Exploring Intermittent Therapy for Metastatic Renal Cell Carcinoma

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals. Exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a Medical Oncologist, Director of International programs for the Cancer Institute at Cleveland Clinic, and Co-Director of the Cleveland Clinic Sarcoma Program. Today, I'm happy to be joined by Dr. Moshe Ornstein, a Genitourinary Medical Oncologist here at Cleveland Clinic. He's here today to discuss intermittent therapy for patients with metastatic renal cell cancer. So welcome.

Moshe Ornstein, MD, MA: It's great to be here. Thank you for having me.

Dale Shepard, MD, PhD: So give us a little bit of an idea. What's your role here? What do you do here at Cleveland Clinic?

Moshe Ornstein, MD, MA: So, I am a genitourinary medical oncologist. I treat patients who have kidney, bladder, prostate, and testicular cancer. But particularly what I do, is I spearhead the renal cell carcinoma, or the RCC research efforts in the cancer center.

Dale Shepard, MD, PhD: Excellent. So we're going to talk about renal cell cancer. We're going to talk about some work you've looked at, intermittent therapy. But let's take a big step back 'cause there's lots of people that might be listening in with a wide range of backgrounds. Kidney cancer, metastatic kidney cancer, how do we manage it currently?

Moshe Ornstein, MD, MA: It's a great question. It's really changed a lot over the years. So, we'll leave the localized disease out of it and adjuvant therapy out of it, and we'll just focus on the metastatic setting, if that's okay. There have been multiple eras of treatment for metastatic RCC, what I would call kind of the old-timer treatment or the olden days, so to speak, which really means before I started practice.

Dale Shepard, MD, PhD: I was going to say, it wasn't that old. Come on now.

Moshe Ornstein, MD, MA: It wasn't that long ago, but as my mentor, Dr. Rini, used to say, it was before Moshe Ornstein's times. And this was probably in the 1980s and '90s, where the majority of patients were treated with interferon or interleukin-2. And then starting around 2005, we moved on from the cytokine era to what we would call the targeted therapy era. And drugs like sorafenib and sunitinib and axitinib, a variety of vascular-directed therapies, or VEGFR-TKIs, were developed, and they became really the standard of care.

Starting in about 2015, the first immunotherapy, the first checkpoint inhibitors were developed for kidney cancer, starting with nivolumab in the refractory setting. So we have the cytokine era that we really don't use much of it anymore. The targeted therapy era from about 2005 to 2015, and starting in 2015 until the presence, really the immunotherapy era. Immunotherapy started as nivolumab in the refractory setting and is now an immunotherapy-based regimen in the frontline metastatic RCC setting. I would say probably 95% of patients are treated with an immunotherapy-based regimen as their first treatment for metastatic RCC.

Dale Shepard, MD, PhD: And so specifically, what we're going to talk about is an effort to limit therapy, not necessarily add a therapy. Is that right?

Moshe Ornstein, MD, MA: It's correct. And it's very interesting, because the way we get these studies funded is we have to actually go to pharmaceutical companies, and you have to imagine what the discussion is like with a pharmaceutical company. We turn to Pfizer, or we turn to BMS and we say, "We would like your help and your funding to give less of your therapy." And believe it or not, they're generally actually on board with the concept.

So this really stems from the general biology of kidney cancer. We know it's an extremely heterogeneous disease. What I mean by that, is I have probably 10 to 15% of patients in my clinic who have metastatic kidney cancer, we can see the disease on the scans and we're not treating them. We just watch them. And we have prospective data to support that. So on the one hand of the spectrum, you have patients with metastatic disease who can just be on surveillance.

Dale Shepard, MD, PhD: And just to interject really quickly, are these patients, who from the get-go, have not had therapy at all? Or patients that have had treatment and then you're observing?

Moshe Ornstein, MD, MA: Great question. It's both.

Dale Shepard, MD, PhD: Okay.

Moshe Ornstein, MD, MA: So it's patients who may have had their kidney removed a few years ago and have slowly enlarging lung nodules, or it's patients who were on systemic therapy for months to years, for whatever reason came off, be it financial, physical toxicity, whatever the reason, and we say, "Let's just watch for now."

But it speaks to the heterogeneity of the disease biology, such that on the one side you have patients with metastatic disease that we can see on the scan, and we're just watching it. And on the other end of the spectrum, you have patients who have just a couple of small lesions that grow rapidly and it's nearly impossible, despite our best efforts, to get their disease under control.

Dale Shepard, MD, PhD: And I guess as you look at those populations and a lot of other diseases, there's lots of biomarkers. Is there anything that can help you right now predict who's who?

Moshe Ornstein, MD, MA: The short answer is no, and the long answer is also no. There's a lot of effort in kidney cancer, whether it's other PD-L1, whether it's other genomic clusters. We have ongoing trials here that we're actually looking at that, ctDNA doesn't seem to really play a role the way it does in cancers like bladder cancer. So we are really stuck using clinical criteria. We're looking at how a patient feels, we're looking at their scans. Maybe we're looking at sites of disease, knowing that liver metastasis or brain metastasis and bone metastasis are poor actors. But at the end of the day, it's a clinical decision.

Dale Shepard, MD, PhD: So, you looked at a group of patients with ipilimumab and nivolumab to see if we could alter the way that those two drugs are given and how long. And give us an idea, what would normal be like? What would a standard therapy look like? And then what drove that push to say, "Why don't we limit that therapy?"?

Moshe Ornstein, MD, MA: So the standard treatment paradigm for all patients in kidney cancer is essentially give therapy, continue to give therapy, give some more therapy, until either there is some toxicity reason that we absolutely positively have to stop or there's cancer progression that we need to move to a next line of therapy. But there's no built-in treatment breaks within the current treatment paradigm. It's treat, treat, treat.

It leads to a lot of problems. It leads to problems on the financial end. It obviously leads to problems on the physical toxicity end. Some of these drugs, specifically the tyrosine kinase inhibitors from that targeted therapy era I mentioned, have really chronic toxicities that impair a patient's quality of life, hand-foot syndrome, mucositis, diarrhea, they can manage it and we can help them with that, but it's really the chronic toxicity that can be truly limiting.

The story of giving patients breaks really goes back, at least in our work, over a decade ago. And the first work that we had done here on this was actually a study published in 2017 that looked at a very similar concept with sunitinib. Sunitinib is one of those TKIs from that targeted therapy era. It was the standard go-to frontline treatment for metastatic kidney cancer. A good chunk of patients responded, patients probably had a median survival of one to two years. So really nothing drastic.

And what we realized long ago with the TKIs, is actually as part of their development, they might be given on a two week, on one week off schedule, or a four-week on two week off schedule, or a three-week on and one week break schedule. So we realized that by the very nature of their development, there is clearly a role for giving patients an extended break.

So we ran a study of 37 patients back in, was published in 2017, it started earlier than that, gave patients four cycles of sunitinib for frontline therapy. And patients who had a greater than 10% tumor burden reduction, in other words, patients who were having some response to therapy, they got a break. It was actually done initially as a feasibility study. The feasibility was, would patients want to come off therapy? The study had 100% feasibility. All the patients said that, "Hey, if you think it's okay for me to come off therapy, I'll come off therapy."

So everyone agreed to it. And the amazing thing about it was, that there are still some patients from that study who came off at the time of publication, who had been off therapy and never went back on. And the median progression-free survival in that study was over 20 months. The median overall survival in that study was over 33 months. So these patients, despite taking these breaks, were doing well.

Now, they weren't on break forever. They would go on break for 12 weeks, get scans. If their cancer grew, they went back on therapy. If their cancer stayed quiet, they stayed off therapy. And that was this intermittent approach that we began to develop. We were doing it in clinical practice for patients based on toxicity, but we wanted to study it prospectively. And really, the summary from that study is that it was feasible to give patients extended breaks off of TKI therapy without compromising their long-term outcomes.

Dale Shepard, MD, PhD: So, when we think about the approach with ipilimumab and nivolumab, interestingly, you have patients with metastatic disease and you're looking for the trigger to start treatment, but once you start, there's not this thought of stopping. Right? Currently, in standard practice, how long do people stay on the immunotherapies? Again, that's indefinite?

Moshe Ornstein, MD, MA: Right. So the initial trial with sunitinib was super helpful in telling us that this is a good proof of concept for the disease. It didn't tell us much about what to do with immunotherapy. We ran actually a similar trial with nivolumab in the refractory setting, but I'll leave that aside for now. The issue with immunotherapy, and this is across the board in all malignancies, we just don't know how long to treat patients. We have patients who get one or two doses of immunotherapy, they have some sort of itis, so they'll get a pneumonitis or a hepatitis, they come off of therapy and their cancer never grows again. We have some patients who will be on therapy for three to six months, have a nice response, and then we keep treating them because that's the standard to go on, essentially forever.

In kidney cancer and in some other cancers, the newer trials are putting a stop time on the immunotherapy of two years. So I would say now in kidney cancer, if you're starting a patient on ipinivo and ipilimumab and nivolumab in the front line setting, the way it works is you give them a double dose. So you give them an ipinivo in combination for four doses, and then you move them onto nivolumab as a monotherapy, and you would stop at two years. And the same applies with the IO-TKI regimens. If you're giving them excitinib and pembrolizumab, cabozantinib and nivolumab, lenvatinib and pembrolizumab, any of these regimens, essentially you're stopping the immunotherapy at the two-year mark. And one could say if they're on the immunotherapy, it's not such a big deal, they're probably tolerating it, well just let them go to two years.

The issue with that is, again, there's a cost issue built in, and there's missing work to come in for the every three or four week infusion, and we just never know when a patient's going to have a life-changing side effect from the immunotherapy. So what we wanted to do in this study is we asked a simple question. We asked initially, what's the point of treatment at which patients have their best response? In other words, how long do they need to be on therapy for us to feel comfortable they've achieved probably a maximum benefit? So we looked at the study that led to the development and approval of ipinivo in Frontline RCC, the CheckMate 214 study. And in discussions actually with the company, they told us that the depth of response was probably around nine months. And that's what we figured in this study. So we took patients who got up to four doses of ipinivo combined, followed by six months or so of nivolumab monotherapy. And if they had a response to treatment, we took them off therapy.

And a similar cycle. We watched them for 12 weeks and rescanned them. If they stayed with a sustained response, no disease progression, we kept them off. If they had disease progression, we actually gave them ipinivo again. What we really were looking for is to say, what would be a good treatment-free interval that would be meaningful for patients? Meaning how long of time off therapy would a patient say, "Boy, this was a good idea"? We figured that to be about nine months. Where did we get that from? We sort of pulled it out of a hat, but figured that three months is probably not long enough, 12 months is probably shooting for the stars.

What we found in the study is we had some issues with accruing to the study. We had to close it early because of changes to the treatment paradigm, but of the patients that enrolled in the study, about 80% of them had a treatment-free interval that exceeded nine months. In fact, the median treatment-free interval was about 34 months. So you're talking about once patients come off of therapy, again, acknowledging it's at highly specialized center, that they're able to stay off therapy, at least in the context of this trial, for years. We had a couple of patients who did have disease progression while they came off therapy. We re-treated them with ipilimumab and nivolumab, neither of them had a response again to therapy. I don't know that that's because of their treatment-free interval or just at some point most of these patients do have disease progression and become immune resistant.

But again, it goes back to showing that it's not a practice-changing study, but it is practice-informing, in the sense that if somebody's having some mild toxicity to treatment, or somebody needs to skip a dose for whatever reason, and they've already been on treatment for six to nine months, that we don't, so to speak, lose our mind to keep everybody on treatment all the time, exactly on schedule forever. Where we go from here is a little bit more complicated, because to develop this in a prospective randomized phase three fashion is going to be very difficult. In fact, it might be close to impossible.

There is, however, a study called The PDIGREE Trial. It's a cooperative group study that actually just completed accrual, where they do have built into the protocol, that patients who got ipilimumab and nivolumab and had a complete response at a year's mark stop therapy. So there is some larger phase three data emerging with this built in, but I would caution that it's certainly not a standard of care to stop therapy after nine months. The standard of care would be at least two years. But it provides reassurance for those patients that need those breaks, for those patients that have the toxicity, and therefore need to come off of study and you're trying to think about whether or when to restart their treatment.

Dale Shepard, MD, PhD: So one thing that's interesting, you talked about when the same question was sort of looked at with sunitinib, that people were sort of willing and quite honestly eager to take a pause. Whereas here, you mentioned briefly the study closed early with accrual issues, and part of it was that because patients were feeling well, doing well, and they didn't have that same toxicity burden?

Moshe Ornstein, MD, MA: We highlight that as a theory in the discussion, because there was another very large cooperative study of intermittent treatment with immunotherapy in a variety of cancers, but I think specifically run within a GU oncology setting. And they also had a lot of trouble with accrual. And again, it does speak to the difference between the chronic toxicity of TKI therapy, where patients are having diarrhea, mucositis and hand-foot syndrome, and they have an opportunity to take a break, they're going to jump at it. Whereas you have a patient who's on immunotherapy and feels fine, they might say, "I don't want to take any chances." So I think the study is more reassuring to the doctors who are giving the immunotherapy, that if for some reason there needs to be an early stopping point or an extended, it provides reassurance.

Dale Shepard, MD, PhD: I guess when you approach patients about therapy, do you not necessarily plan to take the break, but do you sort of set expectations with patients that this could be a possibility that you'll take a break?

Moshe Ornstein, MD, MA: Off of a clinical trial, the expectation is they'll go for the two years, but if I need to stop their therapy because of toxicity, or if they're nervous about delaying a treatment by a couple of weeks because they're going to a vacation, that's important for them and for me to go on. I do tell them that we have reassurance that taking an extended break in someone who's already been on for six to nine months, is not going to be the difference between a longer-term response or a shorter-term response. Can we say that certainly? Obviously, we can never say things like that in medicine, but I think it does provide that degree of reassurance for a patient.

Dale Shepard, MD, PhD: Which is great. So, interesting work. It's always important to know what to treat with, but maybe sometimes when not to treat. So, having that sort of reassurance is good.

Moshe Ornstein, MD, MA: Yes, I think it does, again, provide that for patients and doctors, and the work is not over yet. We're working on some of the translational aspects to figure out are there, as we started with those biomarkers, are there changes in certain blood samples that occur for patients while they're on therapy or off therapy? Can we detect when a patient is likely to progress based on a blood test instead of waiting for scans? So there's still more work to be done here, but at least the foundation has been set.

Dale Shepard, MD, PhD: Fantastic. Great work. Thanks for sharing with us.

Moshe Ornstein, MD, MA: Thanks so much for having me.

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