Dean F. Bajorin, MD, presents urothelial cancer, and reviews the expected survival rates for bladder cancer patients who receive first line treatment, and discusses new treatment options.
Back to Symposium Page »
it is now my pleasure to introduce Dr Dean Bergeron from Memorial Sloan Kettering Cancer Center. Dr. Bergeron is well known for his work in the treatment of patients with genital urinary cancers, and his topic today is new approaches to recurrent or advanced bladder cancer. We thank him for joining us. Remember, if you have questions, please use the chat function, and we will address them during the panel discussion. Over the next 30 minutes, I'm going to discuss your theory of cancer, new approaches to advance and recurrent disease, and my disclosures are as shown on this slide. So let's start with the basics and that is that. What are the survival distributions or expected survival for patients who received systemic chemotherapy for first line treatment you'll see in the left hand panel are those patients who are cisplatin eligible to randomized trial of G. C versus them back? And the median survival is basically 14 to 15 months in the right hand panel. Our patients who are cisplatin eligible. This is a randomized trial of gem carbo vs MK V, and you can see that the median survival is around 8 to 9 months, so clearly there is room for improvement, for the treatment of our patients in terms of survival with this disease. This is the timeline of approved your ethereal cancer treatments, and I'm going to draw your attention to the top part of the panel. And that is there are five new immunotherapy drugs. Tesla's map member Eliza Bob Tavola mob, a value mob and devalue mob that have been approved for the treatment of patients with your ethereal carcinoma. And on the far right, there are two new drugs the tyrosine kindness inhibitor to fit, nip and below the, uh, anti antibody drug conjugate unfortunate Videoton also recently approved for the treatment of refractory disease, and I'll discuss each and every one of these. So the first drug that was approved for first line your ethereal, uh, first line treatment of your through carcinoma was a test Elizabeth, and you can see in the top right panel here. The durability of response actually looked quite encouraging, and those patients who responded but you'll see in the left hand panel the overall survival was very encouraging, and that is that the median survival in this series was 15.9 months. Clearly, that looks encouraging over the 8 to 9 months that we had previously seen with chemotherapy alone. So this makes a good candidate for combinatorial therapy. The second drug that was approved was the use of federalism have been cisplatin ineligible patients, the same exact patients based on CIS platinum ineligibility that's been published by golf, ski and colleagues. You'll see in the top left hand panel that these, uh, small uh, triangles show the start of a response. And you can see that responses start between nine and 12 weeks after the initiation of therapy. And that with that, swimmers plot in the top left hand panel that many of these patients continue to respond well after the initiation of therapy in the top right hand panel, you'll see that the progression free survival is approximately 23 months. But that is in contradistinction to the bottom right hand panel. Will you see that the overall survival is 11.5 months in this series of patients, and that there is a distinct plateau in the curve, which is different than what you saw with chemotherapy alone in patients who was just platinum ineligible? So both of these drugs are good candidates for exploring combinatorial therapy as first line treatment. So the question is, how do we integrate both chemotherapy and immunotherapy in the treatment of metastatic urethral carcinoma? I'm going to discuss both the simultaneous treatments and phase three trials as well as the sequential treatments. So let's start with the, uh, simultaneous treatments. So there are two trials. Keynote 3 61 and in vigor 1 30 which asked a similar question. A randomization between single drug, a combination of chemotherapy plus a single drug or chemotherapy alone. Patients could be either CIS platinum eligible or ineligible for both of these trials, and so patients who were cisplatin eligible would be treated with cisplatin plus Jam City, and patients who were cisplatin ineligible would be treated with carbon platinum. Plus Jim City Pebble is a mob and a test lab. Tesla's a mob were both drugs as a single agent and in combination. And remember, prior to these two trials, those drugs were approved without the need to screen for PD l one positivity. However, during the conduct of these two trials simultaneously, both uh, data safe Torri safety and monitoring committees identified that those single drugs did not impart a sufficient survival when used in the entire population and recommended that these drugs now require P. D on one positivity in terms of their utilization. So that now remains the f d a. Uh, utilization policy. So let's take a look at the two trials. The in vigor 1 30 trial again was locally advanced or metastatic. Your ethereal carcinoma, the typical stratification, uh, that we expect in terms of these trials in the top, right, you will see that there are three arms. A Tesla is, um ab plus platinum gem. Now, remember either carbon platinum or CIS platinum based on their eligibility. Mono therapy was armed, be an arm C was placebo plus platinum and jumps into the and the key and key endpoints of this trial were, uh, progression free survival and overall survival. And that is arm A vs on RMC. So these are characteristics. But suffice it to say that this is a well, uh, powered study with over 1000 patients on study, and you will see that they are equally distributed with regard to the different prognostic features. One thing that was an observation in this study was Platon ineligibility. now. In this trial, patients were allowed to be treated according to the investigator's choice, with recommendations for corporate platinum in CIS Platinum Ineligible patients. And you'll see, However, about 25% of patients were ineligible for CIS platinum. Yet about two thirds 66 to 70% of patients actually receive carbon plant based therapy. So a discordance see between eligibility and the choice by the investigator. So the progression free survival for the intent to treat population was a primary endpoint. And we can see that this was statistically significant, however, did not meet uh, the, uh, pre specified end point in terms of statistical significance. There was a difference in progression free survival from 6.3 to 8.2 months. Uh, in terms of the, uh, differences in these two, uh, treatment arms. But you can see, uh, that these curves only separate on the latter part of the curves. The second observation is this. And that is looking at the, uh, force plots with regard to response. Uh, excuse me in terms of progression free survival, and you'll see in the box that is outlined in red, that for patients who received CIS platinum that there seemed to be more benefit for patients who receive cisplatin based therapy than was seen for patients who received corporal platinum based therapy, suggesting a synergy between CIS platinum chemotherapy and immunotherapy, at least in terms of progression free survival in terms of the overall response rate, whether you receive the Tesla is a mob or placebo, it turns out that the response rates were quite similar, and the duration of response for both treatment arms was also quite similar. Also examined was the the overall survival of the I T T population, and you can see that the hazard ratio here for the survival distributions is 0.83 and statistically significant one sided. But the 95% confidence limits reached one, and this did not meet the pre specified level of significance. Uh, that was designed into the trial in terms of the subgroups. Uh, you can see here the forest plots, and again you will see that intriguing, uh, issue of, uh, cisplatin based chemotherapy, appearing to impart a survival advantage 21.7 months versus 13 months in patients who received the placebo and that was not seen in the patients who were treated with carpal platinum based therapy. The second trial is the Kino 3 61 trial. So let's look at this data. We see similar design, uh, that the, uh, hypotheses that were tested were progression free survival benefit. Uh, and the overall survival benefit both in the intent to treat patient populations again a well designed trial. And you can see that it was also well powered again. Well over 1000 patients in the trial, uh, in the across all three treatment arms. These are the patient characteristics, and the two boxes are illustrated to show that these patients had extensive disease, including substantial number with, uh, liver metastases. You'll see slight differences here in terms of CIS platinum and carbo platinum treated patients again CIS, platinum, soybean or carbon platinum chips. I mean, depending on eligibility, and that less patients in this trial were treated with carbon platinum based therapy. The progression free survival, using a blinded interpretation of the studies, shows that, uh, the, uh, differences in median was only a little over a month in progression free survival, and you can see that this was a hazard ratio of 0.78 statistically significant, but not uh to the pre specified level. And you can see in the forest plots that there were no real major changes in terms of progression free survival. Uh, you can't see in the bottom two rows that there are some differences with regard to those patients who are treated with CIS platinum based therapy having a little bit more of a benefit. That is a hazard ratio of 0.67 verses 0.86 for the patients who receive carbon plant in but really nominal differences. Uh, in terms of the forest plot in terms of overall survival, you can see that there was a almost three month difference in the median. But the hazard ratios 0.86 and the 95% confidence limits straddled one. And so this did not reach the pre specified statistical level of significance. And so this trial did not demonstrate a benefit in terms of overall survival. By adding temporal is a map to chemotherapy in first line therapy. When looking for clues in terms of subsets of patients who might have differed with regard to benefit, we can see that there was nothing that really stands out in the forest plots as a subgroup that was distinctly favorable in terms, in terms of benefit by the addition of federalism. App to the chemotherapy double its. So those are the two trials for combinatorial therapy. Uh, let's take a look at the sequential therapy, and here we have a clear difference. This is the Javelin 100 study. This is designed quite differently. Patients were treated in the community with either carbon Platini or Jim uh, Jim Sabin and CIS Platinum Gym side, I mean, and it was only after treatment where they enrolled on a trial. These patients had to have either a c r, a, P, R or stable disease that is non progressive disease and then were entered on the study of a value mob. As an achievement of that would continue to either unacceptable toxicity or to withdraw or two best supportive care. And this treatment free interval after the completion of chemotherapy had to be roughly 4 to 10 weeks. You can see that the statistical design was quite robust required 700 patients for this two armed trial. Let's take a look at the data. The select baseline characteristics are shown here. Site of disease Baseline Metastases PD L one positivity, the type of first line therapy and the best response to prior chemotherapy. And they are evenly distributed across both treatment arms. You'll see here, in terms of overall survival for the, uh, overall patient population did quite well. The value mob treated patients had a median survival of 21.4 months versus best supportive care alone of 14.3 months. This was highly statistically significant, with a hazard ratio of 0.69 consistent with a 30% reduction in mortality at any point in time. And looking at the PD l one positive population, we can see that the median survival was not yet reached for the patients receiving immediate Value Mob and was 17 months for the patients with best supportive Care alone again has a ratio of 170.56 and highly statistically significant when looking at the subgroup analyses. The force plot shows that every single parameter that we just recently discussed showed benefit across the board, so there was no singular population that did not show benefit. We're looking at progressive progression free survival by an independent radiology review. We can see that the progression free survival was 3.7 months versus two months, which was statistically significant, has a ratio of 20.62 That was also seen in the patients who were PD l one positive. Yeah, one issue with regard to the study is patients who were randomized, the best supportive care alone and at the time of progression did they receive therapy? And you can see that I've circled in red, the PDO one and P D one inhibitor utilization and patients randomised the best supportive care alone. You'll see about 53% but not 100% or or a high number had received, uh, second line immune therapy. So we need to watch these issues with regard to the trials and include them in our interpretation. So let's take a look at the simultaneous versus sequential and vigor. 1 30 was not a positive trial, but this may be influenced. Influenced by the number of cisplatin eligible patients who actually received carbon platinum based therapy, the overall survival trend may be driven by the cisplatin treated patients. I showed you an interim analysis. We look forward to the final analysis in the keynote 3 61. Neither PFS or OS reached statistical significance in that subgroup of CPS greater than 10% or the PD L one positive patients was similar to the i T T population. But there are also considerations here that may have influenced the overall survival observations. In contrast, the Javelin 100 trial was statistically superior in terms of survival compared to the best supportive care. And that drug is FDA approved for this indication. So now let's look at the muscle invasive urethral cancer population and the controversies and adjuvant therapy and the data that have just recently emerged with regard to these treatments. So let's go back. What are the recommendations for muscle invasive disease? Well, for patients who have muscle invasive bladder cancer without obviously metastases in the pelvis. Uh, it is recommended to receive cisplatin based chemotherapy. For patients who are knowledgeable, they should go to surgery alone. Uh, the prognosis directly depends on the pathological response that is seen in the suspect of the specimen in the left hand panel. It's broken out into multiple subsets, including those with residual disease that is less than P T to those that are PT two and zero and in the bottom. And the left hand panel is the worst outcome of patients who are either node positive or P t. Three or P. T. Four. You can break this down into two groups on the right hand side, that is, those who have sterilized the muscle invasive component the less than P T to do extremely well with about a 90% long term survival, at least in our hands. And this has been seen in multiple studies and in the bottom you'll see the patients who did not reach that criterion and that long term survival is 37%. This has been seen in multiple studies now, in terms of patients who did not get neo adjuvant chemotherapy. What are the guidelines? And it is recommended for CIS platinum eligible patient to receive cisplatin based chemotherapy. But for patients who are ineligible for CIS platinum, observation is the standard of care. We know we can combine these groups, that is, you can divine excuse me, define a high risk muscle, invasive, uh, subset of patients after suspect me if you've had prior neo adjuvant chemotherapy and you have greater than P T to disease or you did not have any prior chemotherapy and you have PT three or greater disease. Those patients can be combined and have a universally poor survival in the left hand panel and in the right hand panel are disease free survival and overall survival, respectively, for phase two randomized trial using a vaccine that was ineffective. But you can see that the survival distributions are consistent in both arms of this trial. So this has led to three trials. The Ambassador trial checked me to 74 in a bigger oh one. Oh, looking at the use of single agent therapy after, uh, chemotherapy And, uh, suspect me for those patients who have high risk disease or those patients who are ineligible for CIS platinum. After suspecting me alone Ambassador trials still running and accruing, I urge you to consider your patients for that trial asking this important question in terms of checkmate 274 and a bigger 010 Those results are now available and let's walk through them. And bigger 010 was presented last year at G. You ask Oh, by Dr Hussein. It is a trial. Looking at the patients that I just described. In terms of eligibility, patients were randomized 1 to 1 to either a textualism ab, given for 16 cycles or one year versus observation. And the end points of that trial included disease free survival in the I T T population and key secondary endpoint was the overall survival in the I t T population. Uh, this trial has been now reported in terms of those two outcomes disease free survival here, uh, is shown. And unfortunately, this trial did not reach its, uh, primary endpoint. You can see that the median disease free survival differed by just a few months. But these serves these curves are really super imposible and the P value crossed one, uh, and not statistically significant in terms of disease free survival by PD l one status you see in the left hand panel, the low or zero express, sirs, and in the right hand panel, the High Express sirs. And we can see that there is really no discernible benefit in either of these two subsets and trying to distinguish, uh, low or high express sirs in terms of the forest plots, we can really see here that there are slight differences in those patients who had upper track versus bladder primaries, Uh, and patients who had p t to disease versus PT three or P t. Four disease. But again, uh, minor differences across the board. This is the interim analysis of the overall survival. And as we can see, uh, the medians are not yet reached, but there are no major differences as of this point in time. Uh uh. In terms of the overall survival, when we look forward to the long term survival that will be reported, uh, from the trial. Checkmate 274 Trial is just announced in terms of its data. Uh, last week, checkmate 274 Design is very similar to what I just showed you for the vigor trial, uh, again, the same inclusion criteria that we just spoke about. Median follow up for the population is 21 months for the naval, the whole mob arm and, uh, 19.5 for the placebo. Warm. You can see on the right hand panel. The randomization is novel. A mob given an agreement setting for one year. And then that was random randomized to placebo. Given also ivy every two weeks for one year. Stratification factors are shown and the primary and points where the disease free survival in the I t. T and in all randomized patients with PD l one positive tumors using this ass a, uh and then secondary endpoints included non European real track record free survival, disease specific survival and overall survival. Patient disposition is shown here. You'll see that 55 to 56% of patients, uh, discontinued treatment and you'll see that an Ebola mab arm that was for disease recurrence and 25% versus 42% in the placebo arm. So much greater for those receiving placebo. Secondarily, you'll see that in terms of the baseline demographics in terms of tumor origin, it was 80% for patients having bladder primaries and 20% by design of patients having upper tract disease. In terms of PDO one positivity, it was 40% in both arms and in terms of prior neo adjuvant therapy again, 43% in both arms shown here are the endpoints for disease free survival in the I T T population and in the PD l one positive population, the hazard ratio and the I t T population was 0.70 highly, statistically significant, consistent with a 30% reduction in this population. Uh, in terms of the risk, Uh, and in pd l one, uh, positive patients, it was 0.53 highly, statistically significant, consistent with a 47% risk reduction in death or recurrence. When we look at the forest plots, you can see that based on age uh, sex region and baseline, No major differences. Uh, in the, uh, patient populations and in terms of select groups looking at bladder and upper tract, it looks like upper tract did less well. But small numbers of patients that therefore the 95% confidence limits are quite wide. And all the other groups showed no discernible differences. Non European real track recurrence that is outside the EU tracked, eliminating those patients who might have had second non threatening primaries. And in the I t T population, you see the hazard ratio of 0.72 and in the PD l one positive patient population 10.54 very encouraging in terms of distant metastases free survival, you can see the population in the left hand panel 0.74 in a pdf one. Positive patient patients 0.60 again highly encouraging for Makassar. Distant metastases. Free survival. So let's last finish up with refractory disease patients who have progressed despite multiple prior therapies and take a look at the world of targeted therapy and antibody drug conjugate. What we know about this disease is there are a large number of mutations, uh, in a number of different pathways. Uh, and so there are also a number of different drugs that are under study. We're gonna focus on one of the most common mutations, and that's FGF or three and F g f R. Two that are seen in your ethereal carcinoma sword. If it is a oral pan f g f r one through four inhibitor, which is a tyrosine kindness, and it's been studied in a Phase two trial. This trial looked at the standard dose of 8 mg and could be tight, traded up or down, depending on tolerance or toxicity. Uh, this was a well designed study demonstrating efficacy of this drug for patients who have either an F g f R three or two mutation or an F g f R fusion in this study, the response rate was 40%. Really, this is better than anything we've seen in prior chemotherapy, an immediate survival of 14 months. Also better than what we have previously seen with any type of therapy, you can see here in the swimmer spots that a number of these patients had continued response beyond the 10 month period of time. Uh, and so the maintenance of these responses is highly encouraging. Uh, toxicity is expected from this family of tyrosine kinase inhibitors. Most notable is HIPAA phosphate anemia, and we know that hypothesis. Fatima is a biological effect of this drug, but there are also skin and nail changes and occasional a central retinopathy. So it's encouraged that all patients who received this drug are seen by ophthalmologists at baseline and followed during therapy. And so we can see that this the results from this phase two trial has resulted in the Phase three trial comparing to fit nib with chemotherapy or embolism hob immune therapy. But in the meantime, this oral pan F g f R inhibitor has received FDA approval for patients who harbor F G F R mutations. The next drug is enforcement Venda button This is an antibody drug conjugate it actually targets neck and four, but next and four is ubiquitously expressed on your ethereal carcinoma. Originally, staining was necessary, but because it's ubiquitously expressed, it can be given without staining. Uh, this is a drug conjugate, and the drug is a that is attached to this antibody is M M e a micro tube. You'll disrupting agent. Uh, and it has been shown to be quite effective. This is a phase two trial that included all patients who had one prior systemic therapy. Uh, and prior checkpoint therapy was allowed. Uh huh. There were no grade three toxicities. Uh, that, uh exceeded 5%. However, there are two types of toxicities that we draw your attention to this drug is now approved, and that is, uh, in patients with diabetes. One must watch the glucose levels extremely closely because they have better care. Diabetic ketoacidosis has been observed. And then now, most recently, there's been a warning with regard to the possibility of cutaneous rashes and even Stevens Johnson syndrome that has been observed rarely, uh, on study or in patients treated off study. We can see here in terms of the response rate very encouraging. The overall response rate was sent in this trial with a 4% respond complete response rate, and you can see whether they were bladder primaries or primaries in the renal pelvis or your order that we see responses across the board. Here you can see the overall survival, which was 13.6 months. And then in the right hand panel you'll see an orange. Those patients who have been treated previously with immunotherapy. The median survival was 14 months again, highly encouraging. And just recently, this past week, the Phase three trial was reported randomizing and for enforcement video button to chemotherapy and previously treated patients. Uh, and that trial demonstrated the superiority of enforcement vendetta. So this drug is FDA approved for this indication, uh, for your patients. So thank you very much for your attention. And we will, uh, proceed on with the question and answer period.
