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 2023.
I'm Vincent Chu. I'm a medical oncologist at Dana Farber and our discussant will be Doctor Tony Shuri. So the new data for kidney cancer at A O this year, I would put into three major categories. We had a major phase three trial reported for the first time examining immunotherapy in the refractory setting for kidney cancer. After prior immunotherapy, we had several important updates on frontline trials. And then the third theme was really some important new data looking at treatment of variant test technology, nonclear cell, kidney cancer as a bit of setting the stage for the new data. I'll remind you that the NCCN guidelines here are presented for current recommendations for first place stomach therapy, really focusing on doublet combinations. Um I will go over this a little bit later in the refractory setting, especially after prior immunotherapy. What's striking about the NCCN guidelines as they stand is that there are no preferred regimens. And that is because the 2nd and 3rd line and beyond trials that we've done in the pre immunotherapy era largely don't extrapolate to post immunotherapy and new trials are badly needed in the 2nd and 3rd line setting. So the first question that was addressed is whether there's a role for PDL one recall after progression on prior immunotherapy in patients with kidney cancer. And this was addressed by the contact three study, a randomized phase three trial of a Taso Liza plus cabozantinib versus cabozantinib alone. And as a background for this trial, the discussant doctor David Brown read a Twitter poll where about a third of oncologists said that they do consider or even routinely perform immunotherapy recall in patients who had previously failed or progressed on immunotherapy for kidney cancer. Although I should say that of course, patients don't fail, treatments fail. And so this practice of immunotherapy challenge is widespread for immunotherapy re challenge, but it had never previously been evaluated in a randomized phase three trial. Therefore, contact three was designed to answer this question both for clear cell kidney cancer and for nonclear cell kidney cancer patients were randomized to a Tas Azuma and cabozantinib versus cabozantinib with primary end points of progression free survival and overall survival. Inclusion criteria included patients with any subtype of kidney cancer. But also patients had to have had cancer progression on immunotherapy within the last six months. Patients who received adjuvant therapy were allowed. But as you'll see, very few adjuvant patients were actually enrolled, patients were excluded if they had received cabozantinib or amor inhibition or multiple lines of immunotherapy baseline characteristics are presented here. Pretty much as you would expect for a refractory RCC trial a few things to point out um male gender was the predominant over female gender as is expected in RCC. Majority of patients were white. Most patients had a clear cell histology with a minority of nonclear cells and almost no patients received adjuvant treatment. The first line therapy patients received were quite typical. I think unreasonable for modern trial. About a third of patients receive combination immunotherapy with I and some patients receive first line TKIS. Although if you add together all the patients who received doublets, Ayro Cabo, sorry, not Cabo Neville. Um but but uh doublets in general with IOTK I, those accounted for about 20% of the study population and a significant number of patients also received prior second line involved the map. The first outcome slide was there an improvement in progression free survival? The answer based on the Kamara curves was clearly no. A Taser Lia did not improve progression free survival based on Kazini alone in the IO refractory setting. Looking at subgroup analyses, there was no obvious subgroup that benefited from the addition of a Tasa to Cabozantinib in the interim analysis of overall survival. Similarly, there was no difference seen between arms again, adding a Taser Liza does not add to overall survival benefit of Kaal Zanini in the 2nd and 3rd line setting. And of course, the P values for these curves are all nonsignificant secondary end points included response rate. And as you can see in the table shown here. The response rate was exactly the same. Um by central review between the Cabozantinib and Cabo A Taso arms. The objective response rate that ongoing response rate data cut off was also quite similar duration of response if anything was numerically longer in the Kazan loan arm. But that didn't reach significance looking at what patients received after patients. What came off this trial, most patients came off trial due to progression and among patients who came off, trial patients received via inhibitors or to inhibitors. And interestingly not a small number of patients still received subsequent immunotherapy. Even after this um prior immunotherapy and contact free trials, adverse events were mostly as expected for the adverse event profile of Cabozantinib and Taza. And as expected, the grade three or four adverse event rates and serious adverse events rates were higher for the combination arm compared to the monotherapy arm. I would remind you that both arms patients received 60 mg of cabozantinib. So unlike the Cabo Nevo trials, which used 40 mg of cabozantinib, the cabozantinib exposure was similar in both arms. Although in the combination arm, there was more dose reduction or interruption of the cabozantinib TK I looking at specific AES, the adverse events that were experienced were again typical of Kazel map. So in summary contact three was the first randomized phase three trial to rigorously evaluate PDL one inhibition after progression on prior PD one or PDL one, the addition of cables anti uh the addition of a Taso Liza to cabozantinib did not improve clinical outcomes. And this was uniform essentially across all subgroups, but the combination was more toxic. So this trial does not support the use of cabozantinib and a TASA in the refractory setting for RCC and show that single agent TK I namely cabozantinib actually has an impressively high response rate of 41% in the immunotherapy refractory setting. Next, we'll discuss some updates in first line treatment. Axitinib and pembrolizumab is a standard NCC and recommended first line regimen for clear cell kidney cancer based on prior results from KENO 426 at A O. We got new data updates from KENO 426 at the five year analysis. As a reminder, this trial randomized patients with any IM DC risk group to either suit which was the old standard of care or to ani plus pembrolizumab. The primary end points were overall survival and progression free survival. In this data update, progression free survival continues to be better in the combination arm of Cini plus tempera compared to Sunni nib. And the hazard ratio remains significant at 0.69. Looking at the best overall response in the I TT population, the overall response rate continues to be higher in the combination arm compared to the Sunni monotherapy arm and the cr rate was higher as well at 11.6% duration of response was also better in the combination arm as you would expect for two agents that included immunotherapy and the median duration of response was 23.6 months compared to 15.3 months. However, overall survival was actually a little bit concerning, although I would point out that overall survival continues to be significantly better in the nib and pembrolizumab um arm compared to Sunni nib. The hazard ratio for overall survival appears to be getting closer to one over time with the upper end of the 95% confidence interval. Now at 0.99 and this seems to show that perhaps the responses on the combination arm are not entirely durable looking at patients who were im DC favorable or risk. The hazard ratio for overall survival had a wide confidence interval but was numerically 1.1. So the overall survival uh has a ratio numerically not favoring suit nib over, not favoring oxy Pember over. So, although progression free survival continues to favor the combination, the intermediate and poor risk subset favors the combination more compared to the favorable risk patients looking at subsequent anti cancer therapy. Uh most patients received subsequent therapies and as as would be expected for patients who received through NNI. In the first line setting, most patients received PD one PDR one inhibit inhibitors. Whereas for patients receiving combination IOTK I, most patients received dig F inhibitors along very similar lines. We also had updated data from clear, which was the trial that led to approval of lenvatinib and pembrolizumab compared to Sunni nib in the first line setting as a reminder, clear, actually had three arms standard of care nini versus Leva Aus versus Leva and Pembrolizumab. Although this data will focus on the Leni and Pembrolizumab versus Sunni comparison in the final overall survival analysis, Leva Neb and Pembrolizumab does continue to be superior to nini with a hazard ratio of 0.79. But we see a trend similar to what we saw in the AX Pemble data, which is that the hazard ratio appears to be getting somewhat closer to one with the longer term. Follow up again suggesting that some of these responses are not entirely durable over time, but patients are eventually progressing. Looking at the overall survival analysis in the IM DC subgroups again, similar to what we've seen in other IOTK I trials, including what we just saw with ambro. When we look at le pere, the overall survival hazard ratio seems close to one in patients with favorable risk. Whereas the hazard ratio is 0.74 favoring the combination arm among patients with intermediate and poor risk. When we look at patients with extended follow up, uh there is a ongoing PFS benefit and the IM DC subgroups for favorable and intermediate poor risk PFS. Both groups do continue to favor Lini and pembrolizumab with hazard ratios that are actually quite low 0.5 and 0.43. Looking at objective response rate for independent review. Um there is still a much higher overall response rate for limb plus pembrolizumab compared to with Sunni monotherapy. Interestingly, there was data presented on the final OS analysis by best overall response. And not surprisingly, patients who achieved a complete response had excellent long term outcomes. While uh with each progressive de uh detriment in the overall response, patients had somewhat worse outcomes for overall survival with patients with progression disease doing worst out of all the patients. So in summary, these are the updated first line combination trials for renal cell carcinoma, clear cell overall. As we can see all four combinations that include a PD one do continue to be superior over monotherapy. Although it looks like the hazard ratios for the IOTK I trials might be moving closer to one over time as opposed to a Bevo where the hazard ratio for overall survival has perhaps been a little bit more stable. Although there's a very strong caveat that these are not direct comparisons and cross trial comparisons come with many uh potential risks including the fact these trials were done at different time points and so patients had different access to subsequent therapies. Cosmic 313 was not updated here but was presented by Doctor Shiri previously. And as a reminder, cosmic 313 showed a progression free survival benefit over it being evil with overall survival still immature. And this slide, the credit goes to doctor Lalai um who compiled all this data. So in summary, does the updated data change our immediate approach to first line treatment? And RCC I would argue uh probably not in a major way, but it does raise the question of whether Tkiio responses are going to be somewhat less durable than ioio responses over time. And really the cosmic 313 data as it matures may help to answer that question for now, for patients with favorable risk depending on whether the patient is symptomatic. For symptomatic patients. IOTK, I still remains standard of care. But for patients who are asymptomatic ioio with IPIL still remains a reasonable option in selected patients given the tail of the curve with that regimen and for other selected patients who wish to avoid IO toity VF monotherapy is not unreasonable. Given the or hazard ratios, the overall survival hazard ratios in the favorable risk population remain close to one among patients with intermediate or poor risk for raid or como patients. IVO remains the preferred regimen given the high response rate to immunotherapy for rado orto histology and for patients with symptomatic metastases, IOTK I is a preferred given their higher overall response rate in patients with asymptomatic disease. All the immunotherapy containing combinations remain reasonable choices. Another quick update from Checkmate nine was uh updates on health related quality of life and this was presented by Doctor Stella and an exploratory analysis based on IM DC subgroups. The take home message from this exploratory analysis was that the health related quality of life which was previously reported to be better in Cabo Neville versus Suit Nib still declined in Cabo Neil among the favorable risk patients. Although there remains a improvement in health related quality of life among the intermediate and poor risk patients. Again, pointing out that I think uh speaking to the point that in IM DC favorable risk, many patients are asymptomatic from their cancer. And so the detriment and quality of life is largely driven by toxicity of treatment, which is important to counsel patients. I would uh briefly go over this interesting randomized phase one trial. CBM 588 is a probiotic which is be phytogenic and alters the gut microflora in a way that purportedly may improve response rates to immunotherapy. Previously, the group that was led by Doctor Pala City of hope showed that CBM 588 added to it be evil appeared to improve response to I in this new phase one randomized trial. CBM 588 was added to Cabo in patients receiving first line treatment for RCC. This trial which again was a randomized phase one trial actually did not meet its primary end point which was changed in bifidobacterium species in the gut microflora based on stool. However, similarly to what was seen in the IVO trial, there seemed to be actually an improvement statistically significant in progression free survival for patients receiving Cabo Nevo plus CBM +588 response rates were also higher in the combination arm. This was a very small trial. This was not the primary end point but still given the prior epinal data continues to intriguingly raise the question of whether CBM 58 8 may be an active adjunct to immunotherapy. I will finish off by giving some updated data in variant histology, kidney cancer. We know from data prior to as o that several combinations are active in variant testos and the data is broken down by pop chromophobe translocation and unclassified RCC. This year, we had updates on three combination regimens for variant test technology RCC, namely Cabo Neil Len, Pemble and Cabo Beil. I'll start with Kale Snip and the map. This was previously published led by Doctor Lee and in the updated phase two trial results, we see that there continues to be impressive performance for this IOTK I regimen with an objective response rate of 54% uh in first line at 36% in the second line. In updated data from Leib and Pembrolizumab which was previously presented at ESMO. In the first line setting, response rates also continue to be impressive with an overall response rate across the trial of 49%. 54% in 28% in Chromophobe, 52% in unclassified and 67%. Those small numbers in translocation RCC. So both those phase two trials continue to show strong results compared to the previously related data and support the use of Cabo Neil and then Pemble in variant histologist, Doctor mcgregor presented the first data release from the phase two triplet trial looking at cabozantinib, Nevala and IPILIMUMAB in patients with advanced RCC with variant testos. One of the key takeaways was that this triplet turned out to be toxic. And this is similar to what we see in patients who were treated on cosmic 313 with the same triplet regimen. Most patients um had toxicity and 29% of patients required high dose steroids response rates were somewhat low compared to what we saw in the prior doublet therapies for variant testos with a partial response rate of 21% and a stable disease rate of 50% with a breakdown by his shown here. And so in summary, the updated data for variant testo shows that for popular RCC IOTK I combinations remain active with Cabo Nevo and Le Pemble. Strong options for first line treatment for patients with Chromophobe RCC who really have poor response rates across the board. The previously reported regimen of LEVA plus alys remains reasonable. Although we now see that lava plus pembrolizumab is also a very reasonable regimen for this histology and for translocation patients, Cabo Nevo and Lee remain the uh most most strongly supported combinations. And so with that, uh concludes my summary of the asco renal cell carcinoma data. And I'll invite invite doctor Shuri to give his comments on these data. No, thank you, Vincent. That's a great um summary overall. I think um contact three was a very important study. We're lucky that we're able to convince and that that could be a win-win uh opportunity here. I think important to realize that a TZO despite being PDL one inhibitor is an active agent in RC with a response rate of 25% in untreated patient from emotion 1 50. It's also important to notice that the patient uh included in contact three where a patient whose tumor progressed on prior immune checkpoint inhibited as the last line of therapy. This does not um include patient whose experience disease progression yearly before let's say went on other treatment and then recalled and doesn't include patient um whose tumor progressing after a even, let's say paroli up for six months or a year. That's an important distinction. And I think we need to keep our eyes uh very close on kidney two that finish accrual. And the fabric Cancer institute was the top ACCRU in the United States. Uh That's a study of another TKI A plus minus a PD one inhibitor. And follow up and the question here would a PD one inhibitor perform better than a PDL one inhibitor? Of course, here, this is renal cell NGU oncology, paving the way for other cancers because no one melanoma blood, uh no one melanoma uh or lung cancer. Um You know, ever asked in a randomized phase three A plus PD one PDL one versus A. So we're the first um there won't be any more updates from contact three. The study is, is that negative? Uh you mentioned Pembroke and Pemble uh has a ratio closer to one P value 0.99. It's, you know, unsettling a bit that uh responses, some of the responses are not uh stable enough and durable enough. Uh But this, these studies are positive uh for overall survival. Uh I think more opportunities certainly uh I uh for the future and to build on vege fio, I am settled with favor risk. I don't give single agent TKI, I don't give single agent IO unless there is a, a complete um complete uh contra indication to, to A TKI. I do a fio based on a PFS response rate and a SCR benefit. Um Then you presented at the end, I think an important uh uh study from um from uh multi group and endy phase one that follows the evil A B uh study with CB ma live bacterial product where 20 versus stem patient and here 20 versus 10 with uh I think the fact that that's beneficial bacteria didn't go down. I think that was the thing. Could be a good thing. A PFS 5.8 months in the control group. We haven't seen that with um a single agent unless all these patients are poor risk. So it remains to be seen, interesting uh proof of uh concept. Uh Finally, the unclear cell I would have removed io from anything chromophobe. However, seeing Pember 28% response rate is very interesting. Remain to be seen. Uh what that means. Uh Sunni forecast finished IP versus and hopefully we will know uh more nice presentation.
