Newly Approved Treatment Options for the Management of Metastatic Kidney Cancer- Lauren Harshman and Toni Choueiri

Lauren Harshman, MD, Alicia Morgans, MD and Toni Choueiri, MD discuss combination therapy for the management of metastatic kidney cancer with the recent approval of pembrolizumab plus axitinib. The combination was approved for all patients regardless of risk category. This adds to the treatment armamentarium for metastatic kidney cancer with the already approved nivolumab plus ipilimumab regimen. They discuss the safety profiles of each of the combination approaches taking into consideration the dual IO approach versus the combination of IO plus VEGF blockade. The discussion leads to the ongoing research evaluating whether these drugs can be sequenced based on the response in the ongoing OMNIVORE trial. 

Biographies:

Lauren C. Harshman, MD, Senior Physician Assistant Professor of Medicine, Harvard Medical School

Toni K. Choueiri, MD, Jerome and Nancy Kohlberg Professor of Medicine, Harvard Medical School, Attending Physician, Solid Tumor Oncology, Dana-Farber Cancer Institute, Director, Genitourinary (GU) Oncology Disease, Center, Dana-Farber Cancer Institute, Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute

Alicia Morgans, MD, MPHAssociate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

Read the Full Video Transcript

Alicia Morgans: Hi. I'm delighted to have here with me today Dr. Lauren Harshman who is a Co-Director of the Kidney Cancer Center at the Dana-Farber and Brigham and Women's hospital. As well as Dr. Toni Choueiri who is the Director of the Lank Center for GU Oncology at the Dana-Farber. Thank you guys so much for being here. 

Toni Choueiri: Thank you. 

Lauren Harshman: Thanks for having me. 

Alicia Morgans: So, I wanted to talk with the two of you today about multiple things. But, one of them is thinking about the metastatic setting in kidney cancer. There has been a lot happening, new approvals just last week even. And I'm just curious how the two of you think about sorting through the options in metastatic kidney cancer. 

Lauren Harshman: Sure. Well, I think we are now in a situation of an embarrassment of riches of different options for our patients, which is really wonderful. And now, we come down to choosing which regimen and how. And the two major regimens I think people are going to be in the clinics looking at their patients saying, "Which should I choose?", are the dual IO nivolumab checkpoint-inhibitor against PD1 plus ipilimumab anti-CTLA-4 antibody, versus pembrolizumab, again, a PD1 antibody, plus the axitinib, VEGFR tyrosine kinase inhibitor, and how do you choose? 

So, pembrolizumab plus axitinib just approved last week by the FDA in all patients no matter what risk. And then nivolumab plus ipilimumab approved over a year ago and now used frequently in the clinic for patients mostly with intermediate or poor-risk disease. And, they have different side effect profiles. When you have two IO's you have increased risk of autoimmune toxicity, something we call immune-related AE's. And then when you have pembrolizumab plus axitinib, you now have the combination of immunotherapy. So, you have the risk, but maybe lower of significant autoimmune toxicity, but then you have the chronic toxicity that might come along with VEGF blockade. So, these are the most important regimes. I think that in the clinic it will be easy to choose a combination where you know it's going to hit all good, intermediate, and poor-risk patients with a combination. 

But, one reason I think, to think about using dual IO over the combination, is that when you give the combo of nivo plus ipi, you only use four doses of ipilimumab. And then they go on nivo maintenance. One drug, once a month, that is generally very well-tolerated unless they get the immune-related adverse event. So, you have this benefit, potentially, of quality of life without the chronic TKI toxicity. So, I think that's one reason to plug the dual IO. What we're always reaching for are these durable complete responses. And, while we have to be very careful about putting trial against trial, there is a slightly higher rate in the dual IO of these durable complete responses. All that said, both give really high objective response rates and overall survival compared to sunitinib in Phase III. That is significant. I'll see what Tony has to think about this. 

Alicia Morgans: Yeah, a huge advance. And I love the way that you're sort of thinking through ... we focus on those poor-risk patients, or intermediate, just thinking through what the patient has to actually do on a day-to-day basis to get the therapy. That is really interesting to think about the dual IO strategy. What are your thoughts? 

Toni Choueiri: Yeah. I don't know if I want to say an embarrassment of riches. It is an embarrassment of riches, but we've been so, in a way, as an investigator, greedy in kidney cancer and pushing the envelope further for survival which we will still push with new drugs, new targets completely. As well as optimizing treatment. Meaning what? We know very well now that has Dr. Harshman mentioned that survival over sunitinib in both combinations was achieved. But still, the patient can progress whether don't have any benefit at baseline, or the cancer acquired resistance later. Even after a period when things seem to be in check. So, we have a long program here with Dr. Harshman and others on looking at biomarkers. Is there any specific feature of the tumor in the blood or tissue that makes it higher change to respond to the combination, or even to one drug? Because we know one drug is less side effects, but on an average, yes, it works more. But, if we're able to do that, that's great.

The second thing is Dr. Harshman involved with our center, is do we need the drug to be combined? Can we do trials where we would start by one drug, see what happens, and add the second drug? So, Dr. Harshman has a trial that is proposed and one that is ongoing, actually both with these kinds of drugs. The OMNIVORE Study and the OPTIMIZE. 

Lauren Harshman: Yeah. So, in OMNIVORE, which is actually nearly complete, we started out with about 60 patients and everybody will get nivolumab, and only those patients that don't have a complete response or a partial response, we then add in the ipi. Because we know that when you add the ipilimumab you increase the risk of the immune-related adverse events. Whether you say 30-60% of patients are going to require steroids from that combination, can we require less of that, cause less toxicity, by only giving ipilimumab if they truly need it and don't get that ideal or optimal response? And we're also only giving two doses of ipi and seeing if we can induce a response by doing that, and longer disease control. 

So, we have nearly completed that trial. We're doing some very exciting work with David Braun and the Wu Lab here in single-cell sequencing. So, that's one way of trying to figure out who needs the dual IO combination. That's a small study, it'll require a larger Phase III down the line, hopefully, if we see a signal. But, now that we have the pembro/axitinib combination, it also begs the question of who would benefit just as much from pembro monotherapy, and who needs that added VEGF blockade. So, that's called the OPTIMIZE Trial. It's been approved by Merck, but we are still in the planning phases with Pfizer and getting a drug for the axitinib because it is not standard of care to start with pembro and if they don't have an optimal response add axitinib. We're doing a little tweak in that we want a really optimal response in order to determine whether you need to add that axitinib. 

What we didn't mention, actually, in the OMNIVORE trial, is we're also asking the question of, can we stop the PD1 blockade? So, in OMNIVORE, if you get that partial response or complete response after 16 weeks we then stop the nivolumab and watch the patient scan every week. If they progress, then we add back. If they progress further on the nivo, we add the ipi. With OPTIMIZE, we will stop the pembrolizumab after six months if they get a complete response, or a really optimal PR, which means tumor shrinkage more than 60%. For those patients that don't get that ideal PR, or have stable disease or progressive disease, we add axitinib and see if that's what they needed to really get a longer duration of disease control. 

Toni Choueiri: I do think this is extremely important for the next five or maybe ten years. Especially if we don't have a new target that leads to significant responses. Why is that? Because we have trials with the VEGF tyrosine kinase inhibitor, not called axitinib, and with other PD1 and PDL1 inhibitors that are ongoing. So, there is a combination of pembrolizumab plus lenvatinib that inhibits VEGF receptor, and the FGFR receptor, a Phase III that is accruing. 

Another combination of cabozantinib, a drug used also approved in first-line and second-line with nivolumab. Again, against sunitinib that finished accrual. So, a lot of it's coming and I do not expect, perhaps unless in a specific situation, that the control arm of sunitinib will be used anymore in future studies. So, nivolumab, ipilimumab, pembrolizumab, axitinib, and other combinations. Such as axitinib/avelumab which also showed efficacy. We will have an embarrassment of riches in that way in terms of combinations. So, the question is, besides what Dr. Harshman is planning, is what else can we do? And what can we do also is, other ways through the cooperative group in thinking largely, not just about sequencing, but about introducing a drug later on?

So, we do have a trial in collaboration with Duke, mostly, with Dr. Zhang and George where it gives nivolumab and ipilimumab, and actually, after complete response, you continue the nivolumab. But, if you don't have that complete response which is a bit over 10%, then you look. If you have progression you switch directly to TKI. Cabozantinib, in this case. But, the majority of patients will have either a partial response or a stable disease by RECIST and in theory, after nivo/ipi you continue nivo. But, do you need to add cabozantinib? So, we have that study called PEDIGREE where we add cabozantinib in the randomized fashion. So, hopefully, this will be a large cooperative group. 

And finally, I want to mention an area dear to my heart, and Lauren's heart is the non-clear cell histologies. 

Lauren Harshman: Yes. 

Toni Choueiri: Which we've been, at Dana-Farber, and with several other collaborators, trying to find the optimal drug, and try to define as much as possible. In terms of the trial, and in terms of translational work, how to treat these patients. This is a large umbrella of patients, like ice cream that comes in multiple flavors in a way. Papillary kidney cancer, chromophobe, unclassified, translocation in younger females that are adult, collecting that cancer, aggressive cancer, we are using checkpoint inhibitor and using also the expertise of our laboratory scientists here to try to decipher the biology behind it. 

Dr. Harshman and myself were part of a trial we finally accrued looking at atezolizumab, which is a PLD1-inhibitor, and bevacizumab a monoclonal VEGF-inhibitor, specifically in non-clear cell histology. Because we know that clear cell data, it's positive, was presented. But this well-tolerated regimen, could it have a place in non-clear cell histology? So, we also continue to focus on that because all these studies that Dr. Harshman and myself talked about, included patients 70-85% of clear cell histology. So, it's hard to not pay attention to this very heterogeneous group of patients. 

Alicia Morgans: Absolutely. Everybody deserves, and needs to have options. I think being at the Dana-Farber, or working across cooperative groups, you can enroll enough patients because that's often a problem if you're trying to do single-center studies. But, absolutely, they need options too. So, if you're a patient or a clinician who wants to get involved for trials for kidney cancer, and they can't come to Boston, what would you advise those patients? 

Toni Choueiri: I would send them the cell phone of Dr. Harshman. 

Alicia Morgans: Perfect! 

Lauren Harshman: I think it's such a great question. 

Alicia Morgans: Because there are so many trials, so I think it's important for people to get involved. 

Lauren Harshman: So, I think clinicaltrials.gov is always a good one to search for something nearby. But, also cooperative groups. If they want to bring trials to their center, I think cooperative groups are a good way to do that. Now, they may have varied numbers of trials for non-clear histologies at that time, but it kind of swings nicely into the discussion about the perioperative space and how to, now that we're doing better but we still haven't had those home runs of significant complete responses and we still need to do a lot better, probably with new targets and ideal sequencing, in the metastatic space, how do we do better and increase cures in the so-called localized disease space? 

So, we've had now 40 years of clinical trials in the adjuvant space from chemotherapies, to older generation cytokines, to now six plus studies of targeted therapies and only one study has been positive for a benefit or met its primary endpoint. And that was with sunitinib in the adjuvant high-risk clear cell space with an equally negative trial of the same disease with sunitinib. That trial only met its primary endpoint of increasing recurrence-free, or disease-free survival by an average of a year, but didn't show a definite benefit in overall survival that we have seen yet. 

So, now moving all of these checkpoint antibodies to the earlier perioperative space, is really the next major question to increase cures. Whether it be in true early non-metastatic, can't see anything, or oligometastatic disease. So, we have different trials. Mostly doing the standard paradigm of pure adjuvant, the patient goes to surgery, nephrectomy, partial or radical, and then they get either a year of pembrolizumab, Tony is helming the KEYNOTE study there, atezolizumab, a trial in motion which has recently finished accrual, both of those are a year. The combination of nivo plus ipi for about six months with, again, just four doses of the ipilimumab. And then, there's a trial in Europe called the RAMPART trial that's using durvalumab plus tremelimumab in the pure adjuvant space. Generally, about a year of therapy all in clear cell and/or sarcomatoid with the exception of the RAMPART trial which allows non-clear cell. 

And then, what we've also been hugely involved with is the PROSPER trial, which is what I would call adjuvant therapy with a twist. Here, if we think about how PD1 blockade words, it's really taking advantage of the fact that the tumor is using an immune escape mechanism of PDL1, the protein on its surface. So, I few take out the kidney first, and then we give the PD1 blockade, maybe we don't really don't have a whole lot of target. We have a microscopic disease that we're targeting, but we don't have a whole lot of target to rev up and really invigorate that immune response. So, if we give therapy ahead of time, when the majority of tumor antigen is in place, we have a higher chance of engaging the immune system and causing a more robust immune response. So, that's the concept behind the PROSPER RCC trial. We're giving one dose of 480mg of nivolumab prior to surgery. That's basically equivalent to a month dosing, even though it's all wrapped up in one. And then they go to surgery, and then we think that you need to continue to prime that immune system after surgery against the microscopic disease with about nine more months of monthly nivolumab. And the patients are randomized to observation, which is another key thing. 

So, no one receives a placebo in this study. Everybody gets the gold standard nephrectomy, and patients really do care about not getting placebo. So, we think we will see it as a harder trial because it's really changing in terms of the accrual and getting it off the ground because we're really changing practice. We have to get the patients before they go to surgery. But, we really do want to hear from people across the country. That's open through the ECOG and NCTN mechanism alliance, SWOG, Canada, a few international sites. And, that's how people in the community can get access to these trials. Not only the PROSPER trial but PEDIGREE and many others. So, I think that's a good mechanism for people in the community that want to be involved in trials. 

Alicia Morgans: Absolutely. And giving them access to cutting-edge thought processes too, about, "How do we best optimize these strategies?". 

Toni Choueiri: Exactly. And the thing is that Lauren has built beautifully, is the science around PROSPER. So, we have an involvement with many scientists looking at tumor DNA and RNA as well as potential blood biomarker. And, what happens before and after the surgery and what is associated with a response? So, it's really a rich trial that brought, in a way, the whole community of kidney cancer investigator in the country together. It's very important, and it's good to have several shots on target because you'll be surprised. It's not just neoadjuvant plus adjuvant, or adjuvant only, but it's also a different drug. It's combination, it's the duration of therapy. Because it's very important that we cure the disease when it's at higher risk, or at least, we delay in a significant fashion, it's the risk of recurrence. When we don't see any cancer on the scans, and it's at the micrometastatic level. So, I think we have a lot of options here. 

One thing about a lot of these studies, especially the PROSPER trial, is the alliance that we put in with the patients advocate to help us spread the news about this important trial and how it can change how we do kidney cancer. We have some efforts now to screening through several blood tests and blood biomarkers. As you know, the blood biopsy paradigm that you're very familiar with both in every solid or liquid tumor has been based, usually, on detecting whether the tumor cell themselves or detecting the genomic changes and the DNA alteration. We are, with the help of colleagues and collaborators in Canada, trying also, in kidney cancer, trying to bring that new test which is based on methylation which can be tissue-specific and can lead to the detection of very small amount of cancer through the paradigm of methylation of abnormal cancerous tissue and try to bring it and look at it for recurrence, look at it as a way to look at minimal residual disease, or even perhaps at screening at some point. Because we want to tackle kidney cancer from the time before it starts, even with the time that is way refractory to the traditional treatment we have. 

One thing Dr. Harshman has been involved with us is the targeting the TOR pathway, the TOR  1 and 2, that could be one of the things so far despite some of the negative trials so far. The other emerging target is HIF-2, that is a master transcription factor that there is some encouraging data. Of course, the drug's not approved yet, that targeting this pathway with small molecules can lead to shrinkage of the tumor that has been two trials presented and hopefully, they'll be more. So, I think that this is part of the bigger pictures. 

Lastly, I want to say, unless you have the last word, is that mentoring is very important. Hopefully, some of us will not just retire, do something, but we need to also focus on our junior folks, on our fellows, on folks that are ready to take this to the next step. So, here at Dana-Farber, and GU, and many other disease centers with the help of Dr. Harshman and others we have a very group of family, of fellows, and postdocs interested in kidney cancer. Some of them are more so clinical, and others are more lab. But, we have meetings and we try to bring to us fresh ideas together there and trying to cross bridges. Labs together, focusing on how we can improve the outcome in kidney cancer. So, it's exciting, wake up every day and it's like, "I want to go to work.". So, that's good. 

Alicia Morgans: Absolutely. So, from including patients and their voices to mentees, trainees, and people across the spectrum of kidney cancer. Surgery, medical oncology, laboratory people. Really, it takes this whole group to make a change and that's how we get to these advances in systemic therapy. Like what we've recently seen, we now have choices. But we also are thinking creatively about, how do we peel back? How do we not do too much? How do we optimize what we give to our patients from the metastatic setting all the way through in the localized setting? And I'm really enthusiastic about the work that you're doing, and I appreciate that you've taken the time to talk with me today. 

Toni Choueiri: Thank you. 

Alicia Morgans: Thank you. 

Lauren Harshman: Thank you. Good to see you. 

Toni Choueiri: Thank you for UroToday.
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