The Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute presents a succinct summary of all the genitourinary cancer clinical updates you need to know from ESMO 2022
if you're joining us we are presenting uh ehsmoh 2022 G oncology conference highlights Dr Vincent shoot will be discussing kidney cancer updates With discussion from dr Tony sherry. Right thank you. Dr burke talk. So we'll be discussing kidney cancer from as mo 2022. Um and the really short of it is that this was a huge conference for kidney cancer. Uh Never before seen. We have five randomized phase three trials and kidney cancer presented for the first time in S 1 22. So lots of exciting data not gonna be able to go over everything today but I'll try to hit some of the highlights. Number one cabo vivo P. The first randomized phase three triplet has superior progression free survival versus that's cosmic 313. We have presented three negative adjuvant or peri operative immunotherapy trials in kidney cancer. It being evil. A tassel and peri operative Nevada mob. So three disappointing large phase three's we had another phase three of them Peg plus Nevo that did not meet its end point in the first line setting another negative phase three in other news Bells, Judah fan data continues to be quite promising in both V. H. L. Germline and clear cell kidney cancer. And will show some data from and Pembroke which has some promising results in non clear cell kidney cancer. So let's start with cosmic 313. This is a randomized phase three trial patients with intermediate or poor I. M. D. C. Risk previously untreated. So first line clear cell kidney cancer. And this is really the first phase three trial to use a modern comparator arm comparing cables, antonym Ipi plus Nevo. This triplet combination with placebo plus P plus Nevo. So really the first Phase three cannot be said enough that had the courage to go up against the doublet That based on characteristics were pretty typical of a intermediate to poor risk population. There was a relatively low, only 65% of patients had apply an effect to me and the rates of affect me in clinical practice have been going down a little bit ever since the publication of Carmina. Looking at the headline results going straight to the point progression free survival was improved for the triplet compared to it being evil with a pretty convincing hazard ratio of 0.73 favoring cabo, the navel and a p value of 0.1, which was significant. Looking at subgroups. Um, the triplet for PFS looked better across most subgroups. The one interesting outlier was that the triplets seem to do better in the intermediate patients versus the poor risk patients. And it's not entirely clear why this was the case. Um one might expect that in patients with really aggressive poor risk disease, that being more intensive with therapy with the triplet would be better. But that was not the case in this trial and we'll talk about some reasons potentially why that might be the case. Looking again at the intermediate versus poor risk as you can see from the Kaplan meier curves intermediate risk, the triplet PFS curve separated early and remained separated whereas in poor risk the curves crossed and the two curves were not significantly different among the I. M. D. C. Poor risk patients. Um It is kind of interesting a little bit that in the poor risk patients you get an early T. K. I. Separation where the cable triplet does better early on and the curves cross later. Again, we'll speculate a little bit about why that might be the case. Looking at tumor response as might be expected. Three drugs has a higher response rate compared to two drugs. Um The partial response rate was higher in the triplet as well versus it being evil. However, the complete response rate was only 3% in both arms, which is quite a bit lower than what we saw in checkmate 214 with it being evil. And you know the there may be some reasons why these patients that are poor complete response rate, but one of them may be that there was a lower rate of no effect to me in this trial population. And we know that in patients with the primary tumor in place, getting that entirely disappear on systemic therapy alone is often times very difficult. These are the waterfall plots showing that there was a greater proportion of responses in the triplet compared to the doublet. But once again the complete response rate was not particularly high safety as might be expected. Three drugs are more toxic than to drugs and I especially want to point out that the proportion of patients receiving all four planned doses of epilepsy map was higher for Iban evil compared to an evil plus cable. And this is probably due to more patients in the triplet arm having toxicity early on requiring either systemic steroids or holding the dilemma map. And clearly many patients who had it be held did not end up receiving other evidences. Um And similarly treatment, the average events leading to discontinuation were higher. Among the triplet are Looking at the safety broken down. There was a increased rate of liver toxicity among the triplet compared to the doublet. And this is consistent with our knowledge that cable in addition to being evil does have some rate of liver toxicity. And this appears to add up a little bit 58% of patients getting the triplet received high dose steroids defined as a predniSONE dose of 40 mg or greater And 35% received title steroids with being evil. So putting this into context. Uh These are our current first line therapies doublet for intermediate and poor risk. Clear cell renal cell cancer. And as you can see this triplet combination is the first triplet to ever show PFS superiority against the doublet. However, with a very strong caveat that we do not have any overall survival data. And so um I think it's fair to say that how the overall survival data pans out from this triplet will really inform where this triplet will or will not fit in into first line clinical practice. So let's move on to a giant and peri operative therapy. There's three trials and we'll start with adjuvant metabolism ab So this is a randomized phase three trial comparing a table is a map for one year versus placebo for one year among patients with resected intermediate high risk RCC that had a clear cell and or sarcoma toid component in a important difference compared to kino 564 which was the servant Embolism IB data that was presented previously and led to the approval of Pembroke in this setting for this particular trial and one any D patients required to be either synchronous orm attack Cronus over 12 months after primary surgery. And as you remember for the pembroke Elizabeth trial. The attack Cronus, anyone, any D patients required to be within 12 months. So a different and when any population here based on characteristics, the vast majority of patients had clear cell kidney cancer and a very small minority had other histology. This is investigators has DFS and as you can see, there is really no significant difference between curves, a Taser lissome ebb and placebo performed very similarly with a p value of 0.5. So not supporting the use of a taser Eliza map in this setting subgroup analyses showed um no standout benefit to a table is a map in any particular subgroup, except that females seem to do better on the table is a map and it's not clear whether that has any biological significance. Um that signal with female sex does not bear out in the other trials, there was some sense that in patients with quite high pd L one expression over 5% there may have been a benefit to a table is a map with a favorable hazard ratio of 50.57. But I'll point out that only 56 patients on a tehsil. So this is a relatively small subset overall survival. Also, really no difference here. Safety was similar to previously described safety of a Taser lizard map, which was quite well tolerated. But my takeaway from this trial is that a Taser listen map was well tolerated but had no benefit in the edge of its setting. The next peri operative trial is prosper, which is a clinical trial that many people at the Fc. I were involved in. This is a trial that randomized patients who were getting reception for RCC to neo adjuvant and adjuvant novela mab versus observation alone. So, there was no placebo on this study. Baseline characteristics are notable that half of patients had clinical T1 or T2 disease prior to randomization and after surgery, about 80% of patients or more had, sorry, about 66% of patients at T three or T four disease, meaning that actually 34% of patients had only pathologic T one T two at the time of surgery. Also want to point out that 20% of patients did not have clear cell RCC at time of surgery. So it's possible that there was some dilution in this trial among patients with lower pathologic stage and also with non clear cell kidney cancers that might have been less likely to respond to immunotherapy patient disposition is worth pointing out that among patients randomized to surgery plus novela mob arm, 404 patients were randomized but only 314 patients actually got any doses of prevention of Allah mob. So that speaks to significant drop out. Um in the kabbalah mob arm of this study, recurrence free survival was the primary endpoint. The trial was stopped early for futility and as you can see there is really no difference between the Nevada map and observation arms scene with a p value of 0.43. We don't currently have overall survival data yet for this trial subgroup analysis show no subgroup with clear benefit to Nepal A map. So next I'll discuss adjuvant novella map plus in bolivar map versus placebo. This is part A of the checkmate +914 trial. This is a randomized trial patients with predominant clear cell histology RCC randomized to six months of ebony bow versus six months of placebo after surgery, baseline characteristics were typical of this population. though. I'll point out that this trial did not include M one N. E. D. And most patients were international disease free survival was again not different between the treatment and placebo arms. Key value of 0.53 and it has a ratio of 0.92 showing really no significant benefit from an EVO versus placebo. Looking at subgroup analyses, there was some sense that patients with Sarcoma toyed features really aggressive histology may have had some benefit from it being evil but this was quite a small subgroup. The total of only 40 patients. Safety was consistent with the previously described safety profile of it being evil, which is to say that it was fairly toxic and certainly the most toxic out of all these peri operative immuno therapies, there were 57% of patients who completed at least four doses of it being evil and 43% of patients on the evil arm discontinued treatment due to toxicity. Um and so this was fairly toxic and um no clear benefit based on DFS. So what is the landscape now for adjuvant, immunotherapy and kidney cancer? Remember from last year we had kino 564 which is P embolism versus placebo for 12 months. And that was a strongly positive trial with a convincing p value. And also what looks like a strong trend towards potential overall survival benefit. So a driven embolism app is approved by the FDA and is the only FDA approved immunotherapy in this space right now. Now the space got more complicated in the last three weeks with three negative peri operative immunotherapy trials. All these trials have some idiosyncrasies. They're not equivalent trials. So let's look at some of the differences between the trials. Well with PD L one blockade, we know that the table is a map and a value map. These PD L one inhibitors seemed to have consistently underperformed PD one inhibitors across multiple trials in renal cell cancer. So potentially this is just a slightly less active agent. As for the peri operative novela map trial, there was only one dose of neo adjuvant novel a map given. And also there was quite a lot of patient drop out. So it remains to be seen as we get more data from this trial whether the drop out and the peri operative issues really buys this trial towards than mel for it being evil. This was a relatively toxic agreement regimen was given for only six months versus 12 months. So it's possible that the toxicity really limited this uh this particular combination. So for now embolism Ab is still FDA approved and it's only is the only adjuvant immunotherapy for RCC. And we need more data from these trials and hopefully biomarkers to help us select which patients actually benefit. The other key news is about Bell's ouDA Fan. So this is the new drug class hit. Two alpha inhibition in renal cell cancer. And we continue to get promising data that bazooka fan does have activity in both V. H. L. And sporadic clear cell kidney cancer. First there was updates from cohort one of light spark 003 which is first line treatment with a non immunotherapy doublet. So this is about Zutphen plus cables, antonym receptor plus two alpha inhibition. In the first line this combination had an impressive overall response rate of 57% and a disease control rate of 94%. This is a small trial but these numbers line up pretty well with our existing doublet combinations, All patients with available scans in this first line trial had reduction in their target lesion size, medium PFS was 30 months and OS was not reached. Uh kind of interesting and the first combination that doesn't involve immunotherapy in the first line space. With this kind of result safety signals were similar to what we know about cables intensive and often the most common adverse events were anemia and diarrhea and patients a small minority had hypoxia which is a known complication about Souda fan. Next life spark 003 cohort to this was previously presented and we got an update through a poster. The overall response rate for cabo Santini plus Bozzuto Fan in refractory RCC patients is 31% And again 86.5% of patients had reduction target lesion size with an overall response rate of 29%. So this shows that the same combination cable often continues to have activity as well in the refractory RCC setting. Next we have an update on light spark 004 which is about Souda fan and Bhl disease. This continues to be extremely impressive monotherapy with 92% of patients reduction target lesion size with an overall response rate of 64%. And as you can see with a waterfall plot that is very very favorable not only in V. H. L. Associated kidney cancer but in other V. H. L. Associated cancers, there was impressive response with the vast majority of patients having too much shrinkage for cns himeji blast, Obama's and peanuts. We continue to see a significant reduction in the need for surgical procedures in these patients with V. H. L. Disease. So on the right side and green is after initiation of often as you can see, the need for surgeries um drops off significantly. The safety profile continues to be consistent with what we know about about Souda fan with anemia fatigue and a small number of patients with hypoxia. And often of course as of last year, but as of this past year is FDA approved in V. H. L. Associated kidney cancer. So a small plug for ongoing phase two and 3 trials targeting this pathway. We have several of these trials currently open that DFc. I haven't embolism ab plus belle Zutphen versus pemberley is opening soon. We have currently open the triplet trial which includes an arm with a fan and embolism OB versus either standard of Caroline pembroke or a triplet with C. T. L. A four plus land pembroke. And we have Zutphen plus cables antonym. What I just presented open here as well versus dilemmas in refractory RCC the phase three trial has completed a cruel and we hope to get data soon and there's also a balance to defend plus than that Never factory trial which is currently open elsewhere. So don't forget as well we have a different hit two alpha inhibitor N. K. T. 21 52 which we also have here is a phase one trial, a couple other important trials to round things out, bam peg is a peg elated. I'll to pro drug which was designed to preferentially activate cd eight T cells. NK cells rather than tear eggs. This was a large randomized phase three trial for bam Peg plus naval in the first line setting among patients with um um are C. C. And unfortunately failed to meet its primary endpoint. The comparator arm was to knit knit or cables antonym. So investigators choice of vegetable sector T. K. I. As you can see single agent T. K. I actually had a better response rate than the bam peg nevel combination. So unfortunate results for this combo and looking at the Kaplan meier curve. There was no significant difference with a P value of 0.19 out of the hazard ratio slightly favored mpeg plus naval. But again, with a p value of 0.19 really did not meet its end point. Um whatsoever. Looking at the intermediate, the poorest population, there was a subset of patients with high baseline pd L one which seemed to have some benefit but it is unclear whether the same benefit would have been had from just single line the volume app. Right. So um what's really unclear is how much of anything bam peg is adding to the volume ab in this particular population. And as we can see, the side effect profile is also bearing this out with the side effect profile of bam Peg plus naval really quite similar to the side effect profile of environment by itself. Again, raising the question of bam Peg may not add much toxicity but also may not add much efficacy. Next we have uh quite I think interesting and actually um potentially practice changing data in non clear cell RCC. So this is a trial of embolism ab plus line that nip this public combination among patients with non clear cell RCC. The majority of patients had popularly RCC and minorities. The patients had homophobia and classified translocation or other. This is the waterfall plot from this study, there was a promising overall response rate of 47.6% and in particular we saw very nice responses in patients with papillary and unclassified or other histology ease. I would want to point out that the response rates for patients with chroma folk histology it seemed considerably lower compared to these other non clear cells. And so here's a nice summary slide that was presented by dr faye looking at regimens in non clear cell kidney cancer as we can see compared to these other historical regiments. Then Pembroke has very nice results in this unwrap demised study. Non randomized study for unclassified translocation or papillary RCC. However, for chrome A four bar CC we probably shouldn't be doing then pembroke and based on prior trials including land ever limits and Aspen, we know that patients with promo for PARCC probably should still be getting a regimen that contains several Linus. So with that I want to close that and I'm gonna ask Dr Shrewsbury are discussing to help us with his comments yep thank you nice presentation. Any any questions? I don't see any Tony, are there any any commentary that you want to make? No, I think it was a very rich meeting in Guiyu and in kidney cancer five Phase 3 trial was impressive. Uh two in the plenary I think uh the question one of the questions that was asked which I you know I answered a log from uh dr Mittal um former alumni from Cleveland clinic. Have we seen T T. P. S. With have two inhibitor. Like when we maximized um de que I. And and and like and and no we have not seen that. We look specifically at this. We have not seen it just you the big picture here. Um you know about the triplet triplet cannot supplement doublet. I don't know. I am not sure yet. Or as at first interim we have another interim in the final analysis was negative knowing you're not going against senator. You're going against the champion. At some point after two years we stopped really literal having events. So that's that's one and that's why the P. I. T. T. Population went up from 4 50 to 550 patients. So the denominator was larger which didn't influence the power at all. The response rates are a bit disappointing. But then you will see in the in the manuscript that a large number of patients had the kidney tumor as the target tumor. And we know here we we this is a large tumor. We rarely achieve even a response that alan cr uh so remain to be seen as a positive trial. The good thing about it is that the curve separate early and there is a plateau which we've never seen with the T. K. I. Plus I. O. Before. So it could be that, you know some of the api effect because it's in both arms adjuvant I think here. Uh You know Vincent. Put really ably. So why the other studies are different as a reminder keynote 564 is the largest, the only one that bordered almost 1000 patients. Everything else between 700 and 800 with some heterogeneous, especially prosper and especially prosper. I think one of the things that bothers me is why the hazard ratio I could understand maybe at iso why it was really almost one. It's almost like giving something and there was no even signal. Uh and this is gonna be for a long time debated. But we're still looking at the data. Thank you.
