Advances of Systemic Treatments in Renal Cell Carcinoma - Jens Bedke

Jens Bedke enthusiastically discusses the transformation in first-line treatment of RCC from monotherapy, which has been the standard of care on the treatment of RCC to now combination therapies.  The first-line therapy with a combination of an immune checkpoint inhibitor and a tyrosine kinase inhibitor (TKI) improved outcomes in patients with clear-cell metastatic renal cell carcinoma (mRCC), as compared with the current standard of care, according to new findings.  Pembrolizumab (Keytruda, Merck) and the VEGF-targeted TKI axitinib (Inlyta, Pfizer) significantly extended both overall and progression-free survival and demonstrated a higher objective response rate than sunitinib (Sutent, Pfizer) in patients with previously untreated mRCC. Jens reviews the data and the impact on clinical practice in this conversation with Ashish Kamat. 

Jens Bedke, MD, Professor and Chairman, Department of Urology, Eberhard Karls University Tübingen, Tübingen, Germany

Ashish Kamat, MD, MBBS Professor of Urology and Wayne B. Duddleston Professor of Cancer Research at MD Anderson Cancer Center in Houston, Texas.

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Ashish Kamat: So, welcome. I have the pleasure of today of having a true expert in the field. Professor Jens Bedke, who's Professor of Urology and Vice Chairman at the Department of Urology in Tuebingen. Welcome.

Jens Bedke: Thanks.

Ashish Kamat: So, you know, of course, you're an expert in many things. But one of the things that really struck out at this meeting here was your presentation of the plenary on the gamete of treatment options for patients with renal cell carcinoma that you presented today. So, for the benefit of our viewers in the next several minutes, if you could summarize your presentation and the advances that have occurred.

Jens Bedke: I think it's a very, very important topic. The systemic treatment of metastatic renal cell carcinoma, as you really have a change in paradigm currently and if you make, really a short and brief summary is that TKI monotherapy is old fashioned and not the standard anymore in the first line setting of metastatic renal cell carcinoma and that therapy has shifted to combinations. These combinations are either IO-IO combinations of ipilimumab and nivolumab, which was recently approved in January this year by the EMA in Europe, by the FDA in 2018, so our colleagues from the U.S. have the availability for this IO-IO strategy a little bit longer than here in Europe, and that we have recently presented data of the combination of TKI, specifically axitinib plus the PD-1 antibody, pembrolizumab and axitinib plus the PDL-1 antibody avelumab, which were published in the New England Journal of Medicine, three weeks ago.

Ashish Kamat: Could you expand on the results of that publication for us?

Jens Bedke: Well the publication, for axitinib and pembrolizumab it's a KEYNOTE-426 trial analyzed the combination TKI axitinib plus pembro versus sunitinib in an all-comer population, and it had two primary endpoints, progression-free survival, and overall survival. And both primary endpoints were positive, and we had a hazard ration of 0.53 for the overall survival, so this is a very, very strong signal derived from this clinical trial, and also progression-free survival was prolonged for a median of 15 months of progression-free survival. While objective response rate, not being the primary endpoint, we had an objective response rate of about, nearly 60% of the patients responding to this therapy, with about 5% of complete responders, and about 15% of partial remissions by this combination. So it's highly active, and, in terms of remissions, it's highly active in terms of progression-free survival prolongation, and also in the prolongation of overall survival.

Ashish Kamat: And how easy was the regimen for patients to tolerate, how many drop offs were there and what tips would you give our viewers on managing those toxicities?

Jens Bedke: I think this is a very, very important point you mention, because if you have a good efficacy, always mention the toxicity for the patient, and as we do not treat the tumor by itself, we treat the patient with the tumor and it must always in a balance between tox and efficacy. While this combination was, I would say, well tolerated as the rate of adverse events in terms of grade three and four adverse events was the same, as the comparative sunitinib. But introducing the IO agent in this combination also introduces another spectrum of side effects namely the IO related side effects. And here you specifically have to care for that and you must be aware of spectrum of IO side effects.

For example if he mention diarrhea, and we know that TKI axitinib has a high rate of diarrhea, but also immune-mediated diarrhea or colitis can occur and sometimes it’s difficult to differentiate in between, so if the patient presents, he, he has the diarrhea as a symptom, and you do not know is it from the TKI or the IO agent. So here I would just give a wise, well, the axitinib has a short half-life of about eight hours, so if he stop axitinib and the symptoms persist, then it's mainly or could be more related to the IO agent, and you should start with the glucocorticoids if it's symptomatic diarrhea, grade three or it's a grade four, which I hopefully, hope not for the patient, yeah?

Ashish Kamat: Right, right and that's an important point because diarrhea that occurs from the TKI's is an adverse event, but it's not life-threatening. Whereas with the IO, diarrhea could result in death of the patient, so it's important to keep in mind.

With the advances that have occurred, and there's been an explosion of advances in renal cell carcinoma, do you think today, in 2019 there is any role for IL-2?

Jens Bedke: Well, I know you are from the U.S., and that IL-2, especially high dose IL-2, has its role there, or had its role. I would say IL-2 is so fascinating because, because the patients have a complete remission, we have this 10% of complete remission rate with IL-2. I mean it's toxic, it's really toxic, so while I have not had it in my hands, because it's not widely used in Germany. Here I would like to compare the high dose IL-2 to ipilimumab and nivolumab as the IO combinations, and I mean we have a general complete remission rate of 11% for ipi/nivo and if you make enrichment or selection of patients based on the PDL-1 positive status, the CR rate goes up to about 16% of the patients PDL-1 positive. So, I would say do not use high does IL-2 unless you're very used to, familiar, have done that for years. Consider that there might be another option ipi/nivo especially in the PD-1 positive patients if you won't like to achieve such a high CR rate, I mean 16%, that's nearly one out of five patients undergoing a CR.

Ashish Kamat: Right. Right, that's a very important point. It is a very toxic regimen and if you don't have experience with it, it's, the incremental benefit doesn't overshadow that of the combination IO therapy for sure.

You know, the other thing that we've have seen a change in paradigm really, has been the role of nephrectomy. Clearly, it was shown to be very useful in the pre-IO era. There is a debate right now in the IO era as to the role of nephrectomy, what are your thoughts on that?

Jens Bedke: I think that the CARMENA trial, this is what you refer to in the first Phase 3 trial of prospective data being generated, pinpoints that the cytoreductive nephrectomy is not for every patient. So, if you have the concept that every patient of metastatic disease should primarily be removed, I think I would say you are the wrong of way.

We have data, or the data of CARMENA included patients with  IMDC intermediate and poor risk, group, and if you have a close look at the poor risk group, I would say this is not the patients we usually perform cytoreductive nephrectomy and lots of data from the IMDC registry or database from Danny Heng, demonstrate patients with four, five, six points belonging to the poor risk prognosis do not benefit from the removal of the primary.

So, you should judge the CARMENA data and the cytoreductive nephrectomy data in conjunction with the shorthand data from Axel Bex, who demonstrated that a deferred nephrectomy and the initial start of systemic therapy and that nephrectomy called or determined as deferred nephrectomy, seems to provide the most benefit for the patient.

And if you consider that in CARMENA, at least patients who survive for six month and longer one-third of the patients had deferred nephrectomy, due to symptoms, due to complete remission, which was, in that way, a protocol violation of CARMENA.

But that these patients had nephrectomy later on. This definitely leads to me for the concept start with the systemic treatment first, and then maybe also, if luck must test, do nephrectomy later on if the patient responds. If a patient is progressing on a systemic therapy at the early beginning and we know there are patients progressing after three, four, five month, really, really early. Then the cytoreductive nephrectomy or the surgery is an additional burden which impacts quality of life for these patients.

CARMENA is not a TKI therapy and we have talked about combinations at the beginning, so I would say while we have to do CARMENA 2.0 to do that in the IO era right now. So we have to repeat that and probably incorporate an arm of deferred nephrectomy, maybe that's a provocative but a STAMPEDE design for the setting of standard of care for systemic treatment and then you can add your different arms in that.

Ashish Kamat: Clearly CARMENA 2.0 would be useful, but until that is available, what is your practice? Do you do deferred nephrectomy in IO combination patients?

Jens Bedke: We do deferred nephrectomy if the patient is responding to the systemic treatment. Please judge the patient if you have somebody with oligometastatic disease confined to one organ system, and the primary and he presents in this condition of metastatic disease, you should consider a metastasectomy and removal of the primary at the same time point and you then could include the patients in one of the adjuvant trials with IO therapy which are currently ongoing and include patients after metastasectomy.

There's not one principle that a patient of systemic disease, metastatic disease, in RCC should definitely start the systemic treatment. You should judge the patient individually, keep in mind that the poor risk patients should definitely have systemic therapy first, then there is a space between the intermediate patients and I think intermediate is not intermediate, you can differentiate between intermediate risk groups and that you also should consider the oligometastatic patients who will definitely benefit from removal of the primary and metastasectomy at the same time point.

Ashish Kamat: Very good points. Excellent conversation. In closing, just as a summary for our viewers, if you could go through the current recommendations for the different agents and the different risk categories. What's first line, what's second line, what should people be using and thinking about?

Jens Bedke: Well my personal opinion is that for the first line you have the highest evidence that's Level IB for axi and pembro in the IMDC favorable, intermediate, and poor risk group. That you have a Level IB evidence for ipi/nivo based on the positive Phase 3 trial data for OS and response rate in the intermediate and poor risk prognosis, IMDC group.

That you have activity data for second line, for TKI, after IO therapy in a fist line setting, but this is very, very, rare, this space, those they are trials ongoing, we need data for that so I would say a TKI is recommended in the second line setting with no specific emphasis on which TKI. And in third line setting, your, well in an expert opinion situation or a multidisciplinary tumor board.

Ashish Kamat: Right, absolutely. Thank you very much for this, this was very informative, and as always a pleasure. Thank you

Jens Bedke: Thank you.

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