Vitaly Margulis, MD, urologic oncologist, Harold C. Simmons Comprehensive Cancer Center, professor, urology, Paul C. Peters, MD, Chair in Urology, UT Southwestern Medical Center, discusses key disease characteristics and patient factors to consider when selecting between immuno-oncology (IO)/IO vs IO/TKI treatment combinations for the management of patients with renal cell carcinoma (RCC).

With the expansion treatment approaches in RCC in recent years, several questions have emerged regarding the selection and sequencing of available immunotherapy and targeted therapy options, particularly in the context of metastatic disease, Margulis begins.

Combination strategies have largely replaced single-agent therapy as the standard frontline approach in this space, Margulis asserts. Accordingly, one key question is whether the initial treatment should consist of an immune checkpoint inhibitor doublet or an immune checkpoint inhibitor and targeted therapy combination, he says.

Another pivotal aspect of treatment approaches in RCC from a surgical perspective is the management of a patient’s primary tumor, Margulis adds.

Clinicians may decide to promptly address the tumor, or may elect to initially administer systemic therapy with plans to reevaluate and address the primary tumor if necessary, he says. These deliberations underscore the complexities surrounding treatment decision-making in RCC.

Several patient factors also influence treatment decisions, Margulis continues. For instance, patients who exhibit bulky symptomatic disease may benefit more from an immune checkpoint inhibitor/TKI combination, Margulis explains, noting that this approach has been shown to rapidly reduce disease burden and alleviate symptoms. Notably, the addition of a second immune checkpoint inhibitor later on in the treatment course may be considered, he adds.

Conversely, treatment selection for patients with relatively stable, asymptomatic disease, who fall within intermediate and high-risk categories, is more varied, Margulis states. IO/IO combinations are an attractive option in this space, as they offer the greatest probability of achieving deep and sustained responses, he details. In comparison, treatment with a checkpoint inhibitor and TKI may yield rapid responses, but are less likely to produce long-term or curative outcomes, he says.

Taken together, these considerations emphasize the importance of tailoring therapies to individual patient needs and disease characteristics, Margulis concludes.

Videos

Vitaly Margulis, MD, discusses key disease characteristics and patient factors to consider when selecting between IO/IO vs IO/TKI treatment combinations for the management of patients with renal cell carcinoma.


Dr Margulis on Key Considerations When Navigating Frontline Combination Regimens in RCC

 What other thoughts do you guys have as you look at how we manage patients at UT Southwestern Medical Center? How would you recommend to deliver effective therapy as a team and deliver therapy to patients? I know I use you 2 a lot. Quite frankly, my practice would be impossible without outstanding surgeons and radiation oncologists. I text you guys all the time and ask for your help. What are your thoughts how to best deliver care and what the future might hold?

 It’s a very dynamic team we have here at UT Southwestern. We’re very blessed. Within the community, I think people ought to open those discussions up. We have emerging data justifying therapy for selected patients. Keeping the door open and the conversations going is very important. From a radiotherapy perspective, also interacting with your radiologists is important. If you don’t have an MRI [magnetic resonance imaging] scanner within the radiotherapy department, sometimes you can collaborate with your diagnostic radiology colleagues to request MRI time for some of these techniques, because you can get better soft tissue resolution and spine resolution, for example, in the case of [stereotactic body radiation therapy]. So [there is] definitely a different type of workflow in the community, but I think that in the end, patients benefit from having more options.

 For me, having direct and open lines of communication between all the providers really does translate into better outcomes. We have these conversations routinely. What do we do first? Why? When do we stop the systemic therapy? How do we consolidate? Having the tumor board presentation of these patients. All these things allow us to leverage better care.

 One more question. It’s not uncommon for me to see patients with large masses where the surgeon says, “Hey, why don’t you talk to this [individual] and see [whether] you can shrink your mass a little bit?” What is your personal practice for this, I would say, still an exploration neoadjuvant space? Let’s say if you look at data from Dr Axel Bex [PhD] with the neoadjuvant axitinib-avelumab [Inlyta/Bavencio]—I think you yourself have a clinical trial that looks at an imatinib-pembrolizumab [Gleevec/Keytruda], with trying to shrink those tumors even before surgery—what are your thoughts?

 We are now in the era where we have excellent response rates with these drugs, and they’re very well tolerated. From a surgical perspective, it’s really not the size of the tumor that makes a difficult or easy surgery. It’s things like, is there evidence of invasion into adjacent structures that is going to require multi-organ resection? We can shrink the tumor and allow for this to retract. Perhaps the patient can avoid colon resection or adjacent liver resection. This decreases the complexity and morbidity of the surgery. Similarly, the clinical trial we have with pembrolizumab-lenvatinib [Lenvima] addresses the situation of a cable tumor thrombus, right? So we know that the higher the tumor thrombus, the closer to the heart, the more complicated the surgery, higher blood loss, [and] higher morbidity to the patient. So can we leverage some of these drugs, some of these response rates, to really decrease the size of tumor thrombus and allow us for less complex resection? In some cases, we’ve converted patients from needing a big open chest surgery to avoiding a chest surgery. We have converted patients from an open, large incision to something that was now amenable to minimally invasive approach with [the use] of some of these drugs. My point is it’s not purely about the size of the tumor, it’s how the nuances go into it. These are very attractive strategies that we and others are actively exploring.

 Thank you so much. With that, I would like to thank my colleagues, Dr Margulis and Dr Garant, for this insightful discussion. And to our viewing audience, thank you for joining us. We hope you found the 

 program to be useful and valuable to your management of patients with renal cell carcinoma. Thank you so much.

Closing out their discussion on renal cell carcinoma, key opinion leaders highlight the value of multidisciplinary care and look toward future evolutions in the treatment paradigm. 

Multidisciplinary Strategies in RCC Management: Future Directions in Care 

Let’s go to the third case. This is now a different era with adjuvant therapies, so let’s talk about this. This 44-year-old [woman] presented with a right lower pole mass, measuring 6.9 cm. She had a right radical nephrectomy, and pathological staging was pT3a, with invasion of the perinephric fat, negative surgical margins, grade 2 of 4, and nothing suspicious for metastatic disease. Dr Margulis, before I continue on the case, what kind of risk would you quote this woman for recurrence?

 This is stage 3, grade 2 RCC [renal cell carcinoma]. There are several tools one can use, [such as] Mayo [imaging] classification, [Union for International Cancer Control], or [University of California, Los Angeles] nomogram. There’s several prognostic tools, [and] I believe there are several others out there. You can plug in things like stage, grade, size of the tumor, and presence of other various pathological features and come up with a prediction of recurrence. I would predict that this person has a 30% probability of systemic recurrence in 5 years.

I totally agree. To be honest with you, for disclaimer, I often don’t use those tools. I just do it over the thumb. If somebody has stage 3 disease, good risk is to be [approximately] 30%. If it’s high grade, it moves more in the direction of [approximately] 50%. If lymph nodes are involved, that’s bad news. That’s roughly how I look at those patients.

So [there’s] no evidence for metastatic disease, and she was very anxious. She wanted to do everything she could to reduce the risk of recurrence, and she initiated adjuvant pembrolizumab [Keytruda], with dosing every 3 weeks. But we had every 3-week follow-ups just to keep an eye on her, at least in the first few months until she declares herself with regards to [adverse] effects or not. She is obese and has some preexisting osteoarthritis. She developed this progressive joint pain that she had before, but to a level she hadn’t experienced before, causing her significant discomfort. So we made a referral to rheumatology. Imaging studies that we continue on the study didn’t show any disease progression, and she initially continued on immunotherapy. But over time, her joint pain got worse. Even the rheumatologist, who initially treated her symptomatically for suspected osteoarthritis, started to believe that there was now an inflammatory component here that warrants immune modulation—in this case, with leflunomide [Arava]—for inflammatory arthritis. So immunotherapy was discontinued, and we will just observe her now as per standard of care.

Dr Margulis, I know you also were involved in some of the studies with adjuvant therapy. In fact, first of all, you helped us recruit a lot of patients to KEYNOTE-564 [NCT03142334] and other studies. So just a reminder for the audience, this was the first phase 3 trial to demonstrate a disease-free survival benefit for patients who received pembrolizumab for 1 year vs placebo. There was [approximately a] one-third reduction in the risk of recurrent disease [and] no worse benefit at this time—and that, we will have to see [whether] this will ever come to fruition—but [there was] clearly a reduction. There were several other trials that were presented in a very large session at [Anatolian Society of Medical Oncology], and they were all negative. Dr Margulis, what are your thoughts on that? I know you were involved with PROSPER [NCT02003924], as well.

 Yes, I think at least some of that has to do with patient selection. In this clinical trial, there were patients [who] were enrolled with no positive disease [who] were resected. Also, [there were] patients enrolled in what’s called M1-NED [no evidence of disease]—patients [who] are actually metastatic and had a complete surgical consolidation—and they were enrolled in this clinical trial, which is why this clinical trial derives its positive benefit. I think this is the group that drives the results of this clinical trial. A lot of these results probably depend on what kind of patients you select. If you select this trial—also separate from selection of some of the patients [who] are probably at a lot less risk for systemic recurrence—of adjuvant pembrolizumab, [it] allowed selection of patients with pathologic T2 disease [who] were high grade and kind of low-volume T3 disease. These patients are probably at a lower end of probability of recurrence and probably were overtreated by this. I suspect that the patients [who] were in M1-NED or node-positive disease were probably undertreated. So for clinical trials, I think trial design and patient selection play a huge role in the types of results we’re going to see.

Several trials were done. One of them was PROSPER that you were very involved with, which was a neoadjuvant treatment with nivolumab [Opdivo]….This trial also allowed non–clear cell [RCC]. A patient with the disease or disease group that might be less sensitive to immune checkpoint inhibition. Clearly, patient selection made a difference. One trial that nobody understands why it’s negative is adjuvant nivolumab, ipilimumab [Yervoy]. That trial still has 1 arm we need to hear from, which is nivolumab monotherapy. But a very curious constellation, if you will, of a good number of large phase 3 clinical trial is negative and 1 being positive. Nonetheless, the data [are] very clear for this particular trial and clearly is an option and is FDA [Food and Drug Administration] approved. What are your thoughts? Also, Dr Garant, let’s say if this trial continues to and has clearly demonstrated [disease-free survival] benefit, but the OS [overall survival] benefit would not be there. Would that change your enthusiasm for this, or would [this trial] have no effect on the use of adjuvant immunotherapy? Obviously, you can get [adverse] effects from using immunotherapy in the setting.

 That’s a great question. [This is] definitely not a conversation I entertain routinely with my patients. But seeing [that] the selection of the positive trial is slightly different than the others, it’s definitely a weighted conversation to be had with your patient. Checking with what their other competing health issues might be. If your patients have a lot of other health concerns, that could also drive their personal decision to pursue regular infusions. So, yes, it’s a really interesting topic and [I’m} eager to get some updated outcomes.

I totally agree. It’s one of my longest visits in the clinic, because I don’t just say, “You need to do adjuvant therapy,” or “Don’t do it.” I say, “Here [are] the data; it has certain pros and cons. Yes, I can reduce your recurrence, but if you give [adjuvant therapy] super early, I am unclear [whether] it’s going to be that much more effective than waiting for it to recur. On the other hand, [with] waiting for a recurrence, you may get a lesion somewhere that you don’t really want, like in your spine. So there’s a certain risk associated with that.” And in my experience, patients will pick their own poison, if you will. Patients come into my office often with an opinion [on whether] they want to do something or not, or they just want to hear it but are hesitant about it. Without an obvious benefit, I don’t twist anyone’s arm, because it’s not clear that we are going to improve over survival. In that space, patients will choose what they want to do. Do they want to sit tight and just be under the microscope for some years, or do they want to engage with immunotherapy at the earliest possible point? These are all things we still need to figure out.

Expert panelists highlight aspects of a final patient scenario, discussing adjuvant treatment strategies in the setting of renal cell carcinoma at intermediate-high risk for recurrence.

Scenario 3: A 44-Year-Old Woman With RCC at Intermediate-High Risk for Recurrence

Lenvatinib-pembrolizumab [Lenvima/Keytruda] is the latest hit on the blood when it comes to PD-1 TKI [programmed cell death protein 1 tyrosine kinase inhibitor] combinations. There are now 3 of those [that are] FDA [Food and Drug Administration] approved and commonly used [combinations]. One of them is axitinib [Inlyta] and pembrolizumab—that was the first combination of a PD-1 and a TKI.

What stands out for those regimens is the increased response rate. If you look at intermediate-risk patients, intermediate-poor risk patients, response rates for nivolumab-ipilimumab [Opdivo/Yervoy] is [approximately] 42%. If you look at good-risk patients, it’s [approximately] 30%. If you mix those 2 together, it’s [approximately] 40%. If you add a TKI, essentially, you get another 20% response rate. If response rate is everything, then a PD-1 TKI is hard to beat. We still have to see the long-term benefits. Is there a tail formation that we like to see on the progression-free survival curve with CheckMate 214 [NCT02231749]? Some of the regimens have a little longer to wait before we get the additional data sets, but clearly, some of those are very effective regimens. Response rates for axitinib-pembrolizumab is [approximately] 60%—similar for cabozantinib-nivolumab [Cometriq]. The lenvatinib-pembrolizumab is a little unique, [as] this regimen really doubled down on the VEGF [vascular endothelial growth factor] inhibitory pathway. Lenvatinib is a little unique [because] it doesn’t cause liver toxicity. They did need to be careful with the dose of the TKI. We do see some synergy there [regarding] liver toxicity with some TKIs and PD-1 inhibitors. They really doubled down on the pathway. The starting dose is 20 mg, which is really high. On the upper end of a VEGF inhibitor, the response rate with this regimen is [approximately] 70%, with a 16% CR [complete response] rate. That doesn’t mean we cure those patients, but clearly we are shrinking the disease very effectively. And the chance for progressive disease as best response, meaning patients progress on the first scan, is only 5%, [which is] similar to the cabozantinib-nivolumab regimen. The disease progression’s best response [is] only 5%. Of the 3, cabozantinib is probably the more liver-toxic agent, so the starting dose actually is not 16 mg, it’s 40 mg. This is probably one of the reasons why it might be a better tolerated [agent] with less need for antihypertensive management, for example. Axitinib-pembrolizumab is a good starting regimen. The disease progression’s best response is [approximately] 11%, so not as potent as if you have a combination with one of the clastic salvage TKIs, if you will.

One of the things I do in clinical practice before I start someone on lenvatinib is really pay attention to the blood pressure and make sure the blood pressure is well controlled. That’s the earliest [adverse] effect, and often it’s a very significant increase. So here, we often work with cardiologists who focus on patients [with cancer] to get the blood pressure under control, especially if a patient is already on 1 or 2 blood pressure medications. Or we get their primary care physician involved, or we deploy our own regimen, but it’s really important. So I tend to already optimize the blood pressure, because otherwise, within 5 days, the patient’s going to call you with very high blood pressures.

Other [common adverse] effects are certainly fatigue and diarrhea. Hand-foot syndrome is less common on this regimen but certainly can happen and can be managed with emollients, urea-based creams, and topical steroids, for example. Diarrhea can be managed with [loperamide (Imodium)]. If needed, we can escalate to something like [Lomotil/atropine (Lomotil)], for example, opium tincture, etc. For those [patients], it’s really more like trying to find the right dose and schedule.

In my own practice, I try to stay at the higher dose and work more with dose interruptions rather than aggressive dose reductions. There [are] some data to support that, from the student experience. I tend to work more with regular dose interruptions if necessary and try to give the patient the higher dose. Dose reduction would go down to 14 mg. However, you may have an individual where you are worried about [adverse] effects and the decreased performance status, so you don’t want to hit the patient too hard up front. You may start with a lower dose, then escalate. But in my practice, I frequently use the dual immune checkpoints because of the long-term outcome that we now have available. If I go to the PD-1 TKI combinations, I tend to go with a potent regimen because, for me, the response rate is everything, and then I tend to be aggressive with the dose and administering that. However, other colleagues are living more on the side of PD-1 TKI combinations. For example, they may choose axitinib-pembrolizumab for the average patient, then go to something more aggressive if they’re really worried about disease progression or response.

There [are] also some quality-of-life data with the lenvatinib-pembrolizumab that was presented—really no surprise here. The quality of life is at least not worse than sunitinib [Sutent] when you combine lenvatinib with pembrolizumab. And clearly, the time to definitive deterioration, which is also reflected or has a component of disease progression, is certainly much longer than when on the sunitinib.

 Dr Hammers, maybe you can enlighten us. In this specific case, why did you choose the IO [immuno-oncology]-TKI combination vs IO-IO?

IO-IO would have been a choice. In fact, I proposed it to him, but [the patient] loved the idea of a 70% response rate and just get it under control. And the truth is I don’t have long-term follow-up data for lenvatinib-pembrolizumab. So if I talk to a patient [who] has good-risk disease, [the] response rate that I can quote [them] officially is 29% for nivolumab-ipilimumab. That sounds very different than a 70% and 16% CR rate. It’s a difficult sell. It takes more time to try to explain to patients why it might be a bad idea to consider that still, even with good-risk disease. But I would say the classic recommendations for good-risk disease is a PD-1-TKI combination. Although, again, I use nivolumab and ipilimumab frequently in this space. So in this case, that’s what [they] chose and that’s what we gave [them]. I offer my patients choices; I typically give them 2 things to choose from, then they pick 1. 

Focused discussion on combination IO-TKI therapy and its role as first-line therapy in patients diagnosed with metastatic renal cell carcinoma.  

Combination IO TKI Therapy in Patients With Metastatic Renal Cell Carcinoma 

This is a patient who also presented in 2017 with hematuria. He’s now 59 years old. He had a large tumor with tumor thrombus. He underwent a left radical nephrectomy, was a clear renal cell carcinoma high-grade, 10.5 cm in the largest dimension. He had no evidence of metastatic disease and essentially cruised along with just some small pulmonary nodules that were really small and really not suspicious at that time. And then in 2019, for the first time, we saw an increase in the right middle lobe in the chest, and a new right adrenal gland lung nodule that was suspected to be problematic. And then things essentially worsened on subsequent scans in early 2020 with some very mild changes in the chest. But now we also had a new 1 cm hyper-enhancing lesion in the distal pancreas, which was biopsied and was found to be positive for renal cell carcinoma. So again, this is a patient 2017 until 2020 when it’s clear that there was a significant problem with recurrent disease. In this patient, we offer systemic therapy, but we also consider focal therapy in some of those patients. He had pancreatic involvement, and Dr Garant can probably expand on that as well. So the decision was made to send them to stereotactic radiation, [and] radiate the pancreas and the adrenal lesion. A few months later, 1 of the lung nodes was enlarging and he received additional radiation to that. And with that, there was stability in radiographic findings. But unfortunately, roughly a year later, he clearly progressed in multiple disease sites. [There were] multiple pulmonary lung nodules as well as a new and enlarging hepatic as well as intermuscular lesions, new right renal and osseous lesions, as well as enlarged mesenteric lymph nodes and [a] suspicious lesion in the proximal stomach. He was started on systemic therapy with lenvatinib [Lenvima] and pembrolizumab [Keytruda]. So PD-1/TKI [tyrosine kinase inhibitor] regimen. He had some blood pressure issues that needed some [medication] adjustment and also some fatigue. He also had some dehydration for which he required additional counseling on when to take breaks and also maintain his hydration status. But imaging studies were very favorable essentially demonstrating response to therapy in all disease sites, and he continues essentially, on this particular regimen now for more than a year with a continued benefit. In March of this year, he had a complication, developed a rectal fistula that required surgical repair. And the decision was made to stop lenvatinib and continue on immunotherapy alone. So this is not an uncommon way to treat favorable-risk patients. Dr Garant, what do you think about this case and how does it fit into the practice or the treatment pattern that we often observe here at UT Southwestern [Medical Center]?

 Absolutely. So this is a gentleman who had favorable-risk disease status post radical nephrectomy, and limited sites of progression, approximately a year and a half after surgery situated in 1 adrenal gland and the pancreas. These are patients who are good candidates for definitive intent of stereotactic ablative body radiotherapy. These are outpatient-based treatments, which require some pretty rigorous immobilization because the treatment accuracy is typically in the order of 5 mm or less. So we’re able to treat these with extreme amounts of accuracy in over classically 3 to 5 sessions. Although sometimes it can be done in only 1 outpatient-based treatment session. Historically, kidney cancer histology was felt to be radioresistant, but there have been some emerging studies which revealed that very brisk exposure to radiation over a few sessions actually leads to profound responses in patients. And so, in this case, I suspect that this patient probably got something along the lines of 3 to 5 fractions of treatment to those 2 sites. The main areas of concern from our perspective are the small bowel and the upper abdominal cavity. The bowel viscus is actually quite radio sensitive, so we plan carefully to avoid the small bowel when aiming at the pancreas and the adrenal area, and also very careful with the spinal cord. Other tissues in the vicinity are typically more resilient, including vessels. So I think that this was a good candidate for SBRT [stereotactic body radiation therapy]. It may have been done as a part of our prospective phase 2 trial at the time. And so, it seemed like a good scenario for that particular approach.

And what does a surgeon think about patients like these? Obviously, probably not a patient that you would have sent for surgical resection. We often talk about oligometastatic disease to kind of try to figure out who are the best patients who would benefit from focal therapy, either surgery, surgical recurrence. Let’s say it was just, for example, an adrenal nodule surgery would have been something to be offered. Sometimes even we go after pancreatic lesions as well. How do you and Dr Garant, Dr Margulis, think about how do you define oligometastatic disease? And how do you select the best patients for this particular approach?

 For me, obviously this is a multifactorial decision. I think some of the factors that I’ve taken to the equation would be time from original surgery to reoccurrence in one of those sites. If it’s something within a year, certainly I’m less enthusiastic. How many sites were involved? In this case, you have pancreas, adrenal, lung, so I think the surgical approaches are less palatable just because of the morbidity associated with surgery. Certainly, this patient was 2 to 3 years after his initial nephrectomy, had a single site or even, for example, a growing tail of pancreas in adrenal site. Those could be addressed very effectively with surgery. We now have minimally invasive approaches to this. A patient could undergo easily a robotic adrenalectomy and distal pancreatectomy and essentially go home the next day. And so things like that. What is a prior surgical history? How hostile will be the abdomen? How much scar tissue would the surgeons have to deal with? Sometimes our radiotherapy colleagues may have some difficulties for abovementioned reasons. Proximity to the bowel, for example, so on and so forth, where surgical approaches may be more palatable. But to me, honestly, the clinical trajectory of the disease probably is one of the most important factors.

Dr Garant, how do you guys define oligometastatic disease?

 That is an excellent question. In our experience, typically 1, 2, or 3 metastases is an easy number to remember, especially in the IMDC [International Metastatic RCC Database Consortium] favorable-risk patients. In the extracranial setting, we’ll typically see that some will go up to 5 metastases. The intracranial scenarios are a little bit different and definitely a topic of further discussion and evolving discussion. But yes, I would say right now in the community, up to 5 lesions is typically broadly accepted as the oligometastatic paradigm. And also, we consider normal tissues around what we want to ablate in estimating our chances of success.

Moving on to the second patient scenario of renal cell carcinoma, panelists reflect on the treatment pathway for favorable risk metastatic disease.

Scenario 2: A 59-Year-Old Man With Favorable Risk Metastatic RCC

 This patient was what we call intermediate risk. Obviously, they have official criteria. So when a medical oncologist or urologist sees patients with metastases for the first time, we try to put them into a bracket. So this is a patient who required treatment within a year. Some patients may have additional lab abnormalities, in particular, let’s say anemia, for example. Essentially, inflammatory markers of chronic disease, if you will, with anemia. Some classic risk factors such as elevated neutrophil count, elevated platelet count, or hypercalcemia. We look at decreased performance status. So this was a solid intermediate-risk patient. If you have more than 2 of those risk factors, you have poor-risk patients, etc. This is how we go about those patients. A special group are good-risk patients, those are patients who were seen by the nephrologist, treated with surgery, with the intent to cure obviously, and then recur oftentimes years later. And those might be from some special cases actually. So he was treated with nivolumab [Opdivo]/ipilimumab [Yervoy], and just to remind our listeners, this is the first doublet of immunotherapy that was [FDA-]approved later on in 2018. The trial CheckMate 214 pit nivolumab/ipilimumab against sunitinib [Sutent]. Actually, roughly almost 1000 patients, 500 patients in each arm. The curious design was that the primary cohort with the regulatory end points of progression-free survival over a survival response rate was really made up of intermediate- and poor-risk patients. Roughly 20% of patients though, were good-risk patients, but they were not part of the regulatory cohort. When this regimen got approved, it got approved for intermediate- and poor-risk only. Although we do use it for some good-risk patients, and the NCCN [National Comprehensive Cancer Network] guidelines reflect that because some of the patients can also have some very durable responses. The other thing that’s nice to know about this oldest regimen in our armamentarium is that we now have some very interesting, and I think worthy and quite frankly to beat, if you will, long-term end points, 5-year overall survival. That is actually quite favorable with around almost 40% of patients living 5 years. The median overall survival is around 46 months for the intermediate- to poor-risk group, and for the intent-to-treat group, meaning including good-risk patients, almost 56 month. It’s really quite unheard of. Roughly one-third of patients never progresses, so at the 5-year mark, and responses can be very durable. The median duration of response had not been reached at the 5-year mark. So this is a very interesting landmark if you will, and how much immunotherapy has changed the way we treat patients. To my medical oncology colleagues, obviously, this patient actually had autoimmune side effects, so those are the classic side effects if you observe. Nephritis is actually not the most common one, but certainly one that we see in those patients often treated with steroids. Sometimes we need to add additional immune suppressive agents. But clearly, one of the reasons why we may have to stop immunotherapy, and as demonstrated in this case, despite heavy immune suppression, the end of tumor benefit can continue for a long time with the patient, who many of us would now think of is potentially even cured from his metastatic renal cell carcinoma. The other thing I would say that’s important to know or to remember with this regimen is that the quality of life is actually unique in terms of when compared to tyrosine kinase inhibitors [TKI]. We do have some quality-of-life data in comparison to sunitinib. And so we have, for example, another set of 5-year follow-up data in that regard. In general terms, when you start a TKI, your quality of life deteriorates quite rapidly. In patients treated with this particular regimen, it actually tends to improve. And also the time to definitive deterioration, if you will, with more side effects that also has to do essentially with disease progression, is clearly much longer for patients treated with this regimen. And roughly 75% of patients essentially were more likely to be less bothered by side effects than if you had a TKI on board, such as sunitinib. So yes, we do sometimes see these scary side effects with inflammation of the colon, inflammation of the kidney like in this case, inflammation of other vital organs, but those tend to get much better after initiating immune suppressive therapy. So that’s just something to remember, that overall, while some of the side effects can be scary and require prominent intervention, that the quality of life typically is unmatched when compared to a TKI.

Key opinion leaders in the field of renal cell carcinoma management discuss the advent of combination immunotherapy in patients with metastatic disease.

Role of Combination Immunotherapy in Metastatic Renal Cell Carcinoma

This program is titled “Optimizing Outcomes in Renal Cell Carcinoma: Translating Evidence to Clinical Practice.” I’m Dr Hans Hammers. I’m a professor of internal medicine and coleader of clinical research and immunotherapy of the kidney cancer program here at UT Southwestern Medical Center in Dallas, Texas. I’m joined today by my colleagues that I work with every day and really gets back to a lot on optimizing the care for my patients, Dr Margulis and Dr Garant. So I would like for you both to introduce yourselves. Dr Garant, would you like to go first?

 Hi, everybody. I’m Dr Aurelie Garant. It’s a pleasure to be here. I’m one of the radiation oncologists at UT Southwestern and the director of brachytherapy as well.

 Hi, there. I’m very glad to be here with you guys. My name is Vitaly Margulis and I’m a urologic oncologist at UT Southwestern and professor of urology here. Thank you very much for having me.

Wonderful. So welcome and thank you for joining me. Today we are going to discuss recent advances in the treatment of renal cell carcinoma and the impact on clinical practice. We will present real-world patient cases and discuss our treatment approach to illustrate how we integrate recent data into practice to manage patients with renal cell carcinoma at our institution. So let’s get started with the first clinical case. This is actually a 47-year-old male in 2017, presented with gross hematuria. And he saw Dr Margulis first. He presented with a large left renal mass distended into the left renal vein, multiple liver lesions. The largest lesion measuring roughly 8 cm in the right liver lobe. He was sent to Dr Margulis initially for consideration of surgery but, rightly so, he biopsied and confirmed renal cell carcinoma and contacted medical oncology for management. So this is a patient who needed therapy within the first year. He didn’t really have dramatic lab abnormalities, but because of the need for treatment, he was essentially intermediate risk. He actually started nivolumab [Opdivo]/ipilimumab [Yervoy] before it was FDA-approved through an access program and got 2 doses of the combination immunotherapy 3 weeks apart. Unfortunately, around the time that he would get the third dose, he experienced significant creatinine elevation which was interpreted as nephritis and he was started on prednisone which led to a very quick normalization of his creatinine levels and started on a taper. Unfortunately, on the taper, we actually observed fairly high doses, consecutive increases in his creatinine which prompted us further and deeper immune suppression with mycophenolic acid. Despite that, he had follow-up scans and those demonstrated a deepened and reallyimpressive immunotherapy responses with decrease in the size of the hepatic metastases, as well as the renal cell mass, the lymphadenopathy, and essentially all the lesions that we knew of at the time. On the mycophenolic acid and the prednisone he developed worsening creatinine level. We actually had to further increase the dose of the mycophenolic acid and then eventually got his nephritis under control. But as you can see, it took us roughly 4 months to do that, and he was quite significantly immunocompromised and received only 2 doses of immune checkpoint inhibition. The next slide we have some more follow-up. In 2018, he essentially continued partial response with really resolution of liver metastases, but he had a renal mass that was smaller, but maintained with viable tissue by imaging studies. On imaging, there was really no other evidence for metastatic disease, with the exception of an L1 lesion, which turned sclerotic. He had a thyroid lesion, which was biopsied and essentially was benign. In June 2018, roughly a year later, doing really well on surgery, and somebody was 48 at the time, we decided to be aggressive and to surgically consolidate. So we went back to Dr Margulis, and together with a liver surgeon, they resected essentially all involved disease with pathology, really showing there was no residual cancer in any of the liver metastases areas that were resected and the small residual kidney cancer in the primary tumor and essentially has maintained NED [no evidence of disease]. He is going to return in a few months for another scan, but essentially, since 2017-18, no evidence for recurrence, just 2 doses of nivolumab/ipilimumab and doing well. So let’s discuss some of the pertinent things on the scan. First of all, Vitaly, you probably remember the case orally. What do you think when you hear this kind of case of this patient and how much advance we’ve made, I would say in the last few years in renal cell carcinoma management?

 I would say that presentation with a relatively widely metastatic disease in the era before we had effective systemic therapies, one could make an argument to go after his bulky primary tumor, but clearly, we now have treatments that are quite effective in controlling not only his local disease but also systemic disease now. I think he illustrates what I consider to be the magnificent success of [the] immunotherapeutic era. He had essentially a complete response, systemically and nearly complete response in his primary. And so I think, in terms of his management, I think we played our cards right. I think we led in with the most effective systemic therapy that we could have given him and consolidated him surgically, and he’s done very well.

 At the time of his diagnosis, I think that the role for radiotherapy was not well established in the setting of hematuria. Back in 2017, we may have gotten consulted to try to relieve some of the hematuria to get him on systemic treatment if he was hemodynamically unstable. Since that time, we’ve had 2 published phase 2 trials in the radiation oncology community confirming efficacy of stereotactic ablative body radiotherapy to patients with limited sites of metastatic disease. And I think this will be addressed in some future cases. We’ll go into greater detail, but back in those days, I think there would’ve been a limited context for us to participate in the care, perhaps just with hematuria at the time.

And he had a very nice deep response, essentially complete response in the metastatic disease sites, but there was some residual disease in the primary tumor. Is that something that you would expect and how does it compare to some of the data we are now observing when we deliver immunotherapy in patients with primary tumors?

 It’s interesting. I think the data is emerging, but my sense is that we are now seeing something in the neighborhood of 15% to 20% complete response rates in the primaries. And I think there are some radiographic parameters that can be used to almost predict a complete response. I don’t think we’re there. I don’t think we can reliably, at this point, say that in somebody who had a complete response systemically, that the primary can be left in place. But I think that is something that us and other groups are actively working on. I think that’s something in the future we can potentially predict.

And then, to me, this case was kind of like the beginning of a change a little bit in practice. Because probably in the past, you would probably rarely have those patients return to you for consolidative surgery. Those patients probably would’ve just been on systemic therapy, just going along from 1 TKI [tyrosine kinase inhibitor] typically before the immunotherapy, or from 1 TKI to another TKI to another TKI. But probably rarely you would see those patients come back to you to then address the primary tumor, right?

 Yeah. I would say that in my practice not a single time. I don’t recall a single instance where somebody on single agent TKI has had a complete response systemically. And certainly, I haven’t had a case where there was a complete response in their primary. So I agree. I think we’re beginning to see those patients back with deep and durable responses

Expert perspectives on a patient scenario of intermediate risk metastatic renal cell carcinoma and corresponding management with combination immunotherapy.

Scenario 1: A 47-Year-Old Man With Intermediate Risk Metastatic RCC 

Vitaly Margulis, MD, assistant professor of Urologic Oncology, UT Southwestern Medical Center, discusses 2 different approaches to administering adjuvant therapy for patients with renal cell carcinoma.

One approach involves the use of a checkpoint inhibitor prior to surgery, followed by surgery, and finally followed by an additional checkpoint inhibitor. This particular strategy can be useful because it allows delivery of the drug with the primary tumor still in place when the antigen load is at its highest, explains Margulis. Thus, the T cells are primed, and then patients can continue their therapy to maintain that response.

However, there is a downside to this approach, says Margulis. Patients will not be able to move onto surgery immediately after the initial administration of the checkpoint inhibitor. Presurgical administration of the drug may delay, or even preclude, some patients from ever going on to receive surgery.

The second approach that Margulis discusses involves a checkpoint inhibitor in a purely adjuvant setting, where the kidney has already been removed. The advantage here, he explains, is that there is no delay in treatment.

Overall, these approaches allow oncologists to examine tissue samples and learn more about how these drugs affect the primary tumor. Moreover, this informs decisions about which patients will benefit from which drugs.

Vitaly Margulis, MD, UT Southwestern Medical Center

Articles