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 GU 2024.
So for everyone who is just joining, this is the conference highlights from As Ogu. My name is Vincent Chu. I am a medical oncologist at DFC I and I'll be reviewing the kidney cancer updates from as Ogu as Ogu had several important updates for kidney cancer. The most immediately applicable. One to our clinical practice is the important update for adjuvant therapy. With new data from keynote 564 showing that pembrolizumab improves overall survival in adjuvant treatment of RCC. We have several other important trials that were presented including checkmate 914 part B showing that nivolumab adjuvant therapy did not meet its DFS end point. Also, we have an interesting alternative formulation of naval aab showing that subcutaneous nevala ma is comparable and non inferior to IV Nevala ma checkmate 67 T as well as updates on several recent major RCC trials. I'll start with the I think in my opinion, the most important study. This is keynote 564 overall survival results from phase three, adjuvant helium versus placebo. This study was presented and led by Doctor Shuwei from our very own length center. The design of the study randomized patients in the adjuvant setting, who were one of three categories, patients could have intermediate to high risk of recurrence or high risk of recurrence for localized RCC. Also included were patients who had a complete resection of metastasis and the primary tumor so called M one ned. Patients were randomized to pembrolizumab or to placebo for one year. Previously, keynote 564 reported DFS benefit for adjuvant pembrolizumab and this did lead to FDA approval for pembrolizumab for adjuvant RCC. Up until now, the overall survival data had been immature. This is the patient disposition for this trial. About 1000 patients were randomized evenly to Pember, Liz IAB versus placebo patients were predominantly in the intermediate to high risk category with 85% in that category with a minority in M zero high risk and also M one ned, a significant minority of about 11% of patients had sarcomatoid features which are known to be high risk and also predict for response to immunotherapy. And interestingly, about 74% of patients were positive for PDL one based on the uh 22 C 35 DX assay. This is the most important Kapler Meyer slide. Overall survival was significantly improved for pembrolizumab versus placebo with a hazard ratio of 0.62 and A P value of 0.002. This is the first adjuvant study to ever show survival benefit in renal cell carcinoma. Overall survival showed improvement in most significant subgroups especially worth pointing out is that overall survival seemed to help patients who were PDL one positive or negative. And very importantly, patients with M zero intermediate to high risk, which was the lowest risk category on this trial still seem to have improvement in survival. And so, in other words, the overall survival benefit is not just being driven by the highest risk patients, disease free survival continues to also favor pembrolizumab with a hazard ratio of 0.72. This is similar to prior reports and of course is significant disease free survival subgroups also favor pembrolizumab across all subgroups. One of the important questions for a trial like this is whether patients were able to receive subsequent systemic therapy if they were on the placebo arm. Indeed, about 80% of patients in both arms received subsequent therapy. And among patients who receive subsequent therapy for patients who are on placebo. Most of those patients received immune therapies as well as subsequent Veg ftkis showing that despite being a multi center international trial, there was a significant access to second line therapies. Safety findings were essentially as previously reported for pembrolizumab and no new safety signals were seen. In summary, we learned from Gasco that adjuvant pembrolizumab reduces the risk of death by 38% among eligible patients with RCC. As doctor Shri pointed out in his discussion, there have been 17 prior randomized control trials in the adjuvant setting. And this is the first trial to show a survival benefit. And pembrolizumab is the current standard of care for RCC. Adjuvant therapy. I will contrast this study with simultaneously reported results from part B of checkmate 914 which reports data on adjuvant neval aab versus placebo in the high risk localized setting. This data was presented by Doctor Mozart, keynote. Uh ches excuse me, ches mate 914 randomized patients to nivolumab placebo or ipilimumab plus nivolumab. Part A of this study was previously reported which compared placebo to IPIL and did not show disease free survival benefit for IPIL. Now, part B is reported which was designed to assess nevala versus placebo and to investigate the contribution of components for IPIL versus naval patients were randomized 2 to 1 to 1 as shown here and the patient population was similar to other adjuvant trials. However, this study did not include patients who were M one ned baseline characteristics are notable for most patients being PT three with any grade N zero with again, a minority of patients having sarcomatoid features about 7%. A different PDL one assay was used for IPIL in this study with only 11% of patients being PDL one positive by the TPS score. This is the primary outcome of the study. The volume did not improve DFS compared to placebo with A P value of 0.4 and a hazard ratio of 0.87. Looking at subgroups there appeared to be a suggestion that nivolumab may have benefited some patients with sarcomatoid features or with high PDL one expression or with low hemoglobin. Though these are um not powered for formal analysis. DFS per investigator was similar, not showing benefit as was a comparison of the DFS by part A and part B. So again, part A it be Neil showed a hazard ratio of 0.92. Whereas part B Neil versus placebo has a ratio of 0.87 drug exposure was significant for Noval Aab. With most patients 80% completing their study treatment and only 20% having discontinued therapy treatment related AES were similar to what's been previously reported with 9% of patients having treatment related to grade three or higher adverse events. So this suggests that the Naval Aab wasn't a problem of getting enough dose, but rather that patients didn't seem to benefit from Naval Aab. In this particular trial, health related quality of life was pretty much as expected with no significant deterioration with meaningful decline uh defined as shown for patients who received Ebola or Placebo. Here's a summary of all recent and ongoing immunotherapy trials looking at adjuvant therapy in RCC. Now we have one trial, keynote 564 showing DFS and overall survival benefit and is currently the standard of care. We have three immunotherapy peri operative trials that have not shown DFS benefit and we have several ongoing trials including Rampart with DVA Trey and life spark 022 with Balzan plus pembrolizumab versus pembrolizumab. I also want to point out that opening soon is strike through the co-operative group which will be looking at pem bro plus Tava Zib versus pembrolizumab with Tava Nib going on for only six months. I'm gonna shift gears a little bit and certainly, um we'll go, we'll circle back on this trial when it's time for discussion, but I'm going to present subcutaneous Novoa A which was discussed by Doctor George compared to intravenous Naval Ma in patients with renal cell carcinoma checkmate 67 T. This is a very interesting study looking at a novel formulation of Naval AAB Nevo is of course standard of care in RCC, but has up until now always been given intravenously. Subcutaneous nevala. A might be for some patients easier to administer and might be easier on the health care system for resource utilization. This particular formulation combines subcutaneous Noval with uh hydro laronidase which helps to dissolve the extracellular matrix and allow for greater uh volumes of sub cute EUM infusion. Patients were randomized to the IV or the sub Q formulation who had Metastatic RCC and had previously received 1 to 2 regimens, essentially 1 to 2 TKIS without prior immunotherapy. The baseline characteristics were as expected with most patients on second line therapy after one prior TK I. In summary, uh the average administration time with sub cu neume was faster, less than five minutes and most patients received treatment without delay. The end points were similar for the PKN points with the uh drug exposures both as measured by C MIN and C average, similar between Naval AAB, sub Q versus Naval AAB IV. The key clinical secondary endpoint of overall response rate was also similar and the non inferiority threshold was met. The overall response rate was 24% for sub Q versus 18% for IV. And these were non inferior results, other secondary efficacy and points were also similar with response rates. Cr pr rates and progression free survival all within um sort of a comparable range. And look at the Kaplan Meyer curve. Certainly the PFS curves look very, very similar safety events were similar as well. Injection site reactions for subcutaneous nivolumab tended to be mild and transitory and no anaphylaxic reactions were seen treatment related, adverse events were similar although numerically lower in the subcutaneous arm. In summary, sub cue, numa appears not inferior, both in terms of PK outcomes and in terms of clinical outcomes to Nevala IV and might be a useful alternative for some patients. I'm going to move now to several updates from previously reported phase three trials. I'll start with patient reported outcomes from Balzan versus Avril Lymus reported by Doctor Powell. We know from before that Balzan was superior to Avril lymus for progression free survival in the refractory setting. And in fact, this data from lights spark 005 led to FDA approval for Balzan. In this setting, updates from patient reported outcomes confirms that Balzan patients had better quality of life compared to patients on lymus and improved time to deterioration for both quality of life metrics, FKS ID, RS and QL QC. 30 a few other significant clinical trial updates from recent major trials and these are going to focus on the doublet trials that now define first line treatment for RCC for most patients. Doctor Tener gave an update on IPIL checkmate 214 showing that overall survival and PFS tend to continue to favor ipilimumab and nivolumab. And in particular, the overall survival hazard ratio favors IPIL versus to nit nib in both intermediate and poor risk. But also that the overall survival hazard ratio for IPIL in the favorable risk patients is improving over time with a hazard ratio of 0.82. I would remind everyone that currently IPIL is FDA approved in intermediate poor risk by IM DC for RCC. But this data would suggest that many patients with favorable risk may also benefit from IPIL. In updates from the clear trial, there was a subgroup analysis presented by Dr Grunwald of response by tumor size. The takeaway from this is that patients with larger renal tumors were less likely to have complete responses, which is not a surprising result and also that patients with larger tumors tended to have worse overall survival. The data continues to support the use of lenvatinib plus pembrolizumab in patients with all tumor sizes in the first line. Finally updated data from nivolumab plus cabozantinib from Checkmate nine presented by Doctor Berlo confirms that PFS and OS continue to favor cabal nil versus SUNItinib. Now with long term follow up of 55.6 months with ongoing improvement also in quality of life for Cabo nil versus unit NIB. This is a summary slide courtesy of Doctor Lalani which gives all the updated hazard ratios for the first line doublet regimens in RCC. These four regimens, Ivo, Ayem Cabo, Nevo and L PMR continue to be our first line standard of care for most patients. At the very end, I want to highlight some important abstracts that were led by investigators at the LA Center. And in particular, Doctor Sibby had a Asal Merit Award for her abstract investigating intermediate endpoints for overall survival through the IM DC. And with that, I would like to pass it on to Dr Shuwei to discuss the landscape of RCC from this uh important meeting. Thanks Tony. No, thank you, Vincent and thank you all for being uh here. We had almost like 50 people. Uh Obviously, it was a, you know, quite uh humbling uh moment to be able to present the result of keynote uh 564. The first adjuvant study was an os uh benefit. Um I think that's, that's probably one of the highlights of the meetings. Uh I think um some of the question ended up around why Nivolumab uh failed. That is ali failed et cetera. These studies are, are, are different. I, I tried here in, um to summarize them. I don't know if you can see, uh my slides here. Can you see my slides? Yes. Yeah. So these slides are different. Um, these studies are a bit different here. Uh And those are the 17 actually um trials uh that were put here. Doctor Seman here helped me uh to put these slides um together 17 studies over 13,000 patient enrolled since 1973. But these studies are different. I invite you to look at this editorial. We had a Nature Review Clinic on college with doctor uh uh Labaki here uh to look at eligibility criteria of all these studies. And you know, they are different, they are in high risk renal cell cancer. Uh But some involve clear cell other involve clear cell and some of them unclear cell. Uh some enrolled M one and ed. And how do you know that when you look at the two year disease free survival on the placebo arm? To me, this is a measure of trial uh risk here. And you see this is really a bit different if you exclude the PDL one inhibitor. And you say, let me focus on adjuvant PD one. That's where the metastatic disease uh where IO did the work and showed an OS benefit. Let me focus on pure adjuvant. Let me focus on clear cell. Uh you look at and you see the denote 564 and checkmate 91 F 54. The difference is of course one year on keynote 564 versus six months on 9141 with Pembroke, keynote 564 and 914 is NAB but the difference in uh disease free survival uh is significant here. Significant, not statistically, this is very important. The 6% 2 years difference in uh DFS. So these are different uh studies. Now, what about subsequent line of therapies here? Um You know, uh you the patient, if they experience progression, it doesn't mean they should get an immune checkpoint inhibitor. This is not a knee jerk reflex and metastatic in renal cell cancer, high risk. Um no uh metastatic disease. When, when the progression happens at that time, a patient uh could have uh observation, could have surgery, radiation, could have TK I if I had their IM DC good risk and they would, they could have IO and if you look and at all the control, including the patient, this is a general denominator here of all the control patient, including the patient who were cured by surgery only, which is a substantial number on the uh placebo uh arm under control here. Uh You see that some studies, actually, these are the modern studies including one with in an inhibitor. Didn't collect subsequent line of therapy including cystic systemic therapy. And you can see here that checkmate 914 is the one that has the least uh percentage of systemic therapy under control on. Maybe because they are the lowest risk. And if you look at what about PD one PDL one inhibitor knode 564 had the most at 20%. And, and the denominator here when you say 20% is the control arm. So it include the folks that did not recur the majority. It includes folks that had surgery that had radiation that had TK I that when you have metastatic disease, very indolent that during the follow up, you know, we followed and we didn't uh hit directly. So there are, you know, explanation, but at least this is not unusual. And to me, the control arm uh does not uh you know, explain these results. Uh Second, uh good to see the quality of life from uh oo five. That is in addition, uh an additional positive thing in addition to uh progression free survival and response rate. Uh and of course, uh Cabo Cabo anonym Neval, although that has a ratio of 0.77 with 95 confidence in terol, the upper limit is now 0.95. It's all in the going in the same direction like uh keynote um 4 to 6 and the clear and finally, the evola um subcutaneous overall. I'm not sure about the use when you can give nivolumab every four or eight weeks. I think there should be um direct comparison with health resource utilization because you could always drop the cost of intravenous nivolumab and increase uh the, the cost of subcutaneous nivolumab and, and get to the uh same result in terms of or even becoming more um you know, expensive and these patients need to be seen. The last thing is you provide a year of subcutaneous involvement. Patient doesn't see, you end up with a massive colitis in the er, and of course one of our own doctor um uh sali uh had a me a ward which was one of five or six overall, which congratulation and that's it.
