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 ASCO 2022.
If you're just joining us, we're discussing geo oncology highlights from Ascot 2022, Dr Vincent Shu will be talking about kidney cancer updates with discussion and commentary afterwards by Dr. Sherry. Thanks very much. Dr burke chunk. So glad to present, You know south carcinoma from Moscow 2022 have no relevant disclosures. Dr Sherry also has no disclosure directly relevant to these sites. Um so from a big picture perspective, we know South carcinoma did not have any immediately practice changing updates, although there were several very interesting updates from clinical trials and some updates that are certainly practiced reaffirming. So the biggest trial for RCC presented at this conference was the Everest trial which has been many years in the making actually um started and rolling back in 2011. So over 11 years ago. This is the Ever Olympus for me no cell um adjustment study which is a phase three study run by Swag presented by Dr Ryan in this study. Design patients with RCC that was completely respected, Were randomized to ever alignments 10 mg For one year vs Placebo for one year. And of note this study was not limited to clear cell kidney cancer but allowed any RCC pathology including non clear cell. One other point of difference between this study and other RCC. Recent achievements studies is that there was quite a diverse patient population. Uh this study included adjuvant patients who are relatively lower risk compared to what we've seen in other randomized trials including patients with P. T. One B disease that were great 3 to 4 as well as P. T. To any great disease. And this is in contrast, for example to the recent keynote 564 study which included only P. T. Two patients if they had great high grade disease or some common features. Statistical considerations. So this trial had a change in the statistics during the accrual period. The original sample size had to be increased due to excessive early treatment discontinuation. And the sample size was increased to about 1500 patients to allow for this high dropout rate. Somewhat impressively. The trial did manage to accrue to a target patient population and accrued over 1500 patients Over a five year period. Randomization to placebo and Evelyn was balanced. Although of note there was a high discontinuation rate in the arm. Uh which 37% discontinued due to adverse events. Only 45% of patients in the Enbrel Amos arm completed the planned protocol therapy. And although of note also, there was a significant drop out in the placebo arm as well and only about 70% of patients in the placebo arm completed therapy, baseline characteristics or as expected for an RCC population and the population in this trial was balanced between the very high and intermediate high risk groups. Although as mentioned, intermediate high contained some patients that were relatively lower risk compared to other adjuvant trials. Treatment discontinuation was not balanced between arms and many patients, 47% discontinued. Two reasons other than progression or death. In the prelims trial. Again, toxicity was a prominent factor here mm hmm. In terms of adverse events. The adverse event profile was more or less as we would expect for 10 mg of several emus. There was a 90% any adverse event rate and a 46% grade three adverse event rate. Which was comparable to what was seen in previous. Um tired seeing kindness inhibitor trials, Lucas itis was a prominent adverse event for every lima's. Although of note the rate of grade three or higher. Newman itis was reassuring. The very low. So this is the top line result from this trial. Recurrence free survival um was numerically lower in the arm compared to placebo with a hazard ratio of 0.85 and a p value of 0.25, which actually narrowly missed the pre specified significant boundary for the primary endpoint. And so this was technically a negative result in terms of the statistical boundary. Although of course, there does appear to be a signal here for recurrence free survival recurrence free survival. According to subgroup analysis showed that Again, numerically there appeared to be a greater benefit among the African American population, though, with the limit of a very small sample size of only 61 patients and as one might expect, the very high risk population had greater benefit compared to the intermediate, high risk population. And this is just the same data but broken down into the Catholic Meyer curves. We can see that among the very high risk patients there was a greater apparent benefit in terms of recurrence free survival with a one sided p value of 0.011. Whereas in the intermediate high risk patients. So this includes the P. T. One B patients for example. There was essentially no difference, see overall survival did not appear significantly different between groups and the capital Meyer curves significantly well not significantly but substantially overlapped between the control and treatment arms. So to put this study into context, this is the list of recent achievement kindness inhibitor studies in RCC. Now of course all the other kinds inhibitors are targeting receptor. Whereas this is the one trial that's targeting M tour the other kind of inhibitor trials all failed to meet the primary end points with the notable exception of S. Track which did show a disease free survival benefit with. And we now know that none of these trials demonstrated an overall survival by Medford. Um This is a slide as um was provided by Dr MacGregor but ultimately it was based off slide by Tony sherry. Similarly, here is the list of adjuvant immune checkpoint studies in reno South carcinoma. Um recently Kino 564 was published which showed a benefit for populism versus placebo and several adjuvant trials have data that are forthcoming. We do know that I am motion 010 is coming in the near future followed probably by check wait 914. Prosper data is not yet available for Nevada map but was recently closed for futility. So in conclusion Deborah lima's narrowly missed the pre specified relapse free survival threshold for significance. Nonetheless, the data does suggest that there appears to be an RFs benefit especially the high risk patients. There's no evidence of overall survival benefit to date in context with the current treatment landscape in the advocate setting it is unclear whether ever alignments will have any role in the adjuvant setting for RCC. Especially given the recent strong data for Pebble is a math in this setting and we're going to wait further I Ci data which will be very informative in the coming year. The second abstract review will be an association between death of response and clinical outcomes. And this is an exploratory analysis of Patients who were treated on checkmate nine the up front setting for metastatic RCC. So as a quick review checkmate nine was a randomized trial that combined excuse me compared to Nevada map plus cables and NIp and demonstrated both PFS and overall survival benefit for cabo's Anthony plus Nepal a map in the first line setting leading to FDA approval of this therapy. In this analysis. The authors investigated the depth of response as a correlate with clinical outcomes. So depth of response was defined as complete response. PO one which means a response by greater than 80%. PR two which corresponds to response between 60 to 80% or PR three which is any pr that didn't reach the other categories when comparing patients who are on the senate nib versus the naval kabul arms. The authors noted that there was a greater depth of response for patients on cable naval versus unit nib With a 38% of patients alive at six months with greater than 60% reduction target lesions from Kabul compared to only 17% from Nepal a matter. The depth of response was associated with more durable and better long term outcomes. And we see that in patients with a P. R. Two or better there was a better 12 month PFS rate. Similarly, overall survival also appeared to be correlated with the depth of response. And unsurprisingly, people with deeper responses also had improved overall survival. And so um when you look at the time to duration of response and objective responses, the median duration of response did improve with each incremental increase in depth of response. And in both treatment arms including in the submitted control arm. Among patients with complete responses. The median duration response was not reached. So what this tells you I think is that among patients who have a very deep response, regardless of how they got there, these patients are likely to have very good long term outcomes and this in context does correlate with findings from several trial trials have asked similar questions. So in keynote 4-6, for example, overall survival among the patients who had very deep partial responses was comparable to those with complete responses. Similar findings were seen in clear and in Checkmate 2 14. And I think the key clinical question in context of ongoing triplet studies is whether there is a clinical and biological association across the board where if you manage to achieve a deeper remission in the first line setting, whether this will in fact correspond to overall survival benefits and if that's true, that would be a strong clinical rationale for triplet therapies in the future. Um of course we eagerly await data from Cosmic 313 which will help to answer this question. The next abstract that our review is Light spark Which is an update from the Phase one trial of Judah fan and with a particular focus on clear cell RCC. So, light spark was a trial investigating 120 mg about Souda fan. In patients with sporadic clear cell RCC in the refractory setting. So this is an update on objective response rates. Um with an updated data cut off. Now the overall gist of the data is very similar to what was previously presented for the 55 patients with RCC who received study. Overall response rate remains similar at 25 And with the disease control rate impressively at 80%. The safety signals were similar to what has previously been reported from with 22% Grade three or higher um toxicity. So next I'm going to present several novel therapeutics in the RCC space with promising early data. The first of these therapeutics is better access, not pronouncing that correctly in combination with in patients with advanced or metastatic clear cell kidney cancer. So this is an interesting concept is an excellent him bitter and we know from our experience for example with that axel is a relevant in RCC. Now this new agent is a different approach to targeting chinese inhibition. Rather it is a decoy AxL receptor and it's a fusion protein containing the extra seller region of human axle which is fused with a uh immunoglobulin heavy chain and this acts as a distracter and um decrease the ligand engagement with the native receptor. So in this phase one B trial, this novel agent, A B. B. S 6 500 was combined with cables antonym among patients with advanced or metastatic RCC that had progressed on prior first line therapy, patients who had prior first line cables antonym were excluded because they would be receiving again on this trial among patients who received prior RCC directed therapy. The majority of patients had received prior being evil and a substantial minority had received prior IOT K eyes Toxicities were relatively manageable with 33.8% of patients experiencing fatigue and 30.8% receiving decreased appetite but the toxicity is actually dominated by the cattle. Exactly part of the combination Facebook efficacy was rather impressive. There was a 42% objective response rate for this combination in patients on second line therapy which exceeds the historical expected response rate for cables antonym. And so it'll be very interesting to see how this combination moves forward. Especially because there are not very many specific AXL inhibitors available in clinics. The authors looked at biomarkers subgroups and in particular patients who had baseline axle gas six ratio greater than 2.3. And among this bomb marker selected population there appeared to be an enrichment of response rates with an overall response rate of 67%. Now of course there's a relatively small population here, only 18 patients but intriguing that this might be a agent that is potentially able to be selected for in a predictive way. So in conclusion excellent ambition with But her except Plus Cable had an interesting signal in refractory RCC. And the phase one portion of this trial is ongoing. So next I'll review an abstract that looked at a new way to combine immune checkpoint inhibitors. So this is meDI 57 52 which is a by specific checkpoint inhibitor for P. D. One S. C. T. L. A. Four. Um And this was investigated as monotherapy in patients with advanced renal cell carcinoma. So we know that p. d. one s. c. tell a four inhibition is of course active cell carcinoma and is approved in the first line setting. We know that higher doses of do seem to correspond with higher toxicity including from prior data in melanoma for example as well as RCC. The higher doses are more toxic. This agent is a mono valent by specific monoclonal antibody that binds PD one were preferentially binding. So tell you four on the PD one activated T cells. And the idea is that those will limit C. T. L. A. For toxicity while hopefully not limiting the efficacy of the C. T. L. A. Portion of the blockade. So this was a first in human study and we'll be looking at the results from the R. C. C. Cohorts. So these are the baseline characteristics. Um Not surprising for RCC population and in the this is the toxicity and safety data And there were fewer Grade three or 4 Ari's in lower doses compared to higher doses. But what's interesting is that the lower dose of this agent at 7 50 still showed very significant anti tumor activity. The overall response rate was quite impressive At 58.3%. And CRS and PRS were both seen. These are the waterfall plots. So as you can see the majority of patients did have a change in the tumor size for the better. And when this data was broken down between the 7 50 the 1500 cohorts. The 7 50 cohort also had significant anti tumor activity and had significantly lower toxicity compared to the higher dose cohort. So the authors of this study are moving forward with investigation of this combination by specific antibody with a focus on the lower dose less toxic cohorts. So in conclusion this medication had impressive first line response rate with some durable response rates in first line RCC And will be further explored in additional Phase two studies. Oops So in conclusion, among the AsCO RCC data, there was no immediately practice changing data. However, there was a giant phase three Evelyn's truck that certainly showed a signal for RFs benefit the role clinically for whatever alignment I think will be very limited given now that we have uh emerging I. O. Data in this setting and several studies looked at emerging agents as well as emerging biomarkers in RCC. With larger studies needed to validate their findings. So special thanks to brad McGregor who generously shared with me his ask a review slides on which I based some of this presentation and happy to answer questions and I'm asking Tony to help us with the discussion part of this presentation. Yeah, I don't see any questions in the chat. Great job and thank you Vincent. Um Doctor Sherry. Any commentary on the updates from Moscow. Yeah, it was you know, a quite lukewarm ask for for G you in general, honestly. But for kidney cancer I think that you and over reliance would have put almost occupation on we were waiting for the result. It tells you how much we should do our due diligence and I don't want to play monday morning quarterback and in getting real eligibility criteria, the study could have been positive Nevertheless. Um I would like to see us in the high risk group. The whole population is the hazard ratio 0.9. I wish it's water under the bridge but that could be something important to see. I think the XL inhibitor could be interesting overall, I know that there are attempts to combine it with my GF IO frontline. The decoy um hypothesis is you know, it's still interesting. There's a lot of values also to have A T. K. I. That is dirty. I think what's interesting is that astrazeneca compound that combines CTL A for MPD one. The thought here, if you do that thing's gonna stay, you know, morley more so local rather than more systemic. Um Yeah, I don't know if Vincent you showed toxicity, Did you show the toxicity? Yes. So the toxicity was significant, especially at 1500, Cohort, although toxicity seemed to be a little bit better than the 750. The great 34 iras were driven by panic plasticity and rash And there was a 26% Grade 34 hip high plasticity rate. The toxicity was a bit on the significant side. I don't know how they're gonna proceed. Not just as an example since it was approved. I believe in thousands 11 or 12 with steve Cody. We don't have 11 years later any other c. T. L. A four inhibitor approved. So at least to my knowledge, unless I missed something in solid tumors. So you know, I think though it's reasonable to explore this agent this drug further, but it was not, you know, the most active esco for kidney cancer. Well thank you DR XU doctor XU very.
