonna be met, there has been two analysis, but at least it's going in the right direction. Bit disappointed with the PFS similar to every alignment. Why would the curve separate after uh you know, six months only this is not single agent io I think the best definition here, uh it could be a biologic one and or a statistical one, the biologic one is the fact that there are patients that just blow through therapy, 34% does not have any effect to a degree that Uly may be even slightly better. And then you can get after 69 months, you weed all the folks that uh may be responsive, you know, and the second one, it could be that the sensory um and the drop off was significant. Initially, a lot of patients, you know, completely came off. Um a study, there could be a discrepancy between central uh review and investigator assessment, although it wasn't uh that much difference. Um but I can't find beside that a different explanation. Um We have to be careful about the anemia and the hypoxia. So in practice, it can show more common gonna be put, be putting more secret patient on therapy. The combination with uh Carbos anin is not proceeding forward. The combination with levain is, but at least it's a proof of principle. Quite interesting to see uh cabozantinib plus. Um but to have 79% response rate, this is io naive in favor risk patient for first time once the patient were recruited by, by Brad and I, at least in the US was that. So um it's a very interesting uh thing to look. Could we envision a study just in those 20% favor risk that is without IO but uh the responses may not be durable. It's a short follow up in a way. Um you know, treated patient. I think um the data was higher versus uh 200 versus 120 is intriguing a bit more um uh toxicity with uh the 200. So glad that most of the studies even before knowing uh 0 13 result use 120. So maybe using EPO as a biomarker is the way to go. Um as a pharmacodynamic biomarker. And then uh finally, I think the study by um the study by the Italian, you know, it's important, that's what we do in practice, we play around with drugs, we stop one, we continue one. The TFS is low probably because of a really one. But at the same time, I wanna say that important study to do hard to do a significant attrition rate, you start at 40 patients and you have data interpretable from 20 patient. You know, we saw that was only for when we do one to another. Great in practice, hard to do, maybe they should start at way more patients. Uh But these are inherent uh bias here in all these studies. But at least, you know, they've done it after many, many years of PK I and uh I, oh I remember when Ian Davis Cali in uh Australia did the SUNItinib followed by AOL A and then switching based on his response, he ended up with one third of the patient at the end and severely underpowered. And then finally, the study in China, actually Tori is I believe or if polymer is approved in the US for nasopharyngeal cancer, if I'm not wrong, it was recent GSIS Tori or toy uh versus GM SIS, there was Tori polymer, there was an OS benefit in nasopharyngeal and there's a study for uh showing response rate 20% in uh actually post uh ioi I don't know the landscape in China although it was last week. Um but, you know, these drugs may be available but not reimbursed. So I don't know if the right word is available or not. Um And they could be imported, but you're right. It's not part of the guideline. So it's very important. I think the discussion of uh street Van Der Welt was, was, was great.
