Phase III VISION study: Lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (PC)

DR BALAR: So Thanks, Neil, for the kind invitation. So I’ll be going over ASCO 2021 updates in GU cancers.

First, I’ll go over prostate cancer updates, some key pivotal data from this year’s ASCO, and obviously what rises to the top is the Phase III Lutetium PSMA-617 study in metastatic castration-resistant prostate cancer. This is the VISION trial.

This was presented at the Plenary Session by Dr Michael Morris. And just to kind of level-set here a little bit, what is 177 lutetium PSMA-617? It’s a PSMA-targeted radioligand therapy, essentially what many people call liquid radiation. And so, basically what this is, is 617 PSMA targeted linked with beta particle emitting radioligand that targets anything that expresses PSMA which is largely restricted to prostate cancer cells and to some degree, salivary glands and lacrimal glands and so forth. And once it gets endocytosed, causes DNA damage. And was tested as part of a Phase III trial. And it’s really restricted, its ability to deliver this directly to the cancer cells is what make this exciting. And it was tested as part of this Phase III study. It’s been in development for a number of years.

And the eligible patients in this randomized, Phase III trial that were randomized 2:1, included patients with metastatic castration-resistant prostate cancer who had progressed on 1 prior androgen receptor pathway inhibitor and at least 1 or 2 prior taxane regimens. They could also concurrently get standard of care treatment but those excluded concurrent chemotherapy/immunotherapy, radium or investigational products. So basically included other second-generation antiandrogens. And patients were randomized either to lutetium PSMA-617 every 6 weeks for 4 cycles plus standard of care versus standard of care alone.

The key data was prolonging OS. Here is a hazard ratio of 0.62, p-value .001, median of 15.3 months versus 11.3 months. And so, immediately this is practice-changing data in the 831 randomized patients.

What’s also striking about the data and what stood out to me is that you saw RECIST responses. So, unlike radium, which was the older kind of liquid radiation that targeted bone and was really developed as a bone palliating or symptom palliating drug, the patients with liver metastases were allowed on this trial and you saw RECIST responses even in patients with soft tissue, nodal, liver metastases. And you saw responses including complete responses in the patients with RECIST measurable disease. And this is highlighted here in the patients who were treated with experimental therapy. Also, you saw PSA responses.

So this is what’s clearly different about this agent as compared to other attempts at radiopharmaceuticals is that on treatment you can measure efficacy on the basis of PSA responses, RECIST responses, and ultimately prolonging survival.

What about safety? With anything that you’re emitting radiation and you’re administering this intravenously, you’re going to get your fair share of toxicity, which is largely going to be marrow-based. And so, you can see a fair degree of marrow toxicity in the form of marrow suppression and white counts, anemia, and thrombocytopenia. And then some other somatic effects, dry mouth, nausea/vomiting, and so forth. But certainly, overall therapy was fairly well tolerated. And overall, relatively low grades of Grade 3 and higher toxicities.

Overall, I agree with the study conclusions of the authors: extended overall survival, delayed radiographic progression-free survival. Therapy was well tolerated and quickly established lutetium PSMA-617 as a new treatment option in metastatic castration-resistant prostate cancer.

Updated safety outcomes from the EORTC 1333/PEACE III trial: Effect of adding bone-protecting agents

DR BALAR: What about other exciting data? So the PEACE-3 study, this was pivotal, and I think an important study that looked at the role of enzalutamide plus radium versus enzalutamide alone, and more specifically asks the question of the role of bone targeting, or bone protecting agents.

The history of this particular study looks back on an older study called ERA-223, which looked at abiraterone plus radium, and this was a study that actually ended up closing early because they saw very high rates of skeletal-related events and basically found that radium plus abiraterone wasn’t such a good idea because of high rates of skeletal-related events.

In this very similar study that looked at radium plus enzalutamide saw very similar issues, the primary endpoint here is radiographic progression-free survival, but the key message here is that they intervened here in this study and said listen, we need to add bone protecting agents, whether it’s zoledronic acid or denosumab and the like. And basically, once they intervened with bone protecting agents you saw that the overall rates of skeletal-related events, both at 12 month and 18 months, basically reduced dramatically and basically came in line in both combination arm as well as the control arm. So, basically, that’s what should have happened in ERA-223, is that if you had required use of bone protecting agents in that study maybe we would not have seen the outcomes that we saw in that trial where radium was combined with abiraterone.

First results from the Phase III PEACE 1 study evaluating abiraterone acetate with prednisone and/or local radiation therapy for de novo metastatic castration-sensitive PC

DR BALAR: What is the other study that I think was also relevant and practice-changing, or at least practice-informing, is the PEACE-1 study. This was a 4-arm study, 2x2 factorial design that looked at patients with de novo metastatic castration-sensitive prostate cancer. That was an evolving trial. This is a study that was developed first in 2013 with the primary question of looking at the role of abiraterone added to standard of care and also with the additional variable of the addition of radiotherapy.

What’s critical here is that the standard of care arm alone actually evolved, which, over time — and that’s why there were many slides in this presentation, but I’ll start at the top — is that the primary endpoint was radiographic progression-free survival. But the standard of care arm alone initially began with ATD alone and then, obviously, CHAARTED reported out and STAMPEDE and so forth, also included docetaxel. And there was cohort G of STAMPEDE, which then included primary radiotherapy to the prostate. And so, essentially, standard of care eventually included potentially all 3.

And so the final question was does abiraterone add to multimodal therapy? There was interaction testing that had to take place, did the role of primary radiotherapy, did that interact with the benefit of abiraterone? Once they found that that actually did not happen, you could actually pool the analysis together. And so, essentially, the question is does abiraterone add to standard of care where standard of care could include ADT, docetaxel and primary radiation to the primary in de novo metastatic prostate cancer? And here, you see a significant benefit in terms of radiographic progression-free survival of nearly 2.5 years at the median and a hazard ratio of 0.54 and p-value that’s 0.001.

So, the authors here, Karim Fizazi, clearly said here that the OS data were immature at the time of this analysis, but the point is clearly well taken. Should we deny the patients an approximately 2.5 years absolute benefit in median radiographic progression-free survival or do we have a new standard of care?

I will tell you myself, and many of my other colleagues who treat prostate cancer, have already taken this kind of multimodal approach of let’s say doing ADT/docetaxel and then quickly following with abiraterone and also treating the primary. And we tend to kind of throw the kitchen sink especially with young patients with de novo metastatic prostate cancer because we feel that upfront multimodal therapy benefits patients long term.

Update on darolutamide tolerability: Outcomes with aggressive hormonal therapy for high-risk localized PC

DR BALAR: So this was the tolerability and extended follow-up from the ARAMIS study. The ARAMIS study was darolutamide in M0 CRPC. And really, the question was, what was the overall tolerability? And it continues to be well tolerated with extended treatment at 600 mg twice daily. This stands out because darolutamide amongst the next generation AR-antagonists has limited CNS penetration. It’s an attractive option. And frankly, I would use this much more often even in M1 CRPC when I can because of its limited CNS penetration. And not surprising, in a majority of patients showed a greater than 50% decline in PSA from baseline. So I like seeing the improved tolerability.

The interim analysis from the AASUR study, which again, we’ve seen trials like this. This is a single institution, single-arm study, that looked at apalutamide, so an AR-antagonist, abiraterone plus prednisone, leuprolide, and ultra hyperfractionated SBRT to very high-risk node-negative prostate cancer. Showed high disease control rates and basically biochemical — 3-year biochemical relapse-free survival as compared to historical controls.

The challenge there is that single-arm study, 64 patients, and you’re comparing to historical controls, I think it’s good data, but I think randomized trials are needed. We’ve seen very aggressive therapy to the prostate in localized prostate cancer demonstrated data like this before, but randomized trials really needed. But I think it’s nice to see that we can maximally treat the prostate and lead to long-term — or at least extended control of the prostate.

Bladder-sparing therapy with pembrolizumab, gemcitabine and concurrent hypofractionated radiation therapy for muscle-invasive bladder cancer (MIBC)

DR BALAR: I’m going to pivot now to bladder cancer updates. This is the area that’s obviously near and dear and close to my heart and I had the privilege of presenting our own investigator-initiated clinical trial of pembrolizumab in combination with gemcitabine and concurrent hypofractionated radiotherapy as bladder preservation therapy in muscle-invasive bladder cancer. This was a multicenter Phase II trial.

The oral abstract session at ASCO this year was thematically bladder preservation and included 3 investigator-initiated trials. And I’m excited because I think this is something that many of us investigators are really passionate about, which is moving toward bladder preservation and offering this as an option to more of our patients with muscle-invasive disease because cystectomy is not the gold standard and is not for everyone and we need to counsel our patients about our options.

And in this treatment schema, which was developed both as a biomarker study as well as an efficacy study, all of our patients had clinically localized muscle-invasive bladder cancer, adequate performance status. They were either cystectomy-ineligible or cystectomy-refusing, meaning they just wanted bladder preservation, and no perioperative chemotherapy. All patients received a single dose of pembro, a maximal TURBT which is resection of their bladder tumor, and then hypofractionated radiotherapy to only the bladder over 4 weeks, twice-weekly gemcitabine over 4 weeks, and then pembrolizumab every 3 weeks for 3 doses. So it was a limited course of immunotherapy. We don’t have this long tail that we have in some of these larger registrational studies. And then 12 weeks later, an assessment for efficacy in the bladder bed with TUR and cross-sectional imaging as well as cytology. And then patients entered follow up with cystoscopies and imaging as well for up to 5 years.

I’ll jump ahead to the primary endpoint, even for the entire population we had 6 patients in the safety cohort and then 48 patients in the efficacy cohort. We pooled all of those patients together, 54 total patients, bladder-intact disease-free survival was 89%. It was 88% in the efficacy cohort. Our target was 80% at 2 years. And so, already in this analysis we’re seeing a benefit in the patients by adding immunotherapy to standard chemoradiation. I will point out that 72% of all the patients enrolled in this study were patients who chose bladder preservation, they just simply did not want a cystectomy and that’s why they chose to enroll in this study.

What about safety? Can you add immunotherapy to chemoradiation? Yeah, you sure can. Low rates of immune-related adverse events. The majority of the toxicities were generally of low grade and frequency. And while 19% of the patients required systemic corticosteroids to manage an immune-related event, the majority were manageable, and they’re listed out here for you individually at the bottom there.

Results from the Phase II HCRN GU16-257 trial: Gemcitabine/cisplatin with nivolumab and selective bladder sparing for patients with MIBC

DR BALAR: The other really cool study was HCRN GU16-257. One of my colleagues uptown at Mt Sinai, Dr Matthew Galsky, developed this trial. Also a very interesting bladder-sparing approach. But here, what he did was combine gemcitabine and cisplatin as neoadjuvant therapy, so 4 cycles of chemotherapy, also added nivolumab, so 4 cycles total, basically 12 weeks of treatment. But at the end of that, instead of directly proceeding to cystectomy, he did what’s called a clinical restaging. There, you do a cystoscopy. You get biopsies of the tumor bed where the tumor was and also cytology and cross-sectional imaging of the bladder. If the patients are in a clinical CR, meaning imaging looks favorable, normal cytology, biopsy is negative, so a clinical CR, then those patients can then have the option to forgo cystectomy and then get additional nivolumab up to 4 months versus go to cystectomy. For patients who don’t achieve a clinical CR, then they go on to cystectomy.

And basically, the purpose of this was to determine the clinical CR rate upfront and then also the ability of that clinical CR to predict “benefit”. Now benefit is in quotes here because honestly, what is benefit? Time of delay of cystectomy and also delaying cystectomy safely, so this is a provocative area where you’re not treating the bladder definitely. I think that’s an important piece here. The bladder doesn’t get radiated at the end of this you just don’t anything with the bladder. That’s it, you just observe.

So in this trial, 76 patients were enrolled, 64 patients made it to clinical staging and then 31 patients made it to clinical CR, and then 30 patients made it to no cystectomy. I’ll point out here that these are the patients who made it to clinical CR, the majority are still alive and in follow up. Now you have several patients here, that are blue lines here, and I’m not going to point all of them out — those blue lines are those patients with recurrences. A number of those patients did end up getting a cystectomy, and those are those green dots, and a couple of those had upstaging to muscle-invasive and even node-positive disease. The problem is, is knowing who those people are going to be upfront. And so, it’s a little bit of a guessing game. So what do you need in addition to that clinical CR?

Biomarkers, right?

So here, and this is the most important piece that I think needs to be teased out for us to know, clinical CR plus that biomarker — I’ll point out to the top here, tumor mutational burden of 10 mutations per megabase or greater, and mutations or mutations and ERCC2 were associated with clinical CR or path CR. So, some of the patients went to cystectomy and had no tumor in their bladder.

So, importantly, if you supplement clinical CR with a biomarker, and there’s a really good study led by Alliance, Dr Gopa Iyer, that’s doing this, biomarkers plus clinical CR, I think you’ve got something where you can avoid treating the bladder.

ATM, FANCC, RB1 alterations, were not associated. So I don’t think these are useful biomarkers, although other studies have suggested as much. I think this is something that we need to look out for. But I think it’s a very provocative study to look out for.

Long-term outcomes from the KEYNOTE-052 trial assessing first-line pembrolizumab for cisplatin-ineligible patients with advanced urothelial cancer

DR BALAR: KEYNOTE 052, this was an update of the first-line study for pembrolizumab, a study that we led at NYU and led to regulatory approval for first-line pembrolizumab in the cisplatin-ineligible population. This was published in 2017. It was a single-arm study of pembrolizumab in cis-ineligible patients, 370 patients were treated, and RECIST response was the primary endpoint.

The purpose of this basically greater than 5 years follow-up was to look at long-term survival, updated response data, duration of response, and what does the tail of the curve look like in the patients who were treated in this first-line, single-arm study?

So this is where we are here. The median survival, if you draw a line from the 50% mark and down is 11.3 months. But really, what we’re looking at is landmark stuff. So we have 19% of patients alive at 48 months, so that’s 4 years. And obviously at 60 months, you see the plateau. It’s roughly about 15% to 20%, which is encouraging. And then, what about the patients who have PD-L1 overexpressing tumors and CPS 10 or greater? Those are actually almost close to 32% of patients at 4 years and longer. So it’s really encouraging amongst the patients who have high PD-L1 expressing tumors, median survival of 18.5 months.

What about the OS by the response? So if you get a response, so 29% objective response rate in the study, what if you’re in a PR or CR in the overall study population? Look at the CRs, overall, only 9 patients out of all the CRs that occurred have died. And at over 4 years, that 4-year landmark survival rate is 88%. So if you’re in a CR from pembro, 88% of those patients are alive at 4 years or longer. And I think that’s incredible data.

So, it just speaks to the durability of those responses.

And then the question is, well, how do you get to those responses? Do those responses and their durability matter whether they were achieved in the context of low CPS tumors or high CPS tumors? The answer is no. So if that CR was in the context of low or high CPS, those durabilities are the same. And the same is the case for those partial responses.

So, no matter how you get to that PR or CR, they’re of the same quality irrespective of the baseline CPS status.

First-line maintenance therapy with avelumab for advanced urothelial cancer: Subgroup analysis of the JAVELIN Bladder 100 trial

DR BALAR: And then lastly, these additional subgroups — I think they had 3 different posters from the JAVELIN Bladder 100 study, and this is one that stood out, which looked at some key clinical and genomic subgroups of the bladder, JAVELIN Bladder 100 study. And in this study, basically just to kind of reframe, is that the JAVELIN Bladder 100 looked at the role of maintenance avelumab versus best supportive care in patients who had already received platinum-based chemotherapy and achieved disease control and with the primary endpoint of OS. And what they found is that the benefit of maintenance avelumab basically extended to all of the other subgroups, whether it was upper or lower tract disease, metastatic versus locally-advanced, PD-L1-positive tumors that were previously treated with first-line gemcitabine and carboplatin. And then the genomic subtypes — now they didn’t see as much of a benefit in the Luminal subtypes, but I think honestly, sometimes you just see some random effects because remember, it’s treatment versus best supportive care, it’s not versus an active comparator.

So I think that when you see these benefits, it’s not all that surprising. But basically, it confirms that maintenance therapy in this trial really did show benefit.

Phase III CheckMate 9ER trial: Outcomes by baseline disease characteristics with nivolumab and cabozantinib for advanced renal cell carcinoma (RCC)

DR BALAR: Let me finish up with renal cell carcinoma updates. CheckMate 9ER, this was another pivotal study that led to the approval of nivolumab and cabozantinib in the first-line setting irrespective of IMDC status, a 651 [patient] randomized Phase III trial of nivo plus cabo versus sunitinib in previously untreated metastatic clear cell renal cell carcinoma. The purpose of this update was really to look at clinically meaningful subgroups, and I think to inform some of the controversy there is. Because in the first-line setting we have axitinib/pembro. We have axitinib/avelumab. We have cabo plus nivo. We have lenva plus pembro. And as a kidney cancer doctor, I’ll get often asked the question, how do you choose between the 3 or 4 options that you have? I always say, listen, get used to 1 or 2 of them, use them well.

However, there are some subgroups where I think that you can see there’s some differential activity especially in liver and bone where you saw some of the hazard ratios favor cabo plus nivo even more so, and I think, clinically you’ve kind of known this. And you can see this here for PFS and OS, that the curves really do distinguish themselves if you looked at this as compared to the intent-to-treat for PFS and OS for liver and bone, they are really striking. And I think there’s some activity here that is differentiating for nivo plus cabo. And also, based on sites of disease.

So, when patients have more than 1 site of disease versus just 1 site of disease, you can see that OS, it appears to be differentiating. Now, granted, patients who tend to have more than 1 site of disease tend to also fall into IMDC, intermediate- and poor-risk groups, as compared to good-risk disease. But highlights again that some of these patients with poorly differentiated tumors, very aggressive disease, perhaps might benefit a bit more from cabozantinib plus nivo. But, again, I think all the combinations are quite active.

Results from the Phase III KEYNOTE-564 study assessing pembrolizumab as postnephrectomy adjuvant therapy for patients with RCC

DR BALAR: The other GU trial — I think GU really stood out at this year’s Plenary session, the KEYNOTE-564 study was the first adjuvant immunotherapy therapy in kidney cancer to read out, but remember, there are more trials to read out. So I think we need to be patient.

So this study looked at patients with clear cell renal cell carcinoma who had undergone nephrectomy or had oligometastatic disease and had Stage IV NED, although that only represented 6% of the patients in this trial, and patients were randomized with intermediate-high risk or high-risk disease to either pembro versus placebo for up to a year. And the primary endpoint is disease-free survival based on the treating investigator. And again, the stratification factors include M0 versus M1 NED. M1 NED was a tiny fraction of the patients that were enrolled into this trial.

So this is what you looked at. These were the patients that were considered eligible for this study, intermediate-high risk, and then the so-called very high-risk patients. I’ll point out, even T2 patients could get on if they had Fuhrman Grade 4 disease or any sarcomatoid features. And then obviously, high risk and M1 NED is patients who had oligometastatic disease and then that were also resected.

So, here are the DFS curves. The curves separate. They essentially have maintained separation. Now I’ll point out that here the number at risk here really drops down dramatically. That explains some of the instability of the curves at the far right. But the hazard ratio is 0.68 and meets statistical significance. And remember, the treatment ends at 1 year. So you have to remember, this 12-month landmark DFS rate is important because everything beyond that is really assessing the benefit of that 1-year therapy and it looks to be maintained even at 2 years and beyond.

What about OS? This is the part that does not yet meet statistical significance, but you can see that the curves separate, and they have maintained separation. So, in my view, that hazard ratio of 0.54, I think this is practice-changing data. And so, if ultimately — and while the number of events hasn’t reached that meaningful rate yet, I think that if the FDA approves this drug, I do think that this is immediately useable in the clinic. And I will discuss this with my patients who are considered high risk.

Pembrolizumab with axitinib as first-line therapy for advanced RCC: Results from a 42-month follow-up of the KEYNOTE-426 trial

DR BALAR: The other study that I think I was actually most excited about for long-term follow-up because I think it really does impact first-line practice. Because right now in first-line metastatic kidney cancer it’s either TKI plus PD-1 versus CTLA4 plus PD-1. And KEYNOTE 426 was a very important trial because it was one of the earlier studies that tested TKI plus PD-1 and I wanted to see the long-term follow-up — this is greater than 42 months follow-up from this study — to see if long-term PFS and OS in that kind of plateau, that table to the PFS curves that we saw with ipi/nivo, if we would see the same with KEYNOTE 426.

So to summarize again, first-line metastatic clear cell RCC untreated, close to 900 patients, 850 or so patients were treated in this trial and randomized to pembro plus axitinib versus sunitinib alone, OS, the curves maintain separation so there clearly still maintains an OS benefit but what I wanted to see were the PFS curves.

And so, if you kind of hallucinate with me for a second here, if you look at these PFS curves, they separate, but remember there is that curve for axitinib/pembro continues to march on its way down. So there continues to be progression of events past 30 months, 36 months and 42 months, whereas with ipi/nivo, it stays flat. So the rate of progression is 33% and it stays flat, basically past 30, 33 months.

And so, what we see with CTLA4-based theory, which is this hardwired immune effect, those are potentially — dare I say are potentially cures or potentially durable CRs, I’m not sure if we see with axitinib plus pembro. And I think that’s something we need to think about when we’re making our first-line treatment decisions.

Updates on tyrosine kinase inhibitor and immune checkpoint inhibitor combination therapy and other novel agents for patients with RCC

DR BALAR: And then the CLEAR study, this was updated analysis presented by Dr Motzer. This was the Phase III 3-arm trial called CLEAR that looked at lenvatinib plus pembro, lenvatinib plus everolimus versus sunitinib. And actually very similar to what we saw with cabo plus nivo versus sunitinib, is that actually had similar to improved health-related quality of life as compared to sunitinib. And I think many of us are actually kind of surprised by that, that sunitinib actually, even against combination therapy, sunitinib still has inferior quality of life data. And so, I guess that reaffirms that TKI plus PD-1 is here to stay and even has better quality of life than sunitinib.

I’m not surprised that lenvatinib plus everolimus had similar or worse quality of life as compared to sunitinib, in particular with everolimus because of the fatigue, rash, some of the metabolic effects and also the mouth sores that patients get with everolimus. So, it’s a tougher drug for patients to take and from a quality-of-life standpoint I’m not that surprised.

So, the nivo plus cabo. So they looked at non-clear cell. I’m not surprised by this because Dr Sumanta Pal had done a randomized study called PAPMET that looked at figuring out what is the best VEGFR TKI in non-clear cell RCC. Cabozantinib had won out in that randomized study. So to find out that nivolumab plus cabozantinib had a very acceptable safety profile and showed some promising efficacy when used in combination with nivolumab is actually not all that surprising. In fact, in clinical practice I tend to use cabozantinib among the available treatment options that we have in non-clear cell RCC. So to have this data is actually very attractive because then it allows us — it actually allows us to get access to these therapies when it comes down to insurers and payers and so forth when I want to treat a patient with non-clear cell renal cell carcinoma. So it was nice to see this data.

And then finally — I always have trouble pronouncing all these new HIF inhibitors — but belzutifan which is MK-6482, not surprisingly in VHL disease-associated clear cell RCC had an objective response rate of 49.2%. It makes sense HIF-1 alpha inhibitors should work and had a favorable safety profile.

So we should look out for more data from this agent in the near future.

Expert perspectives on advances in the treatment of genitourinary cancers

DR BALAR: So how do we put this all together? So in prostate cancer, lutetium PSMA with metastatic castration-resistant prostate cancer is a new standard of care. I think it immediately impacts standard of care and I think the FDA needs to make a decision quickly.

Bone protecting agents would significantly reduce SREs when we’re combining second-generation AR-antagonists and Radium-223. This was a significant concern from the ERA-223 trial. And I think adding the bone protecting agents relieves some of the concern.

And then upfront multimodal therapy in advanced hormone-sensitive prostate cancer improves PFS. So ADT, abiraterone, docetaxel/abiraterone and potentially local treatment to the prostate with RT does that. Impact on OS is unknown, but I still think it impacts practice.

In bladder cancer, we are seeing bladder preservation therapy gain new ground. We’re starting to leverage combination strategies with chemotherapy and chemoradiation. And I’m excited about some of the randomized trials that are currently underway. And the responses, especially CRs to immunotherapy in first-line metastatic urothelial cancer are durable and lead to long-term survival. So we need to know that for our patients that remains an effective option.

In kidney cancer, adjuvant pembro I think is ready to impact standard of care but I’m actually more excited about ipi/nivo in the adjuvant setting. That study has completed enrollment. And I think that is even going to further impact DFS and OS. So stay tuned.

Subgroup analysis from CheckMate 9ER suggests that some clinical subgroups might benefit even more from cabo plus nivo. And then finally, long-term follow-up from axitinib plus pembro really demonstrates differentiating characteristics from KEYNOTE 426 as compared to CheckMate 214 and it’s really not the same as ipi/nivo.

And I think finally data from this long-term follow-up really demonstrates that.