Dr. Zibelman discusses updates on metastatic renal cell carcinoma.
So my name is Matt sobelman. Thank you all for the introduction and thanks for those of you attending today. Um I've been tasked with um giving this update on kidney cancer renal cell carcinoma in 10 minutes or less. Um, so I will do my best to give you as much as we can in that time. The exciting thing about kidney cancer is, it feels like every 10 minutes lately, um, things are changing in the landscape of kidney cancer. So if the standard of care changes before my talk finishes, um, it's nothing I can do about that. Um, so I'm gonna try to talk to you a little bit about the evolution of systemic therapy in the metastatic disease in the first line setting and sort of the new treatments that were in combinations we're using now. Um, a little bit about them, what we do afterwards and then um, a few mentions about some current and emerging therapies that we have, we're excited about. So this is um, a slide that I took from my lecture I gave the fellows about renal cell carcinoma um in um in 2017. And so it's it's I think amazing to look at the slide and and really see how much has changed in in this timeline. Um for at this time we were still giving, I'm T J is predominantly as first line therapy for clear cell renal cell carcinoma intensity alignments, was still actually on the list of potential treatment options. Um the volume and had just started to um you know, take its place in the second line. Therapy is sort of the first candidate for immunotherapy. Um but I think this really just starts to show you the tremendous amount of change that we've seen in such a short amount of time. Um try to show this a little bit further here is sort of a timeline um that of approvals for drugs for metastatic renal cell carcinoma. And you see in about 2005 as the first VHF targeted TK eyes were approved, sort of um part of the T K II era for patients in renal cell carcinoma as well as um introduction of enter inhibitors and for a decade or so this was predominantly on what we were using. Um But then as we got into um uh 2015, 2016, we started to see some new drugs, both with the first approval of a checkpoint inhibitor with the volume knob, as well as some new VHF targeted T K I S and then onto combination therapy, which is sort of where we are today. Um And so um I wanted to kind of talk about sort of the TKS and then sort of the new competitors in the first line setting and so sort of look at it this way we sort of had TKS as sort of the long running champ for for a decade or more and now we have some new contenders in the mix with people um Ahmad and the volume ab exit ramp embolism ab as well as Cabazon to have been the volume at. So I'll talk a little bit about each of these briefly and so first um um um um um and the volume ab combined immunotherapy. So um this is really stems from the checkmate 214 study um initially published the New England Journal of Medicine. Um here's the schema um I won't spend too much time on this, but basically as all these studies were, this was the first line therapy patients got no volume Cabinet Blumen mob versus Summit Nib, which has become the sort of standard um control groups for these studies. Um The um endpoints vary a little bit from study to study um sort of bottom line from this. This is the updated mean overall survival follow up, median overall survival follow up for the study and the intention to population. Um And you see the red line which is the geneva patients, I'm continuing to outperform the synonym patients um with with very promising survival at landmark endpoints. Um If you look at specifically the intermediate and poorest population, um you see that the Nouveau continues to outperform its the control group and students, however, if you look in the favorable regulations minimum actually performs a little bit better and I think on some level this relates to the biology of the disease and these favorable risk. Um somewhat indolent renal cell carcinomas are very driven by V. H. L. Are very sensitive to um angiogenesis inhibitors. Um and I think are probably less immunogen IQ. And thus we maybe don't see quite as robust a response and immunotherapy in these patients. Um And TKS are still a really important part of their care. What I think is exciting about these immunotherapy treatments is the duration of response and this is a nice slide I think trying to underscore that um and this for patients who respond um and still can maintain that response for a long time and there's really a sense of the tail of the curve that we often think about and hear about with these immunotherapy drugs. And patients that are Now 30 months out from treatment continue to sit on this curve with more than 50% of patients there. And so that is certainly an exciting part of combination immunotherapy tree. Um This is the most updated follow up from this study um which sort of shows the some survival um and and other data. Um Some things to point out, I'm obviously the combination continues to outperform the overall um You look at the 48 month time point. So basically four years out Um in the attention to treat population we still have not hit the media and we've just hit that in the intermediate and poor risk patients. So still a lot of patients at four years out, more than half that are still doing well. Um there's an 11% complete response rate Which is I think another thing that people who are pushing for a combination immunotherapy really highlight this 11% cr rate. I'll remind you that this is a complete response rate and not cure rate that's not what's er stands for. And just because these patients have complete responses by resist does not necessarily mean they're cured. Um And what's not shown here, which I think is important is um the disease control rate which um is actually um probably a little bit better in the other combinations. In fact the disease control if they're not shown here is a little higher with Sutent than it is with petaluma map and the volume map. And so it's basically just shows you that although patients can have long lasting responses, the combination immunotherapy, those there are a significant proportion of patients who don't respond and that's where I think adding TK is coming. So contender # two is like sitting in an embolism, yep. Um Here again is the is the schema. I'm very similar um design against synonym. Um Here is what we see for the intention to treat analysis again in survival. The combination continues to do well. Um Same as intermediate poorest, which we see in the lower right corner um In favorable risk. Both arms are performing quite as well are performing about equally, but there's not the advantage to students that we saw in. Um I oh I oh therapy. Um when we look at some other metrics of response, um we see that um in this long term follow up um the combination of embryonic Sydney um has had an increase in complete response at 9%. So approaching what we see with the 11 per cent with epi Nevo um and only 11% progressive disease compared to the 25-30% that we see in with combination uh aluminum volume at and so I think this is one point that I like to drive home is that if you want to get a response, your your likelihood is better if you include TKI. Um And then I think this waterfall plot just shows you the large percent of patients that really have some benefit with combination extended symbolism and then uh newest sort of contender Miscavige antonym and the volume ab. This is from the Checkmate 90. Our study which recently reported its sort of initial results. Again, similar design that we saw in the other studies against unit nib. I'll note that the Cabazon Tsarnaev is 40 mg daily in this study as opposed to 60 as a starting dose. We may be used to um in in you know, as a single agent. Again a benefit in overall survival. Although that was not the primary endpoint of this study. But we see uh Boniva outperforming incident from overall survival. Um overall response rate 55.7%, numerically a little bit lower the next imperialism at but very comparable. Um um Sorry cr rate is 8%. Which is also I'm very promising with some patients still not valuable. So here's sort of a quick tale of the tape combining these. Of course we supposed to say we never compare across studies only to always compare across studies. I think these are similar trials with similar uh control groups. And so I think there are some things that we can take from this. Um Overall survival early is is probably very similar. Um We don't have long term follow up as much with the I. O. T. K. I. Trials. Um But so it remains to be seen if they're able to match the long term follow up that we see in mp Nevo. Um Overall response rate definitely higher with actually Kimbrough and cabin evo than in um carbon evo compared to what we see with indian evo cr rates I think are somewhat similar. And again I'll point out the disease control rate a little bit higher when you have a T. K. I in the group. Um So this is my updated slide about what I recommend for treatment for these patients in the first line um Generally for favorable risk patients, I think there's really no role for 18 evo. And actually Kimbrough or potentially carbon evo would be on the way to go and intermediate or poor risk patients. I think um both I O T K I R I o are potentially options. I tend to favor IOT AI because more patients benefit um and sort of not lose those patients who may not make it to second line therapy. But I think for patients who can't get A. T. K. I. Or who really want to try combination immunotherapy. Um I think I think that is a viable option for some patients. Um So maybe more on the way. Um Let that nib has also been studied in the setting. And recently we saw a press release of the clear trial which combined with that name with Embolism Ab which also met his primary endpoint. So we may have another contender along the way. And of course as I said things are changing quickly. So we're now moving the potential of triple therapy 3 13 is looking at the Naval Plus Abbas internet versus um Geneva alone in an intermediate and poor risk population. And um We also are looking at some new combinations Nectar to 14 which has this long name. I'm not going to try to pronounce this at this time. Which is basically a peg elated form of ill too is another promising drug being looked at in combination in the first line studying. So what do we do after this? Um As as they said in Hamilton, what comes next? So I think it's still a viable option for patients uh stemming from results from the Meteor trial and then when Vietnam ever lima's also really active combination um for patients who have previously been treated um this study, I'll point out was only looked at second line patients, but I think many of us are using these drugs in later lines until in baton, you know, sort of shows its potential role earlier in treatment. Um I think after that we continue to use other veg of targeted therapies um and some patients, although those have really been pushed down the line, I mean, of course clinical trials. So um we're also now looking at combinations in the second line. After those initial therapies. Contact three trial trial we have open here, looks at balboa tezo versus Carlos Santana and patients who have progressed on um uh those combinations I already discussed. Um and then the pedigree trial, which is a bit complicated but I think are really well designed trial which is looking at patients coming off 15 evo patients with a complete response, continue maintenance and volume ob patients who are clear progressors move on to cabos, antonym alone. And it's those patients in the middle that are randomized to maintenance and volume at versus combination. And so these trials will help define these settings. And then one mention of an emerging drug that I think is really exciting. Um this is looking at drugs targeting um the have to alpha pathway which is a pathway that we've been trying to target for a long time. And it was once considered undrinkable. And thanks to work by by many including dr Colin who recently won the uh Nobel prize, we now have an active drug MK 6482 or Bells Bells and a fan. Um which basically targets targets this pathway. Um in an earlier study um 55 patients are treated with medium three prior therapies. Overall response rate was promising 24% of patients with them, a lot more patients achieving stable disease. So we're really good um um disease control rate. Um and we've used this drug in several trials now so have some familiarity with it. Um It has a unique set of side effects that are focused on how to alpha works and how it affects hypoxia and um reach a point in production. But it can lead to anemia and hypoxia as some of the most common side effects. But we found these to be manageable in a lot of patients. So I'll conclude um systemic treatment for first line metastatic RCC really become a disease of combination therapy. Um I O T. K. I. S. And I, oh I oh treatments are all viable beyond that. Um T. K. I. S. Some of the newer T. K. I. S. I think have a role with some new combination trials coming out that might further define that setting. And I think there's a lot of new drugs that we can look forward to in my talks in the coming years. So thank you all for listening.