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Novel Treatment Options for RCC From ASCO 2017: A Review

Interview with Bradley G Somer MD

‘Filmed by PracticeUpdate with permission for inclusion on Uro Onco. More information and additional ASCO coverage can be found at www.practiceupdate.com

Interview transcript

Dr. Jennifer Caudle: 

Welcome to PracticeUpdate. I’m your host, Dr. Jennifer Caudle, and with me today is Dr. Bradley Somer. Dr. Somer is an Assistant Professor in the Department of Hematology/Oncology at the University of Tennessee Health Science Center. He is also a Senior Partner at West Clinic in Memphis, Tennessee. Dr. Somer, welcome to the program.

Dr. Bradley G Somer: 

Thank you very much for having me.

Dr. Jennifer Caudle: 

Okay, well, let’s jump right in, okay?

Dr. Bradley G Somer: 

Okay.

Dr. Jennifer Caudle: 

So, you and your colleagues presented data that was related to the combination of pembrolizumab and IDO inhibitor in patients with advanced kidney cancer. Now, can you tell us a little bit more about this dataset and its implication for this disease, and in particular, is combination immunotherapy a viable strategy in renal cell carcinoma, and how might this combination compare to nivolumab/ipilimumab?

Dr. Bradley G Somer: 

So, a lot of questions there. I’m going to tackle them one by one.

Dr. Jennifer Caudle: 

Yeah. It is a lot of questions. Okay. Great.

Dr. Bradley G Somer: 

So, this dataset was an expansion cohort of the combination of pembrolizumab and a drug called epacadostat, which is an oral agent that is an IDO1 inhibitor. So, now the big rage is trying to find combination immunotherapies, so IDO1 is, and this was an expansion cohort of renal cell carcinoma. It's clear cell carcinoma patients that had received...most of them had received prior therapy. So, an IDO essentially is an immune regulatory molecule, an enzyme that actually metabolizes tryptophan in the tumor microenvironment, so when that happens it essentially creates an immune suppressive effect on the local area.

So, for example, the placenta makes a lot of IDO so that your immune system, a mother’s immune system, can’t detect the placenta, so tumor utilizes that mechanism to make itself invisible to the immune system. So, by using this drug to basically block IDO, it essentially can regulate the immune system to enable it to work more effectively. So when it gets combined with pembrolizumab, which also is an immune checkpoint inhibitor, that’s a combined immune effect that basically the point of this study was to look for what might be considered an enhanced activity, and then looking at the potentially safety effects of it. So in this study, basically, their efficacy was looked at in 30 patients with clear cell carcinoma of the kidney, and in those patients, a third of the patients had a response and about 50% or so had a clinical benefit.

And what was interesting was that if you looked at the patients that had, had zero to one prior line of therapy, it was about 47% response and close to 60% clinical benefit. So it looks like...if you look at just the checkpoint inhibitor alone, like nivolumab for example, probably about 15% to 25% response, so looking at something that might provide 33% response or 50% response, that’s kind of pushing it beyond where you might get with just a single-agent checkpoint inhibitor. So it lends the...at least possibility that this combination effect is real and hopefully to go into the next phase of development. So, the added bonus of that is that the epacadostat doesn’t really add that much to toxicity of what you might see with a checkpoint inhibitor alone, so maybe a little more rash, but it seems that the side effect profile was very similar to what you might expect with pembrolizumab alone, so it looks promising.

Dr. Jennifer Caudle: 

Okay. Good. Yeah. Absolutely. Absolutely. Moving on, data from the...excuse me.

Dr. Bradley G Somer: 

What I was going to say also, you mentioned other combination immunotherapy like nivolumab with ipilimumab, so there’s some early data showing good response with that too, enhanced response at like 40% or so. There’s added toxicity when you combine it with ipilimumab. The main thing looking at now, at what combination therapy works the best with the least amount of side effects, so I think the jury’s still out on that, but I think there’s clear proof of concept to push this to the next level.

Dr. Jennifer Caudle: 

Right. Right. No, that’s very helpful. That’s very helpful. The ProtecT clinical trial, so data from that trial is being presented at this meeting. Can you tell us a little bit more about how this dataset will affect your clinical practice for patients with localized kidney cancer? And of course, I have a follow-up question. Are there any patients for whom you might consider adjuvant VEGF-directed therapy?

Dr. Bradley G Somer: 

So, this is a very interesting story in the sense that we know adjuvant therapy, in a lot of solid tumors there’s clear benefit, but in kidney cancer there’s been a lot of false starts. There’s been a lot of negative studies using early immunotherapy with interferon and IL-2 and stuff like that that really has no benefit whatsoever, and then there was early data presented, the ASSURE data, that was also a negative study using sunitinib. So really it didn’t look like things were going anywhere, but then last year the S-TRAC data showed an enhanced disease-free survival that looked promising in disease-free survival, not necessarily overall survival, so there was some cautious acceptance of that data, but nobody went all in on it.

So now with ProtecT that’s being presented tomorrow, very interesting because the way that that study was done was initially the first 400 patients were treated at the full dose of 800 milligrams. But then when there was patients that had toxicity, they had lowered down the dose to 600 milligrams and did the next 1000 or so patients at 600 milligrams. When they looked at that data, which was the primary endpoint, there was no benefit in terms of risk reduction using pazopanib in these, generally speaking, high-risk patients for adjuvant therapy. But this dataset now looks at secondary endpoint using the 800 milligrams on that first 400 patients, and then takes the combined dataset and looks at the potential benefit, and it seems that there probably is a 25% to 30% decrease in disease-free survival using that 800 milligram dose.

So, again, proof of concept for disease-free survival benefit with a VEGF-inhibitor, the same way that the S-TRAC data showed around the same benefit or so that clearly patients required dose reduction of maybe a third or so and there’s clearly toxicity. Can they tolerate it? Go through the full year that’s required, but I think in my...there’s clearly going to be some cautious embracing of the data. Pfizer has filed for approval with a PDUFA date in about 6 months, so we’ll get a good sense, if that gets approved, I think it will potentially shift everybody toward that as the new standard. I think until that time there might be people embracing it based on the data that we have. I think if this was other solid tumors, like breast cancer and some other difficult-to-treat solid tumors, I think people would be embracing this data already.

So, I think that...I find it good data. I find it interesting data. I think that there are patients who are higher risk that I would consider that, and tomorrow they’re also presenting some data on a 16-gene panel in the S-TRAC data that differentiate high recurrence score from low recurrence score in terms of prognosticating patients who might be at higher risk or lower risk. And maybe that’ll provide additional biologic insight into who ought to be giving adjuvant therapy to and who not to. In order to really push the field, we need an effective biomarker to prognosticate, and I think that when we...looking at some of these PD-1 inhibitors and adjuvant therapy, I think that that is another place that we need to continue to explore and push the envelope there.

Dr. Jennifer Caudle: 

Yeah. That’s a lot of information forthcoming, you know.

Dr. Bradley G Somer: 

Sorry. Yeah.

Dr. Jennifer Caudle: 

No. No. No. I’m just saying there’s a lot on the horizon.

Dr. Bradley G Somer: 

A lot, yeah.

Dr. Jennifer Caudle: 

Absolutely, and I think you spoke to that very well, actually.

Dr. Bradley G Somer: 

It’s a long and interesting story, actually.

Dr. Jennifer Caudle: 

Yeah, but yeah, it really is, and kind of along those lines, you know, my final question really is about any other key trials from this year’s ASCO conference that are likely to change your practice or kind of curious about.

Dr. Bradley G Somer: 

So, I think those are the main things in terms of practice changing things. I think where the field is going, it’s either going to be combination immunotherapy, like we just talked about, or combining immunotherapy with a VEGF-inhibitor targeted therapy. So, there are some data that’s being presented tomorrow on that combination. Some showing impressive results at increased response rate with, for example, avelumab with axitinib in the front line and about 54% response rate, which is high. Jerry and his colleagues are presenting that.

There’s the IMpower150 data with atezolizumab with bevacizumab that also looks at 45% response in the PD-L1 positive patients, also an impressive response. Those are early-phase studies, so I think it’s too early to tell whether there’s going to...that will go the distance, so it’s not necessarily practice changing, but in terms of where the field is going, it’s either going to be combination immunotherapy, which I’m optimistic about, or combining current immune agents with targeted therapy.

Dr. Jennifer Caudle: 

That’s very interesting. Very interesting.

Dr. Bradley G Somer: 

Yeah.

Dr. Jennifer Caudle: 

Well, Dr. Somer, thank you so much for joining us today.

Dr. Bradley G Somer: 

Thank you very much. Thanks for having me.

Dr. Jennifer Caudle: 

Yeah, and thank you for joining us for PracticeUpdate. I’m your host, Dr. Jennifer Caudle, and make sure you check back for more ASCO 2017 updates.

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