Episode 124: Real World Evidence lessons in Kidney Cancer with Professor Daniel Heng

We welcome back the wonderful Professor Daniel Heng from Calgary, Canada where he works as the Head of Medical Oncology at the Albert Child Cancer Centre. If you missed the first episode please treat yourself and go back and listen to Episode 123. Turn off your phone or computer and settle down and hear Danny Heng in the last episode. We talked a lot about biomarker and the IMDC in that episode. In this episode we explore real world evidence in kidney cancer and future directions in kidney cancer. Danny I want to circle back round to the work that you did with IMDC and the IMDC criteria and essentially being able, you mentioned it to start with, you know, you're constantly getting data dumps and people are contributing more. real world data. This is not, you know, trial patients. This is everyone having active treatment in the real world. And it's an incredible feat. The amount of information that you get and gather from this project in terms of real world evidence is truly spectacular. It's way more than just a prognostic scoping system. And what I want to know is what lessons have you learned on the way to, obviously it's a journey, it's a journey of many years, isn't it? But what lessons have you learned on the way and what can, what would you, you know, speak out to people thinking about similar projects and other tumour types? Because ideally you'd have this kind of sort of repository in all in all cancer types, just trying to really get all of that data. So what are your what are your learning points from your journey so far?

Daniel Heng 26:03 I love it. Thanks so much. Those are very, very nice compliments. So I really appreciate it. It's really a group, right? So a huge group of investigators have made the IMDC happen, and without them, it wouldn't happen. So there's only over 50 institutions worldwide. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 26:04 Yeah. Yeah. Mhm. Daniel Heng 26:23 16,500 patients globally, and we get our next data done in about 6 weeks, so we'll find out what the numbers go to then. I think I was a fellow when I started this, and a fellow in Vancouver or Calgary, a lot of people don't even know where Calgary is back then. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 26:30 Mhm. Daniel Heng 26:47 And I think it was really helpful to go from place to place doing fellowships. So I did fellowships in Cleveland. I did a master's in Boston. My friend Tony Schwary is in Boston. Jennifer Knox is in Toronto. Scott North is up in Edmonton. And Christian Kolmansberger is in Vancouver. And so I just got all of these people together to donate their data. Because we were all really excited at that time because it was the TKI era, the dawn of the TKI era. We had never used a TKI before. And so we were all really excited about collecting data there. And it wasn't hard to collect that data. It took maybe 20 minutes to collect each patient. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 27:15 Mhm, mhm. Daniel Heng 27:30 And you really just needed the prognostic factors, their outcomes, and then just do Kaplan-Meier curves. And so that's how it started. In terms of the lessons, I think the biggest lesson is inclusion. I think everyone wants to help. Everyone wants to help participate in something big. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 27:42 The. Daniel Heng 27:49 And if you make it easy for them to participate, like if you pre-populate ethics submissions, if you pre-populate contracts, if you give them examples of data and data dictionaries and things that just make their lives easier, then things will happen. Because as you know, we're all busy people. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 28:09 Mhm. Daniel Heng 28:09 I can't imagine starting the IMDC today, on my desk today, like how am I even going to spend, you know, 20 minutes collecting patient data on one person? And so I think if you make things easier for people, they'll come. I think we show the value of the IMDC with publications. So we don't pay institutions for their data. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 28:18 Mhm. Daniel Heng 28:33 the credit comes from authorship. And so the authorship has been very helpful to be able to spread around to all of the different institutions. And then we've been able to attract great people doing that. And finally, I just want to shout out to all of the residents medical students, all of the registrars, trainees, urologists that help collect this data. And so really the IMDC is built on the backs of trainees, trainees like me. And so I think that was a really, it's just really heartening to see that all of this hard work, all this sweat. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 29:06 Mm. Daniel Heng 29:13 Equity can turn into something like this. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 29:16 And I think you'll be on a trainee now, Danny. I think. Daniel Heng 29:21 17 years ago maybe, but we were always learning. We're always learning. The more you know. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 29:24 Aren't we trainees? A trainees in the hard school of life. I knew you were going to say that, Mike. Daniel Heng 29:31 But. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 29:33 But. Daniel Heng 29:33 Haha. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 29:35 And I have a little phrase where I say clinical trials are the picture, you know, that is the painted picture, but real world evidence when you wrap it around the picture is the picture frame. Not every frame will fit the picture, because if you have a trial that's done primarily in Asia, that might not suit the kind of patient population that we have here in CORNWALL, for instance. You know, so you have to put it into the context. With the real world evidence that you've got, you're able to compare IO-TKI with IO. You've been able to look at BrainMet, you've been able to look at that. You were mentioning about complete response rates in IO-TKI versus IOIO and then progression thereafter. In terms of that, what has shaped your decision making in clinic when you sit in front of a patient? Daniel Heng 30:27 Oh, that's a great question. So you're absolutely right that complete responders, they're special in the I/O era. We didn't really have complete responders that were durable before the I/O era. And I think in the beginning when we had IPPE Nevo, we thought, oh, IPPE Nevo is the only one that can create durable long-term complete responses. And so, and then these IO-VEGF therapies came along and some of their CR rates were like 20%, which is, which is almost outlandish. And so when we looked at, when we looked at the real world evidence, we actually found that complete responses are not that common. So in the IO-VEGF era and in the IO-IO treated therapies, real complete responders in the real world happen about 6 to 8% of the time. So we don't get the 20% that we do get in clinical trials because clinical trials, like you said, John, are really model patients. They're all ECOG, excellent performance status. All of their blood work is fine. Some even fly in from other places to your centre to get the trial. And so obviously, they're healthy enough to fly in and travel to do that. But let's face it, in the real world, we have people, you know, that are in the emerge or A&D that can't get out of bed, that are admitted, that have brain metastases, that have performance statuses of or none of those people are in the clinical trials. And so I think that's why the CR rates are lower in the real world, because you include all of those extra people that are real. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 32:00 Mm. Daniel Heng 32:05 We also found that by comparing these complete responders, Martin Zarba, one of our IMDC fellows, compared these complete responders in the IO-IO and IO-VEGF and VEGF treated patients. Definitely the immunotherapy treated patients, the complete response lasted longer. The Kaplan-Meier curve is a lot better than in the VEGF. In the VEGF CRs, there are more relapses. I was interested to know, though, that the relapse rate for IO-IO and IO-VEGF treated patients were about the same as about 10%, and so I thought that was very interesting. So, how does this shape my conversation with the patient? I no longer think that IpiNivo is the only thing that can. create long-term complete responses. That can happen with IO-VEGF therapy and there is a tail of the curve with IO-VEGF therapy as well. Don't get me wrong, I do use a lot of Ipi-Nivo in intermediate poor risk patients as well. But I think more about IO-VEGF therapies. You know, in the favourable risk group, you know, for example, I use a lot of Axi Pembro in the favourable risk group just because they're going to be on this for a very long time. So we want something tolerable. I use a lot of Lenvatinib Pembo in patients who need a very good response. I use Cabo Nivo a lot for patients with bone metastases, and I use a lot of Ipi Nivo for intermediate and poor risk individuals who don't really need a response today, but are intermediate and poor nonetheless. So that's how I think about the patient sitting in front of me. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 33:43 And we think about, and that's very much our meta-static setting. Obviously, we've had changes in the adjuvant setting happening recently. You know, Belzutifan joined the party after Keynote 564, you brought Pembrolizumab in. Now we've got Belzutifan. And actually, we finally had Rampart. report. So we finally have got two little radar blips that have said immunotherapy has a place because there was always this discontent that, you know, why is five, why is pembrolizumab sitting on its own? Is that something that HIF2 alpha, is that something else that might factor into prognostic scoring and Daniel Heng 34:05 Mhm. Mm-hmm. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 34:25 how that moves forward or is it just another drug and we'll see how it pans out over time. Daniel Heng 34:31 Yeah, it could be. So it could be a biomarker for efficacy for adjuvant therapy. The LiteSpark 22 data of belzutifan plus pembrolizumab versus pembro alone in high-risk resected patients was mirrors a lot how keynote 564 started. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 34:35 Yeah. Yeah. Daniel Heng 34:52 So Keynote 564 just started with the PFS benefit. No OS benefit yet. We'll see how it goes. And then the OS benefit came. And now we all use it in a lot of our patients. We have that patient discussion with everyone. Not everyone gets it, but not everyone gets the drug, or chooses to get the drug. But I think having the conversation is mandatory. And now we're in the Light Spark 22 era. It's not Health Canada approved yet. It is FDA approved now. And so we're going to start to see a lot of its use in America. And in the rest of the world, we'll see, you know, when does it become approved. And then we'll have to look at ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 35:19 Mm. Daniel Heng 35:32 who should we choose to get this if it gets approved? Like, should it be everyone, like a blanket statement that everyone should get it? Or should there be certain people that should be treatment intensified? So similar to the prostate cancer world, where we're intensifying treatment with ARADS or with PARTNERSHIP inhibitors, should we be intensifying treatments with HIF? And I wonder if HIF will become a biomarker for that. I wonder if the stage, like how high risk the patient will be, will become a biomarker for that as well. And so that part is still evolving. I suspect a lot of countries are waiting for overall survival benefit just because of the cost of belzutifan, or if the cost of belzutifan drops, then maybe it won't be as much of an issue. But I think, you know, that's an evolving field that's, you know, just changing minute by minute here, which is really exciting. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 36:19 Yep. Yes. Yeah. And in terms of, you know, unanswered questions that you have, somebody said, what is itching at the back of your head, Danny Heng, that's not been answered yet in research, in RCC. What would you be, what trial would you like to write? And see it happen. Daniel Heng 37:01 Oh, there are so many different questions. Because adjuvant therapy is new, what I'd like to, a bit of a gap for me is what happens after adjuvant therapy when they relapse. And so a bunch of countries have different rules. And so in Canada, we have a six month rule. If you relapsed on Pembro, ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 37:12 Mhm. Daniel Heng 37:23 and you got Pembro within six months, you're no longer allowed to use immunotherapy. And that makes sense because, you know, you progressed on immunotherapy. So why should we give immunotherapy again? But if it's after six months, then all of a sudden it's a dog's breakfast and you can use whatever you want all over again. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 37:38 Mmh. If you get on a plane and go to the UK, you have to wait another six months, 12, 12 months. Daniel Heng 37:45 Exactly. And it's 12 months in the UK. And so where does, what is the correct cut point? Because I think this is all very arbitrary, right? No one really knows. I think in Canada, we chose six months just to err on the side of being liberal to allow physicians to make decisions about what is the right thing for the patient, but should it really be 12 months? ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 38:09 Is that not the Canadian position to be liberal? Is that? Daniel Heng 38:12 Yes, it is. It is indeed, indeed. But I think, you know, my question is, you know, should be you using a VEGF inhibitor? Should you still be using IO therapy? Because I don't think that's answered yet. And so, and when should that be? It's really difficult to construct a trial like that because ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 38:15 The. Yeah. Mhm. Daniel Heng 38:31 the adjuvant therapy keeps changing because now we're going to be adding belzutifan. Maybe we'll be doing something else. Maybe we'll be doing durva tremi in very high risk patients. And so it's difficult to start a clinical trial like that right now. So we're relying on real world evidence to collect data on, okay, what happens to these people? And we actually found that a lot of these people don't even get systemic therapy. They just get radiation. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 38:35 Me. Daniel Heng 38:56 radiation because it's a single solitary site of metastasis, or they just get surgery. And I truly believe that adjuvant therapy that we give changes the biology of patients' kidney cancer. They change the biology of relapse. So instead of relapsing with 10 pulmonary nodules, you'll relapse with one pulmonary nodule. Or instead of relapsing with liver and brain metastasis, ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 38:59 Mm. Daniel Heng 39:18 you'll have one, you know, pulmonary nodule that we have to resect. And so I'm seeing that a lot more in our patients that relapse after adjuvant therapy that, and maybe it's because we're following them closer and we see these smaller things sooner and maybe that's why I feel that way. But maybe that's a knock on effect from having adjuvant therapy. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 39:43 And then, yeah, I mean, everything you've said, I've just thought of 100 other things that I don't know the answer to either. So it's just like, you know, what about timing, timing of relapse, six months, 12 months, 18 months, three years, does it matter? You know, if you resected a metastasis, just the one, do you presume there's ongoing immunomodulatory effects from what you've had before? Should you re-challenge? Do you add in a CTLA4 at that point? Daniel Heng 40:19 I don't, I don't. Haha. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 40:21 Velcro helps. Slip-ins. Which you're currently wearing. Which I'm mostly wearing. Daniel Heng 40:23 Ha ha ha! The. Ha ha ha. Ha ha ha! Ohh. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 40:34 Oh, sorry, I interrupted you. No, I don't know. Yes, so basically, I think that's that trial would be incredibly messy to run, wouldn't it? So, but, but as you said, the real world data, and maybe we will potentially try and start. And that was in the adjuvant setting. What about in the metastatic setting? I'm really, we're really working your hard here, Danny. Daniel Heng 40:43 It WARD. I love it. You know, the CARE 1 trial is very exciting to me with PD-1 as a stratification factor. And I wonder if the next generation, like CARE 2, CARE 3, CARE 4, would have other biomarkers as they develop, like with Kim 1, with Brian Reaney's optic trial, stuff like that. So, you know, everyone says this biomarkers are exciting, but we're not there yet. That's been kidney cancer for like 15 years, 20 years. And so, but one day we'll get there. One day we'll be as good as lung cancer, where we have a whole bunch of different targeted mutations, but we're just not there yet with kidney cancer. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 41:23 Mmh. All right, Danny, we have gone through quite a lot there. We've worked too hard. We have talked about the IMDC. We have talked about real world evidence. We've talked about the benefits of collaboration. We've talked about potential future directions. Do you want to give us three takeaway points for what we have talked about and what's meaningful to you? Daniel Heng 42:01 Oh, sure. So 3 takeaway points. The first is, we didn't talk about this much, but prognosis has quadrupled in RCC. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 42:09 Oh, whoa, whoa, whoa, whoa. Sorry to interrupt you, Danny Hang, but let's talk about prognosis. Are you some kind of charlatan? I thought you were the prognostic scoring man. Is this the wrong Danny? Have we got the wrong Danny Hang on, Mike? Daniel Heng 42:13 Okay. Ha ha ha! I am indeed a charlatan. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 42:26 I, I just don't know why you keep on using his full name. It's a trademark. Daniel Heng 42:30 Oh, it's just my thing. Danny Hang, Danny Hang. Everyone just says Danny Hang. No one says Danny. No one says Daniel either. They just say Danny Hang is just normal. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 42:41 So, Danny, let's talk. So, yes, the IMDC. You've got the IMDC was in the TKI era, but you have updated it into the immunotherapy era. So, what was a favourable Daniel Heng 42:46 Haha. Haha. Yeah. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 43:02 an intermediate and a poor risk looking at late night. Daniel Heng 43:05 Yeah, so it's interesting, like often the medians haven't even been reached yet, but they've quadrupled from before. So for example, in the interferon era, an overall survival of an RCC patient, medicine RCC patient would be 12 months. And then in the TKI era, it'd be 24 months. Now with our combination therapies, we're at 48, 50, 55, pushing that. So So we've really more than quadrupled our overall survival. So that's the first point that I wanted to make. The second point is collaboration is everything. And so, especially in rarer diseases, kidney cancer is the top 10 tumor, but it's hard to do research on your own in the little city of Calgary, for example. For example, you know, how do you get enough patients to do research on that? And so collaboration with others is everything. And then I guess the third thing, I didn't have time to think about the third thing, but the third thing is I hope that we can inspire the next generation of oncology trainees, fellows, residents to think about real world evidence, to think about how we can use real world evidence to inform practice, to make reimbursement decisions, to help payers expand portfolios, for example, with real world evidence, because it does happen and it can be very impactful. Oh. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 44:32 And Danny, see, I'm just going to stop at Danny. Well done. No, I'm not. Okay, Danny Hen. We love to give out. What are we giving out, Mike? Well, I think we're going to give out a wish. Do you want to say a wish? If you had, if you Brutal, we've actually reduced. We've not been briefed on this at all. We've reduced Danny Heng to sarcasm. That's our biggest. Daniel Heng 44:46 Oh, what a surprise! Ohh. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 45:00 Achievement. Still nice though. I still feel like he's being nice to me. Daniel Heng 45:00 Ha ha ha. Good, thank you. I am, I am. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 45:06 If you had one wish, and actually you did say, because we did mention this before we went live, does it have to be oncological? Because you're in that sphere, you can have an oncological wish and you can just have a general wish if you want to share that as well. Daniel Heng 45:21 Okay, so my oncological wish, oh, this is probably going to be boring, but my oncological wish is to have a composite biomarker with a whole bunch of different things in it that can adequately predict who should get what treatment in metastatic disease and who should get adjuvant therapy. in localised disease. So that's a boring wish. But I think it's very important. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 45:45 Would you call it the hang? Would you call it the hang marker? Daniel Heng 45:50 No, it's way beyond its way, 'cause it'll need like you know, 100 different things in it, so, so, so it'll be everyone, everyone's marker. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 45:52 Right. Yeah. But every kidney cancer talk will be cut by 5 minutes as a result. Daniel Heng 46:05 Right? Oh, that could save a lot of time. Yeah, that could save a lot of time. But my general wish, my non-oncological wish, is to do karaoke again with you guys. I understand there's Uncle Okie, and that's a British thing. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 46:08 What are you going to meet about? Yeah. Oh. Ohh. Daniel Heng 46:26 And so my non-oncological wish is to participate in that next year. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 46:32 So our promise to you and Ricky Fraser and Will Ince will be listening as well and Anna Olson, Brian. We're going to have Madrid Onco-Oke. I'm sure Monty Pal will be there as well. We'll have Danny hang there. We will make this happen. T-shirts will be provided. Yes. Daniel Heng 46:49 Love it. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 46:52 The. Daniel Heng 46:52 I look forward to the T-shirt. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 46:55 Danny, thank you so much for your time. What an amazing, probably a couple of episodes, John. So yeah, thank you so much for your time. So insightful and again, amazing work you've done.